Methods and systems for identifying individuals with perioperative neurocognitive impairment and / or post-viral cognitive impairment

Abstract

The present specification discloses a system, method, and use for identifying an individual at risk of perioperative neurocognitive disorder or identifying or confirming a diagnosis of post-viral cognitive disorder. The disclosed system, method, and use employs an individual's episodic memory score, working memory score, or both, optionally in conjunction with one or more additional risk-related factors from the individual, to determine a PND risk score or a PVCI diagnostic score. In an embodiment, the individual's risk status susceptibility to perioperative neurocognitive disorder is determined by comparing the PND risk score with a predefined threshold criterion. In another embodiment, the individual's diagnosis of post-viral cognitive disorder is identified or confirmed by comparing the PVCI diagnostic score with a predefined threshold criterion. The disclosed system, method, and use can further include determining a weighted score for each value of one or more risk-related factors, and further providing a treatment recommendation based on the individual's risk status susceptibility.

Description

[Technical field]

[0001] This application claims the benefit of priority pursuant to 35 U.S.C. § 119(e) of and is entitled to the filing date of U.S. Provisional Patent Application No. 63 / 137,802, filed January 15, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] With the advancement of modern medicine, an increasing number of older adults are undergoing medical procedures to treat diseases and disabilities, with the primary goal of improving their function and quality of life. Many of these procedures involve surgery and anesthesia. For example, in Western countries, approximately 37% of all surgical procedures are performed on patients aged 65 years or older. Unfortunately, impaired cognitive abilities are the most common complication experienced by older adults undergoing such surgical procedures.

[0003] Since the 1980s, clinical trials have consistently demonstrated cognitive decline in older adults following anesthesia and surgery, even in the absence of symptoms. The studies have identified older age, lower premorbid IQ, and fewer years of education as risk factors, with postoperative delirium being the most common complication. However, the cognitive impairments observed following anesthesia and surgery are diverse and complex, ranging from acute delirium to chronic postoperative cognitive impairment, which has led to the classification of such cognitive changes as perioperative neurocognitive disorders.

[0004] Individuals suffering from perioperative neurocognitive disorders are at risk for serious complications, including dementia and death. Sadly, the pathophysiology of perioperative neurocognitive disorders and the causal relationship between surgical procedures and the development of this disorder remain unclear. Furthermore, although risk factors are recognized, there are still no accurate or standardized means to identify individuals at risk for perioperative neurocognitive disorders. As a result, individuals with perioperative neurocognitive disorders are not routinely assessed or treated. Thus, perioperative neurocognitive disorders present a major challenge to the rapidly growing aging population, negatively impacting cognitive domains such as memory, attention, and concentration after surgery.

[0005] Recently, it has been observed that individuals suffering from viral infections are at risk for significant post-viral cognitive impairment. Studies in individuals of various ages have pointed to an association between cognitive decline and exposure to neurotropic infectious agents, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), and Toxoplasma gondii (TOX). Increasing evidence now indicates that infection with Sars-CoV-2 causes neurological abnormalities in a significant proportion of affected patients. There are at least four possible pathogenic mechanisms by which viral infections directly affect the brain, resulting in cognitive as well as mood disorders: 1) direct viral encephalitis, 2) systemic inflammation, 3) end organ dysfunction (liver, kidney, lung), and 4) cerebrovascular changes. In most cases, cognitive impairment due to viral infections may result from one or a combination of the above.

[0006] The present specification recognizes this need and provides methods and systems for identifying individuals at risk for perioperative neurocognitive disorders and diagnosing individuals suffering from post-viral cognitive disorders, as well as methods and uses for treating individuals suffering from these disorders. Summary of the Invention

[0007] Aspects of the present disclosure disclose systems, methods, and uses for identifying individuals at risk for perioperative neurocognitive disorder (PND) prior to surgery. In some aspects, the disclosed systems, methods, and uses include comparing an individual's episodic memory score, working memory score, or both, with a risk stratification matrix to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive disorder. In some aspects, the disclosed systems, methods, and uses include determining a standard deviation deficit by comparing to a normative mean to capture the individual's episodic memory baseline, working memory baseline, or combined episodic memory and working memory baseline; determining a PND risk score based on the standard deviation deficit of the episodic memory score, working memory score, or combined episodic memory and working memory score; and determining the individual's risk state susceptibility to perioperative neurocognitive disorder by comparing the PND risk score to a predefined threshold criterion. In some aspects, the disclosed systems, methods, and uses include comparing the individual's episodic memory score, working memory score, or both, in conjunction with one or more additional risk-related factors from the individual using a risk stratification matrix to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive impairment. In some aspects, the disclosed systems, methods, and uses include determining a standard deviation deficit by comparison to a normative mean to capture the individual's episodic memory baseline, working memory baseline, or both, determining baseline values ​​of one or more risk-related factors for perioperative neurocognitive impairment in the individual, determining a PND risk score based on the standard deviation deficit for the episodic memory score, working memory score, or both, in conjunction with the baseline values ​​for each of the one or more risk-related factors, and determining the individual's risk state susceptibility to perioperative neurocognitive impairment by comparing the PND risk score to a predefined threshold criterion.The disclosed systems, methods, and uses may further include determining a weighted score for the value of the episodic memory score, the working memory score, or the combined episodic memory and working memory score, and each of the one or more risk-associated factors, and further providing a treatment recommendation based on the individual's susceptibility to the risk state.

[0008] Another aspect of the present disclosure discloses a system, method, and use for diagnosing an individual suffering from cognitive impairment following a viral infection, i.e., post-viral cognitive impairment (PVCI). In some aspects, the disclosed system, method, and use includes comparing episodic memory scores, working memory scores, or both for an individual in conjunction with using a risk stratification matrix to identify or confirm a diagnosis of PVCI in the individual. In some aspects, the disclosed system, method, and use includes determining a standard deviation deficit by comparing to a normative mean to capture the individual's episodic memory reference value, working memory reference value, or combined episodic memory and working memory reference value; determining a PVCI diagnostic score based on the standard deviation deficit of the episodic memory score, working memory score, or combined episodic memory and working memory score; and determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PVCI diagnostic score to a predefined threshold criterion. In some embodiments, the disclosed systems, methods, and uses include comparing the episodic memory score, working memory score, or both for an individual in conjunction with one or more additional risk-related factors from the individual using a risk stratification matrix to identify or confirm a diagnosis of PVCI in the individual. In some embodiments, the disclosed systems, methods, and uses include determining a standard deviation deficit by comparison to a normative mean to capture the individual's episodic memory baseline, working memory baseline, or both; determining baseline values ​​of one or more risk-related factors for post-viral infection cognitive impairment in the individual; determining a PVCI diagnostic score based on the standard deviation deficit for the episodic memory score, working memory score, or both in conjunction with the baseline values ​​for each of the one or more risk-related factors; and determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PVCI diagnostic score to a predefined threshold criterion.The disclosed systems, methods, and uses may further include determining a weighted score for the value of the episodic memory score, the working memory score, or the combined episodic memory and working memory score, and each of the one or more risk-related factors, and further providing a treatment recommendation based on the individual's diagnosis.

[0009] Other aspects of the present specification disclose a method for treating perioperative neurocognitive disorder or post-viral cognitive disorder by administering a composition comprising one or more fibrates. Other aspects of the present specification disclose a composition comprising one or more fibrates for use in treating perioperative neurocognitive disorder or post-viral cognitive disorder. Other aspects of the present specification disclose the use of a composition comprising one or more fibrates in treating perioperative neurocognitive disorder or post-viral cognitive disorder. Other aspects of the present specification disclose the use of one or more fibrates in the manufacture of a medicament for treating perioperative neurocognitive disorder or post-viral cognitive disorder. Non-limiting examples of fibrates include bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. Perioperative neurocognitive impairment includes, but is not limited to, delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Aspects of the present disclosure disclose systems, methods, and uses for prospectively identifying individuals at risk for perioperative neurocognitive disorder (PND). In some embodiments, the disclosed methods and systems prospectively identify individuals at risk for PND prior to surgery or other procedures. In some embodiments, the disclosed systems, methods, and uses employ an episodic memory score for the individual to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive disorder. In some embodiments, the disclosed systems, methods, and uses employ an episodic memory score for the individual to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive disorder in conjunction with one or more additional risk-related factors from the individual. In some embodiments, the disclosed systems, methods, and uses employ a working memory score for the individual to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive disorder. In some embodiments, the disclosed systems, methods, and uses employ a working memory score for the individual to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive disorder in conjunction with one or more additional risk-related factors from the individual. In some embodiments, the disclosed systems, methods, and uses employ both an episodic memory score and a working memory score for an individual to determine a PND risk score that, in conjunction with one or more additional risk-related factors from the individual, captures the individual's risk state susceptibility to perioperative neurocognitive impairment. In some embodiments, the disclosed systems, methods, and uses employ both an episodic memory score and a working memory score for an individual to determine a PND risk score that captures the individual's risk state susceptibility to perioperative neurocognitive impairment. The disclosed systems, methods, and uses may further include determining a weighted score for the value of the episodic memory score, the working memory score, or the combined episodic memory and working memory score, and each of the one or more risk-related factors, and further providing a treatment recommendation based on the individual's risk state susceptibility.

[0011] Aspects of the present specification disclose perioperative neurocognitive disorder (PND). PND defines a syndrome characterized by progressive deterioration of sensory and cognitive function during the preoperative or postoperative surgical period. Although prevalence is high, with reported prevalence rates of 20-80%, PND is not observed exclusively in older adults. PND may have an acute delirium phase and / or a more chronic cognitive impairment phase that tends to persist over time. Current recommendations for classification of PND are based on objective assessment of impairment or decline in one or more domains compared to controls or normative data, subjective symptoms (patient or informant), and assessment of activities of daily living (ADL) using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). See Evered et al., Br. J. Anaesth. 121(5), 1005-1012 (2018; and Mahanna-Gabrielli et al., Br. J. Anaesth. 123(4), 464-478 (2019), each of which is incorporated by reference in its entirety.

[0012] In general, PND defines seven broad categories: 1) preoperative neurocognitive impairment, 2) postoperative delirium, 3) delayed postoperative neurocognitive recovery, 4) mild postoperative neurocognitive impairment, 5) severe postoperative neurocognitive impairment, 6) mild neurocognitive impairment, and 7) severe neurocognitive impairment. Preoperative neurocognitive impairment includes any cognitive impairment or decline diagnosed in an individual preoperatively. Postoperative delirium includes any acute cognitive impairment or decline diagnosed from postoperative day 1 up to seven days or at the time of discharge (whichever occurs first) in which an individual exhibits acute and fluctuating impairment in attention and consciousness. Delayed neurological recovery includes any cognitive impairment or decline diagnosed from postoperative day 1 up to 30 days, where the individual exhibits mild cognitive impairment (MCI) based on objective impairment 1-2 standard deviations below control / baseline, subjective symptoms, and no impairment in ADLs, or objective impairment 3 or more standard deviations below control / baseline, subjective symptoms, and dementia, and ADLs are impaired. Delayed neurological recovery is referred to in older literature as early postoperative cognitive impairment.

[0013] Mild postoperative neurocognitive impairment includes any cognitive impairment or decline diagnosed 30 days to up to 12 months after surgery, where the individual presents with objective impairment of 1-2 standard deviations below control / criteria, mild cognitive impairment (MCI) based on symptoms, and ADLs are not impaired. Severe postoperative neurocognitive impairment includes any cognitive impairment or decline diagnosed 30 days to up to 12 months after surgery, where the individual presents with objective impairment of 3 or more standard deviations below control / criteria, dementia based on symptoms, and ADLs are impaired. Mild neurocognitive impairment includes any cognitive impairment or decline diagnosed 12 months or more after surgery, where the individual presents with objective impairment of 1-2 standard deviations below control / criteria, mild cognitive impairment (MCI) based on symptoms, and ADLs are not impaired. Severe neurocognitive impairment included any cognitive impairment or decline diagnosed 12 months or more postoperatively, objective impairment of 3 or more standard deviations below control / norm, dementia based on subjective symptoms, and impaired ADL. Mild postoperative neurocognitive impairment, severe postoperative neurocognitive impairment, mild neurocognitive impairment, and severe neurocognitive impairment have generally been grouped together in older literature and referred to as long-term postoperative cognitive impairment.

[0014] Aspects of the present disclosure disclose systems, methods, and uses for identifying or confirming a diagnosis of post-viral cognitive impairment (PVCI) in an individual. In some embodiments, the systems, methods, and uses of the present disclosure employ an episodic memory score for an individual, optionally in conjunction with one or more additional risk-related factors from the individual, to identify or confirm a diagnosis of PVCI in the individual. In some embodiments, the systems, methods, and uses of the present disclosure employ a working memory score for an individual, optionally in conjunction with one or more additional risk-related factors from the individual, to identify or confirm a diagnosis of PVCI in the individual. In yet other embodiments, the systems, methods, and uses of the present disclosure employ both an episodic memory score and a working memory score for an individual, optionally in conjunction with one or more additional risk-related factors from the individual, to identify or confirm a diagnosis of PVCI in the individual. The disclosed systems, methods, and uses may further include determining a weighted score for the value of the episodic memory score, the working memory score, or the episodic memory and working memory combined score, and each of the one or more risk-related factors, and further providing a treatment recommendation based on the diagnosis of the individual.

[0015] Aspects of the present specification disclose post-viral cognitive impairment (PVCI). PVCI defines a syndrome characterized by deterioration of cognitive function during or after viral infection recovery. Although prevalence is high, with reported prevalence rates of 20-80%, PCVI is not observed exclusively in the elderly. In most cases, PVCI represents a chronic phase of functional impairment that tends to persist or worsen over time. There are no current recommendations regarding the means of diagnosing or identifying PVCI, and therefore the present specification is based on an objective assessment of impairment or decline in one or more cognitive domains compared to normative data, and therefore follows the DSM-5 diagnosis of mild neurocognitive disorder.

[0016] Part of the flexibility humans exhibit during behavior results from access to multiple memory systems that provide diverse information. Two well-studied memory systems are episodic memory and working memory. Episodic memory is a longer-lasting memory that allows for recalling and re-experiencing personal events, whereas working memory is defined as memory that is only active and relevant for a short period of time. Because the hippocampal region of the brain has an established role in memory function and is particularly vulnerable to the deleterious effects of inflammation caused by surgery or viral infection, such cognitive impairment in regions closely associated with hippocampal function is likely to be associated with PND and / or PVCI. As both episodic memory and working memory are hippocampal functions, the methods and systems of the present invention take advantage of the fact that poor episodic memory and / or working memory before surgery are risk factors for PND, and poor episodic memory and / or working memory after viral infection are determinants of PVCI.

[0017] Aspects of the present disclosure disclose analyzing an individual's episodic memory to generate an episodic memory score. In some embodiments, the individual's episodic memory score is determined by comparing performance on an episodic memory test (EMT) with a control's episodic memory score. In aspects of these embodiments, the control episodic memory score is obtained from normative data compiled from the general population. A negative score value may indicate that the individual performed worse than the normative average, and a positive score value may indicate that the individual performed better than the normative average. In aspects of these embodiments, the episodic memory score is determined by the following formula: Z EMT =-(EMT 個人スコア -EMT 規範平均 ) / EMT 規範SD .

[0018] In some embodiments, episodic memory in an individual is determined using episodic memory tests, non-limiting examples of which include list learning tests, recognition memory tests, and paired-associate learning tests.

[0019] In some embodiments, assessing episodic memory is accomplished using a list learning test. List learning assesses a wide variety of functions, including short-term auditory-verbal memory, learning speed, learning strategies, retroactive and prospective interference, the presence of disruptive confabulation in memory processes, information retention, and the difference between learning and recall. Tests designed to capture list learning usually include a pre-test phase that includes multiple trials, where in each trial, the individual is presented with a list of unrelated words one by one and asked to recall as many words as possible (free recall), and a test phase, where the individual is presented with different lists of unrelated words one by one and asked to recall as many words as possible (interference list), and then asked to repeat the original list of words presented in the pre-test phase at a later time (delayed recall). One particular example of a list learning test is the Rey Auditory Verbal Learning Test (RAVLT). The RAVLT includes a pretest phase in which the individual is presented with a word list A of 15 unrelated words one at a time and asked to recall as many as possible (free recall), repeating this process five times, and a test phase in which the individual is presented with a different list of 15 unrelated words (word list B) one at a time and asked to recall as many words as possible from word list B (interference list), and then asked to recall as many as possible of the 15 words from word list A 20-30 minutes later (delayed recall). Two other examples of list learning tests are the word list tasks from the Consortium to Establish a Registry for Alzheimer's disease Neuropsychological Assessment Battery (CERAD-NAB) and the California Verbal Learning Test (CVLT).

[0020] In some embodiments, determining episodic memory is accomplished using a recognition memory test (RMT). Recognition memory assesses the ability to encode and then retrieve linguistic information, thereby assessing verbal memory and new learning, with recall utilizing the frontotemporal network and recognition assessing the hippocampal region. Tests designed to capture recognition memory typically include a pre-test phase in which an individual is shown a series of words one at a time and then asked to recall as many as possible, and the individual is scored on which words he or she remembers, and a test phase in which the individual is presented with two words, one from the original list and one distractor word, and then asked to immediately choose which word they have seen before in a forced-choice paradigm, and then once at a later time. One particular example of a recognition memory test is the Cambridge Neuropsychological Test Automated Battery (CANTAB) Verbal Recognition Memory (CANTAB VRM). The CANTAB VRM involves a pre-test phase in which individuals are presented with 18 words displayed on a screen and asked to recall as many as possible (free recall), and a test phase in which individuals are presented with 36 words (including 18 words from the pre-test list and 18 distractor words) and asked to respond with "yes" or "no" if the individual has seen the word before. After a 20 minute delay period, another recognition test is then administered, this time using the same 18 words from the pre-test list, but with a new set of 18 distractor words.

[0021] In some embodiments, determining episodic memory is accomplished using a paired-associate learning (PAL) test. Paired-associate learning is the ability to remember associations between one stimulus and another. Tests designed to capture paired-associate learning typically include a pre-test phase in which an individual is exposed to a list of randomly assigned pairs of stimuli, e.g., verbal or visual stimuli, and a test phase in which one of the paired stimuli is presented in which the individual must recall the second associated stimulus. One particular example of a paired-associate learning test is the Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning Task (CANTAB PAL). CANTAB PAL displays boxes on a screen and randomly opens them one at a time to reveal a hidden pattern inside. The patterns are then displayed one at a time in the middle of the screen, and the participant must touch the box where the pattern was originally located. If the participant makes a mistake, the pattern is reproduced to remind the participant of its location. As the test progresses, the stages become more difficult as the number of patterns to be memorized increases. Another example is the Weschler Memory Scale and the Verbal Paired Associates, in which eight pairs of unrelated words are learned over four learning and test trials, followed 30 minutes later by a delayed recall test and a recognition test.

[0022] Aspects of the present specification disclose analyzing the working memory of an individual to generate a working memory score. In some embodiments, the working memory score of the individual is determined by comparing the performance of a working memory test (WMT) with a control's working memory score. In aspects of these embodiments, the control working memory score is obtained from normative data compiled from the general population. A negative score value may indicate that the individual performed worse than the normative average, and a positive score value may indicate that the individual performed better than the normative average. In aspects of these embodiments, the working memory score is determined by the following formula: Z WMT =-(WMT 個人スコア -WMT規範平均 ) / WMT 規範SD .

[0023] In some embodiments, working memory in an individual is assessed using working memory tests, non-limiting examples of which include the spatial working memory test, the spatial span test, the digit permutation test, and the N-back test.

[0024] In some embodiments, assessing working memory is accomplished using a spatial working memory (SWM) test. Spatial working memory tests designed to capture working memory typically require the retention and manipulation of visuospatial information. The test places significant demands on executive function and measures strategy use and errors. In one particular example of a spatial working memory test, participants must search for tokens hidden in a box. Participants must touch the box to open it and reveal either a yellow token or an empty box. Once participants find a yellow token, they must touch the outline on the right side of the screen to "save" it in the computing device. Participants must then continue searching in the box until all tokens are found. An important test instruction is that once a token is found in a box, participants should not return to that box to search for another token, as the computer never hides a token in the same box. The color and location of the boxes used are changed from trial to trial to discourage the use of stereotypical search strategies. As the trial progresses, the number of tokens to search increases.

[0025] In some embodiments, assessing working memory is accomplished using a spatial span test. Spatial span tests are usually designed to assess the capacity of working memory, which is a component of working memory that allows for temporary storage and manipulation of location information. Spatial span tests usually involve presenting a series of flashing stimuli to an individual one by one, and then asking the individual to recall the stimuli in the same order as they were presented after the presentation is complete. Non-limiting examples of spatial span tests include the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Span (CANTAB SSP) test, and the Wechsler Memory Scale, Spatial Span test.

[0026] In some embodiments, determining working memory is accomplished using a digit permutation test. A digit permutation test is usually designed to capture working memory by assessing verbal working memory ability. A digit permutation test usually involves presenting an individual with a series of numbers of increasing complexity and asking the individual to repeat each number immediately after presentation. The test continues until the individual cannot remember the complete sequence of numbers or until the number is repeated incorrectly.

[0027] In some embodiments, assessing working memory is accomplished using an N-back test. N-back tests designed to ascertain working memory typically involve presenting a series of stimuli one by one to an individual, and then for each stimulus, the individual is asked to recall the stimulus that was presented N times before, where N can be 1, 2, 3, etc., and the higher N, the more difficult the task. In one embodiment, an individual is presented with a series of numbers one by one, and then asked to recall the number that was presented two times before.

[0028] Aspects of the present disclosure disclose analyzing both an individual's episodic memory and working memory to generate a combined episodic memory and working memory score. In some embodiments, the individual's combined episodic memory and working memory score is determined by comparing performance on both episodic memory tests and working memory tests as disclosed herein with episodic memory and working memory scores of a control. In aspects of these embodiments, the combined episodic memory and working memory score of the control is obtained from normative data compiled from the general population. A negative score may indicate that the individual performed worse than the normative average, and a positive score may indicate that the individual performed better than the normative average.

[0029] In some embodiments, the episodic memory and working memory combined score is generated by first separately assessing the individual's episodic memory as disclosed herein to generate an episodic memory score, and the individual's working memory as disclosed herein to generate a working memory score. Once determined, these two scores are then added together to generate the episodic memory and working memory combined score. In aspects of these embodiments, the episodic memory and working memory combined score is determined by the following formula: i) Determine the episodic memory score using the following formula: Z EMT =-(EMT 個人スコア -EMT 規範平均 ) / EMT 規範SD 2) Determine the working memory score using the following formula: Z WMT =-(WMT 個人スコア -WMT 規範平均 ) / WMT 規範SD and 3) determine a combined episodic and working memory score by adding the two scores and taking the average using the following formula: Combined Risk Score Z CMT =(Z EMT +Z WMT ) / 2.

[0030] The range of abilities referred to as cognition is diverse and includes learning and memory, language skills, perception, attention, executive function, and abstract thinking. A cognitive assessment evaluation should objectively assess specific cognitive domains. In some embodiments, a cognitive assessment evaluation is performed to obtain both a preoperative cognitive baseline and a postoperative cognitive determination for an individual.

[0031] Aspects herein disclose determining an individual's risk-related factors, which typically include information about the individual's personal and medical history, as well as a cognitive assessment. Information from the individual's condition and medical history may include, but is not limited to, age, sex, height, weight, body mass index (BMI), education level, IQ, Emotional Quotient, and other biometric information, physical examination results, information about past viral infections, information about cognitive concerns from the individual and family, information about changes in behavior, mood or thinking such as hallucinations, delusions, personality changes, apathy, depression, anxiety, disorientation, and confusion, information about changes in physical health such as difficulties walking, balance, speech, and coordination, tremors and stiffness, information about substance abuse and withdrawal symptoms, whether this is an initial assessment or a subsequent assessment of the individual, whether the individual currently has symptoms of cognitive impairment, whether the individual has a medical history of cognitive impairment, whether the individual has been diagnosed with cognitive impairment in the past, whether the individual currently has symptoms of an inflammatory related disease, infection or physical illness, whether the individual has a medical history of an inflammatory related disease, infection or physical illness, whether the individual has been diagnosed with an inflammatory related disease, infection or physical illness in the past, and whether the individual is currently taking anticholinergic medications. Additionally, perioperative information such as operative time, type of surgery, anesthesia management, and intraoperative physiology may also be collected. Any or additional factors may also reduce cognitive reserve and be at risk for postoperative cognitive changes.

[0032] Aspects herein disclose determining one or more risk-associated factors to generate a reference value for each of the one or more risk-associated factors. In some embodiments, the individual's risk-associated factor score is determined by comparing the value of the risk-associated factor to a control's risk-associated factor score. In aspects of these embodiments, the reference value for the risk-associated factor is obtained by comparing the value of the risk-associated factor to normative data compiled from the general population and determining whether the individual's risk-associated score is within a range of acceptable values ​​indicating that the individual is not at risk or whether the individual's risk-associated score is outside a range of acceptable values ​​indicating that the individual is at risk. In aspects of these embodiments, when determining the inflammation reference value, a C-reactive protein (CRP) blood level of less than 10 mg / L indicates a non-risk condition inflammation reference value, and a CRP blood level of 10 mg / L or more indicates a risk condition inflammation reference value. In aspects of these embodiments, when determining the age reference value, a person less than 60 years old indicates a non-risk condition age reference value, and a person 60 years old or more indicates a risk condition age reference value. In aspects of these embodiments, when determining the BMI baseline, a value less than 30 indicates a non-risk status BMI baseline and a value equal to or greater than 30 indicates a risk status BMI baseline. In aspects of these embodiments, when determining the education baseline, a value greater than 12 years of formal education indicates a non-risk status education baseline and a value equal to or less than 12 years of formal education indicates a risk status education baseline. In aspects of these embodiments, when determining the medication baseline, no use of a risk status medication indicates a non-risk status medication baseline, while use of an antihistamine, gastrointestinal antispasmodic, antivertigo / antiemetic, antidepressant, bladder antimuscarinic, skeletal muscle relaxant, antipsychotic, antiarrhythmic, antiparkinsonian, or anticholinergic based medication in the past 8 weeks indicates a risk status medication baseline. In aspects of these embodiments, when determining the disease diagnosis or medical history baseline, the absence of any diagnosis or history of a risk state disease is indicative of a non-risk state disease diagnosis or medical history baseline, while the presence of a psychiatric disease, neurological disease, diabetes, metabolic syndrome, autoimmune disease, cardiac disease, vascular disease, stroke, infectious disease, injury, asthma, or alcohol abuse is indicative of a risk state disease diagnosis or medical history baseline.

[0033] Aspects of the present disclosure disclose determining a PND risk score that captures an individual's risk status susceptibility to PND. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's episodic memory score from the normative mean. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's episodic memory score from the normative mean in conjunction with a baseline of one or more risk-related factors. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's working memory score from the normative mean. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's working memory score from the normative mean in conjunction with a baseline of one or more risk-related factors. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's episodic memory and working memory combined score from the normative mean. In some embodiments, the PND risk score is based on the standard deviation deficit of the individual's episodic memory and working memory combined score from the normative mean in conjunction with a baseline of one or more risk-related factors.

[0034] In some embodiments, the individual's risk status susceptibility to PND is determined using a risk stratification matrix that employs predefined threshold reference values ​​for the episodic memory score, working memory score, and each additional risk-related factor for which the individual's PND risk score is determined and the risk status susceptibility is assessed. In some embodiments, the predefined threshold reference values ​​for the episodic memory score, working memory score, and each additional risk-related factor disclosed herein are determined using normative averages. Normative averages are average values ​​of data or other information (norms) taken from a subject population that establish a baseline distribution of outcomes for a particular population, including but not limited to average values ​​of episodic memory scores, working memory scores, and other risk-related factors disclosed herein taken from a healthy population cohort, or average values ​​of previous episodic memory scores, working memory scores, and / or other risk-related factors disclosed herein obtained from individuals undergoing a method or use disclosed herein.

[0035] In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by an episodic memory criterion value. In aspects of these embodiments, the episodic memory criterion value comprises a score that is one or more standard deviations below the normative mean (Z-score transformation of -1 or less). In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by a working memory criterion value. In aspects of these embodiments, the working memory criterion value comprises a score that is one or more standard deviations below the normative mean (Z-score transformation of -1 or less). In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by a combined episodic memory and working memory criterion value. In aspects of these embodiments, the combined episodic memory and working memory criterion value comprises a score that is one or more standard deviations below the normative mean (Z-score transformation of -1 or less).

[0036] In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by the presence of an episodic memory criterion value and an inflammation criterion value. In aspects of these embodiments, the episodic memory criterion value comprises a score 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), and the inflammation criterion value comprises the presence of a CRP blood level of 10 mg / L or more. In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by the presence of a working memory criterion value and an inflammation criterion value. In aspects of these embodiments, the working memory criterion value comprises a score 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), and the inflammation criterion value comprises the presence of a CRP blood level of 10 mg / L or more. In some embodiments, the predefined threshold criterion value identifying an individual at risk for PND is determined by the presence of a combined episodic memory and working memory criterion value and an inflammation criterion value. In aspects of these embodiments, the combined episodic memory and working memory criterion value comprises a score 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), and the inflammation criterion value comprises the presence of a CRP blood level of 10 mg / L or more.

[0037] In some embodiments, the predefined threshold reference value identifying an individual at risk for PND is determined by the presence of an episodic memory reference value and two or more factors, one factor being an age reference value, an education reference value, or a BMI reference value, and another factor being at least one of a diagnosis or medical history reference value, or a medication use reference value. In aspects of these embodiments, episodic memory criteria include a score of 1 standard deviation or more below the normative mean (Z-score transformation equal to or less than -1); age criteria include age 60 years or older; education criteria include 12 years or less of formal education; BMI criteria include a score of 30 or higher; disease diagnosis or medical history criteria include presence of psychiatric disease, neurological disease, diabetes, metabolic syndrome, autoimmune disease, cardiac disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse; and medication use criteria include use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, and anticholinergic-based medications in the past 8 weeks.

[0038] In some embodiments, the predefined threshold reference value identifying an individual at risk for PND is determined by the presence of a working memory reference value and two or more factors, one factor being an age reference value, an education reference value, or a BMI reference value, and another factor being at least one of a diagnosis or medical history reference value, or a medication use reference value. In aspects of these embodiments, working memory criteria include a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), age criteria include age 60 years or older, education criteria include 12 years or less of formal education, BMI criteria include a score of 30 or more, disease diagnosis or medical history criteria include presence of psychiatric disease, neurological disease, diabetes, metabolic syndrome, autoimmune disease, cardiac disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse, and medication use criteria include use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, anticholinergic-based medications in the past 8 weeks.

[0039] In some embodiments, the predefined threshold reference value identifying an individual at risk for PND is determined by a combined episodic memory and working memory reference value and the presence of two or more factors, one factor being an age reference value, an education reference value, or a BMI reference value, and another factor being at least one of a diagnosis or medical history reference value, or a medication use reference value. In aspects of these embodiments, the combined episodic and working memory criteria include a score of 1 standard deviation or more below the normative mean (Z-score transformation equal to or less than -1); the age criteria include age 60 years or older; the education criteria include 12 years or less of formal education; the BMI criteria include a score of 30 or higher; the disease diagnosis or medical history criteria include the presence of psychiatric disease, neurological disease, diabetes, metabolic syndrome, autoimmune disease, cardiac disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse; and the medication use criteria include use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, and anticholinergic-based medications in the past 8 weeks.

[0040] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND is determined by the presence of an episodic memory criterion and two or more factors, one factor being an age criterion, an education criterion, or a BMI criterion, and another factor being a medication use criterion. In aspects of these embodiments, the episodic memory criterion includes a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), the age criterion includes age 60 or more, the education criterion includes 12 years or less of formal education, the BMI criterion includes a score of 30 or more, and the medication use criterion includes use of antihistamines, gastrointestinal anticonvulsants, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based drugs in the past 8 weeks.

[0041] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND are determined by the presence of a working memory criterion and two or more factors, one factor being an age criterion, an education criterion, or a BMI criterion, and another factor being a medication use criterion. In aspects of these embodiments, the working memory criterion includes a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), the age criterion includes age 60 or more, the education criterion includes 12 years or less of formal education, the BMI criterion includes a score of 30 or more, and the medication use criterion includes use of antihistamines, gastrointestinal anticonvulsants, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based drugs in the past 8 weeks.

[0042] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND are determined by the combined episodic and working memory criteria and the presence of two or more factors, one factor being an age, education, or BMI criteria, and another factor being a medication use criterion. In aspects of these embodiments, the combined episodic and working memory criteria include a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), the age criteria include age 60 years or older, the education criteria include 12 years or less of formal education, the BMI criteria include a score of 30 or more, and the medication use criteria include use of antihistamines, gastrointestinal anticonvulsants, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based drugs in the past 8 weeks.

[0043] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND is determined by the episodic memory criteria and the presence of two or more factors, one factor being an age criteria and the other factor being at least one of a disease diagnosis or medical history criteria. In aspects of these embodiments, the episodic memory criteria include a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the age criteria include age 60 or older, and the disease diagnosis or medical history criteria include the presence of a psychiatric disorder, a neurological disorder, diabetes, metabolic syndrome, an autoimmune disease, a cardiac disease, a vascular disease, a stroke, an infection, an injury, asthma, or alcohol abuse.

[0044] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND are determined by a working memory criterion and the presence of two or more factors, one factor being an age criterion and the other factor being at least one of a disease diagnosis or medical history criterion. In aspects of these embodiments, the working memory criterion includes a score of 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), the age criterion includes age 60 or older, and the disease diagnosis or medical history criterion includes the presence of a psychiatric disorder, a neurological disorder, diabetes, metabolic syndrome, an autoimmune disease, a cardiac disease, a vascular disease, a stroke, an infection, an injury, asthma, or alcohol abuse.

[0045] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND are determined by the combined episodic and working memory criteria and the presence of two or more factors, one factor being an age criteria and the other factor being at least one of a disease diagnosis or medical history criteria. In aspects of these embodiments, the combined episodic and working memory criteria include a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the age criteria include age 60 years or older, and the disease diagnosis or medical history criteria include the presence of a psychiatric disorder, a neurological disorder, diabetes, metabolic syndrome, an autoimmune disease, a cardiac disease, a vascular disease, a stroke, an infection, an injury, asthma, or alcohol abuse.

[0046] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND is determined by the episodic memory criteria and the presence of two or more factors, one factor being an age criteria and the other being a medication use criteria. In aspects of these embodiments, the episodic memory criteria include a score ≥1 standard deviation below the normative mean (Z-score transformation ≤-1), the age criteria include age ≥60, and the medication use criteria include use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based medications in the past 8 weeks.

[0047] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND is determined by the working memory criteria and the presence of two or more factors, one factor being an age criteria and the other being a medication use criteria. In aspects of these embodiments, the working memory criteria include a score ≥1 standard deviation below the normative mean (Z-score transformation ≤-1), the age criteria include age ≥60, and the medication use criteria include use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based medications in the past 8 weeks.

[0048] In some embodiments, the predefined threshold criteria identifying individuals at risk for PND are determined by episodic memory and working memory criteria and the presence of two or more factors, one factor being an age criterion and the other being a medication use criterion. In aspects of these embodiments, the combined episodic memory and working memory criterion includes a score ≥1 standard deviation below the normative mean (Z-score transformation ≤-1), the age criterion includes age ≥60, and the medication use criterion includes use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonian drugs, or anticholinergic-based medications in the past 8 weeks.

[0049] In some embodiments, predefined threshold criteria for identifying individuals at very high risk of PND are determined by episodic memory and impairment criteria for risk-related factors for inflammation, age, BMI, education level, medication use, and disease diagnosis or history. In aspects of these embodiments, predefined threshold criteria identifying individuals at very high risk for PND are determined by episodic memory criteria that are 1 standard deviation or more below the normative mean (Z-score transformation equal to or less than -1), inflammation criteria indicative of high inflammation (e.g., blood levels of CRP equal to or greater than 10 mg / L), age criteria of 60 years or older, BMI criteria of 30 or greater, education criteria of 12 years or less of formal education, medication use criteria of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and disease diagnosis or medical history criteria of the presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune disorders, cardiac disorders, vascular disorders, stroke, infection, injury, asthma, or alcohol abuse.

[0050] In some embodiments, the predefined threshold criteria for identifying individuals at very high risk of PND are determined by working memory criteria and poor criteria for risk-related factors for inflammation, age, BMI, education level, drug use, and disease diagnosis or history. In aspects of these embodiments, predefined threshold criteria identifying individuals at very high risk for PND are determined by a working memory criterion that is more than one standard deviation below the normative mean (Z-score transformation less than or equal to -1), an inflammation criterion indicative of high inflammation (e.g., blood levels of CRP greater than or equal to 10 mg / L), an age criterion of 60 years or older, a BMI criterion of 30 or greater, an education criterion of 12 years or less of formal education, a medication use criterion of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and a disease diagnosis or medical history criterion of the presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune disorders, cardiac disorders, vascular disorders, stroke, infection, injury, asthma, or alcohol abuse.

[0051] In some embodiments, the predefined threshold criteria for identifying individuals at very high risk of PND are determined by episodic and working memory combined criteria and impairment criteria for risk-related factors for inflammation, age, BMI, education level, medication use, and disease diagnosis or history. In aspects of these embodiments, the predefined threshold criteria identifying individuals at very high risk for PND are determined by a combined episodic memory and working memory criterion that is greater than or equal to one standard deviation below the normative mean (Z-score transformation less than or equal to -1), and include inflammation criteria indicative of high inflammation (e.g., blood levels of CRP greater than or equal to 10 mg / L), age criteria of 60 years or older, BMI criteria of 30 or greater, education criteria of 12 years or less of formal education, medication use criteria of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and disease diagnosis or medical history criteria of the presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune disorders, cardiac disorders, vascular disorders, stroke, infection, injury, asthma, or alcohol abuse.

[0052] In some embodiments, the predefined threshold norm that identifies individuals at high risk for PND is determined by an episodic memory norm. In aspects of these embodiments, the predefined threshold norm that identifies individuals at high risk for PND is determined by an episodic memory norm that is at least one standard deviation below the normative mean (Z-score transformation of -1 or less).

[0053] In some embodiments, the predefined threshold norm that identifies individuals at high risk for PND is determined by a working memory norm. In aspects of these embodiments, the predefined threshold norm that identifies individuals at high risk for PND is determined by a working memory norm that is at least one standard deviation below the normative mean (Z-score transformation of -1 or less).

[0054] In some embodiments, the predefined threshold norm identifying individuals at high risk for PND is determined by an episodic memory norm and a working memory norm. In aspects of these embodiments, the predefined threshold norm identifying individuals at high risk for PND is determined by a combined episodic memory and working memory norm and includes a score 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less).

[0055] In some embodiments, the predefined threshold standard values ​​identifying individuals at high risk for PND are determined by episodic memory standard values ​​and inflammation standard values. The standard values ​​of risk-related factors of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying individuals at high risk for PND are determined by episodic memory standard values ​​at least one standard deviation below the normative mean (Z-score transformation at or below -1) and inflammation standard values ​​of blood levels of CRP at or above 10 mg / L. In other aspects of these embodiments, the predefined threshold values ​​identifying individuals at high risk for PND include an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0056] In some embodiments, the predefined threshold standard values ​​identifying individuals at high risk for PND are determined by working memory standard values ​​and inflammation standard values. The standard values ​​of risk-related factors of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying individuals at high risk for PND are determined by working memory standard values ​​of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less) and inflammation standard values ​​of blood levels of CRP of 10 mg / L or more. In other aspects of these embodiments, the predefined threshold values ​​identifying individuals at high risk for PND include an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0057] In some embodiments, the predefined threshold standard values ​​that identify individuals at high risk for PND are determined by episodic memory and working memory combined standard values ​​and inflammation standard values. The standard values ​​of risk-related factors of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​that identify individuals at high risk for PND are determined by episodic memory and working memory combined standard values ​​and include inflammation standard values ​​of a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less) and blood levels of CRP of 10 mg / L or more. In other aspects of these embodiments, the predefined threshold values ​​that identify individuals at high risk for PND include an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0058] In some embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND are determined by episodic memory normative values ​​and age normative values. The normative values ​​of risk-related factors of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND are determined by episodic memory normative values ​​of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), and age normative values ​​of 60 years or older. In other aspects of these embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND include inflammation normative values ​​of blood levels of CRP less than 10 mg / L, BMI normative values ​​of less than 30, education normative values ​​of more than 12 years of formal education, drug use normative values ​​of non-risk state drug use, and disease diagnosis or medical history normative values ​​of non-risk state disease diagnosis or medical history.

[0059] In some embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND are determined by a working memory normative value and an age normative value. The normative values ​​of risk-related factors of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND are determined by a working memory normative value of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), and an age normative value of 60 years or more. In other aspects of these embodiments, the predefined threshold normative values ​​identifying individuals at high risk for PND include an inflammation normative value of blood levels of CRP less than 10 mg / L, a BMI normative value of less than 30, an education normative value of more than 12 years of formal education, a drug use normative value of non-risk state drug use, and a disease diagnosis or medical history normative value of non-risk state disease diagnosis or medical history.

[0060] In some embodiments, the predefined threshold standard values ​​that identify individuals at high risk for PND are determined by episodic memory and working memory combined standard values ​​and age standard values. The standard values ​​of risk-related factors of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​that identify individuals at high risk for PND are determined by episodic memory and working memory combined standard values ​​and include a score of 1 standard deviation or more below the normative mean (Z-score transformation of -1 or less), and an age standard value of 60 years or older. In other aspects of these embodiments, the predefined threshold standard values ​​that identify individuals at high risk for PND include an inflammation standard value of blood levels of CRP less than 10 mg / L, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0061] In some embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by an episodic memory standard value. In aspects of these embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by an episodic memory standard value that is below the normative mean but less than one standard deviation below the normative mean (Z-score transformation less than 0 but greater than -1).

[0062] In some embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by a working memory standard value. In aspects of these embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by a working memory standard value that is below the normative mean but less than one standard deviation below the normative mean (Z-score transformation less than 0 but greater than -1).

[0063] In some embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by a combined episodic memory and working memory standard value. In aspects of these embodiments, the predefined threshold standard value identifying a person at moderate risk for PND is determined by a combined episodic memory and working memory standard value that is below the normative mean but less than one standard deviation below the normative mean (Z-score transformation less than 0 but greater than -1).

[0064] In some embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by an episodic memory standard value and an inflammation standard value. The standard values ​​of risk-related factors of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by an episodic memory standard value that is below the normative mean but less than one standard deviation below the normative mean (Z-score transformation less than 0 but greater than -1), and an inflammation standard value of blood levels of CRP equal to or greater than 10 mg / L. In other aspects of these embodiments, the predefined threshold values ​​identifying a person at moderate risk for PND include an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0065] In some embodiments, the predefined threshold values ​​identifying people at moderate risk for PND are determined by working memory and inflammation criteria. The criteria of risk-related factors of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying people at moderate risk for PND are determined by working memory criteria that are below the normative mean but less than one standard deviation below the normative mean (Z-score transformation is less than 0 but greater than -1), and inflammation criteria of blood levels of CRP equal to or greater than 10 mg / L. In other aspects of these embodiments, the predefined threshold values ​​identifying people at moderate risk for PND include age criteria of less than 60 years, BMI criteria of less than 30, education criteria of more than 12 years of formal education, drug use criteria of non-risk state drug use, and disease diagnosis or medical history criteria of non-risk state disease diagnosis or medical history.

[0066] In some embodiments, the predefined threshold values ​​identifying a person at moderate risk for PND are determined by a combined episodic and working memory criterion and an inflammation criterion. The risk-related factor criterion values ​​of age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by a combined episodic and working memory criterion that is less than one standard deviation below the normative mean (Z-score transformation less than 0 but greater than -1) below the normative mean, and an inflammation criterion of blood levels of CRP equal to or greater than 10 mg / L. In other aspects of these embodiments, the predefined threshold values ​​identifying a person at moderate risk for PND include an age criterion of less than 60 years, a BMI criterion of less than 30, an education criterion of more than 12 years of formal education, a drug use criterion of non-risk state drug use, and a disease diagnosis or medical history criterion of non-risk state disease diagnosis or medical history.

[0067] In some embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by an episodic memory standard value and an age standard value. The standard values ​​of risk-related factors of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by an episodic memory standard value that is below the normative mean but less than one standard deviation below the normative mean (Z-score transformation is less than 0 but greater than -1), and an age standard value of 60 years or older. In other aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND include an inflammation standard value of blood levels of CRP less than 10 mg / L, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0068] In some embodiments, the predefined threshold values ​​identifying people at moderate risk for PND are determined by working memory and age criteria. The criteria of risk-related factors of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying people at moderate risk for PND are determined by working memory criteria that are below the normative mean but less than one standard deviation below the normative mean (Z-score transformation is less than 0 but greater than -1), and age criteria that are 60 years or older. In other aspects of these embodiments, the predefined threshold standard values ​​identifying people at moderate risk for PND include inflammation criteria of blood levels of CRP less than 10 mg / L, BMI criteria of less than 30, education criteria of more than 12 years of formal education, drug use criteria of non-risk state drug use, and disease diagnosis or medical history criteria of non-risk state disease diagnosis or medical history.

[0069] In some embodiments, the predefined threshold values ​​identifying a person at moderate risk for PND are determined by a combined episodic and working memory criterion, and an age criterion. The risk-related factor criterion values ​​of inflammation, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND are determined by a combined episodic and working memory criterion that is below the normative mean, but less than one standard deviation below the normative mean (Z-score transformation is less than 0 but greater than -1), and an age criterion of 60 years or older. In other aspects of these embodiments, the predefined threshold standard values ​​identifying a person at moderate risk for PND include an inflammation criterion of blood levels of CRP less than 10 mg / L, a BMI criterion of less than 30, an education criterion of more than 12 years of formal education, a drug use criterion of non-risk state drug use, and a disease diagnosis or medical history criterion of non-risk state disease diagnosis or medical history.

[0070] In some embodiments, the predefined threshold standard values ​​identifying individuals at low risk for PND are determined by episodic memory standard values. The risk-related factor standard values ​​of inflammation, age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard values ​​identifying individuals at low risk for PND are determined by episodic memory standard values ​​above the normative mean (Z-score transformation of 0 or greater). In other aspects of these embodiments, the predefined threshold standard values ​​identifying individuals at low risk for PND include inflammation standard values ​​of blood levels of CRP below 10 mg / L, age standard values ​​below 60 years, BMI standard values ​​below 30, education standard values ​​of more than 12 years of formal education, drug use standard values ​​of non-risk state drug use, and disease diagnosis or medical history standard values ​​of non-risk state disease diagnosis or medical history.

[0071] In some embodiments, the predefined threshold standard value that identifies a person at low risk of PND is determined by a working memory standard value. The standard values ​​of risk-related factors of inflammation, age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard value that identifies a person at low risk of PND is determined by a working memory standard value that is above the normative mean (Z-score transformation is 0 or greater). In other aspects of these embodiments, the predefined threshold standard values ​​that identify a person at low risk of PND include an inflammation standard value of blood levels of CRP less than 10 mg / L, an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0072] In some embodiments, the predefined threshold standard value that identifies a person at low risk of PND is determined by a combined episodic memory and working memory standard value. The risk-related factor standard values ​​of inflammation, age, BMI, education level, drug use, and disease diagnosis or medical history are all non-indicative. In aspects of these embodiments, the predefined threshold standard value that identifies a person at low risk of PND is determined by a combined episodic memory and working memory standard value that is above the normative mean (Z-score transformation is 0 or greater). In other aspects of these embodiments, the predefined threshold standard values ​​that identify a person at low risk of PND include an inflammation standard value of blood levels of CRP less than 10 mg / L, an age standard value of less than 60 years, a BMI standard value of less than 30, an education standard value of more than 12 years of formal education, a drug use standard value of non-risk state drug use, and a disease diagnosis or medical history standard value of non-risk state disease diagnosis or medical history.

[0073] Additionally, the risk stratification matrix can further stratify the individual's PND risk score to assess the individual's risk condition severity. In some embodiments, the risk stratification matrix disclosed herein can apply a weighted score to each threshold criterion value assigned to the episodic memory score, the working memory score, the combined episodic and working memory score, each additional risk-related factor, or any combination thereof. In some embodiments, the weighted score assigned to each threshold criterion value by the risk stratification matrix is ​​developed from data obtained from information compiled on PND, such as information obtained from observational studies, interventional studies, and clinical studies.

[0074] In some embodiments, stratifying the individual's PND risk score results in a recommendation that the individual undergo additional monitoring or treatment for PND before and / or after surgery. In some embodiments, stratifying the individual's PND risk score results in classifying PND as preoperative neurocognitive impairment, postoperative delirium, delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment) or severe neurocognitive impairment (or long-term postoperative cognitive impairment).

[0075] If an individual's PND risk score meets certain predefined threshold criteria, the risk stratification matrix disclosed herein indicates that the individual is at risk for PND. In addition, depending on which predefined threshold criteria are met, the risk stratification matrix disclosed herein can identify the degree of risk state susceptibility as well as the degree of cognitive impairment. In some embodiments, the risk stratification matrix disclosed herein can identify the degree of risk state susceptibility as very high risk for PND, high risk for PND, medium risk for PND, low risk for PND, or no risk for PND. In some embodiments, the risk stratification matrix disclosed herein can identify the degree of risk state susceptibility as very high risk for PND, high risk for PND, medium risk for PND, or low risk for PND. In some embodiments, the risk stratification matrix disclosed herein can identify the degree of risk state susceptibility as high risk for PND, medium risk for PND, or low risk for PND.

[0076] In some embodiments, to determine an individual's risk status susceptibility to PND, the weighted scores assigned to each threshold reference value by the risk stratification matrix for the episodic memory score, working memory score, combined episodic and working memory score, and each additional risk-related factor are based on Table 1.

[0077] [Table 1] TIFF2024504116000002.tif236170TIFF2024504116000003.tif229169TIFF2024504116000004.tif23316 8TIFF2024504116000005.tif232170TIFF2024504116000006.tif235170TIFF2024504116000007.tif50169

[0078] Aspects herein disclose determining a PVCI diagnostic score that identifies or confirms a diagnosis of PVCI for an individual. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's episodic memory score from the normative mean. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's episodic memory score from the normative mean in conjunction with a baseline of one or more risk-related factors. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's working memory score from the normative mean. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's working memory score from the normative mean in conjunction with a baseline of one or more risk-related factors. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's combined episodic memory and working memory score from the normative mean. In some embodiments, the PVCI diagnostic score is based on a standard deviation deficit of the individual's combined episodic memory and working memory score from the normative mean in conjunction with a baseline of one or more risk-related factors.

[0079] In some embodiments, the identification or confirmation of an individual's diagnosis of PVCI uses a risk stratification matrix that employs predefined threshold criteria for the episodic memory score, the working memory score, and each additional risk-related information for which the individual's PVCI diagnostic score is determined and the identification or confirmation of PVCI is assessed. In some embodiments, the predefined threshold criteria for identifying or confirming an individual's having PVCI are determined by an episodic memory criterion value and an inflammation criterion value. In aspects of these embodiments, the episodic memory criterion value comprises a score of 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), and the inflammation criterion value comprises the presence of a CRP blood level of 10 mg / L or more. In some embodiments, the predefined threshold criteria for identifying or confirming an individual's having PVCI are determined by a working memory criterion value and an inflammation criterion value. In aspects of these embodiments, the working memory criterion value comprises a score of 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), and the inflammation criterion value comprises the presence of a CRP blood level of 10 mg / L or more. In some embodiments, the predefined threshold criterion that identifies or confirms that an individual has PVCI is determined by a combined episodic and working memory criterion and an inflammation criterion. In aspects of these embodiments, the combined episodic and working memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation ≦−1) and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0080] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by the presence of an episodic memory criterion and two or more factors, one factor being a viral infection criterion and another factor being an inflammation criterion. In aspects of these embodiments, the episodic memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0081] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by a working memory criterion and the presence of two or more factors, one factor being a viral infection criterion and another factor being an inflammation criterion. In aspects of these embodiments, the working memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0082] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by a combined episodic memory and working memory criterion and the presence of two or more factors, one factor being a viral infection criterion and another factor being an inflammation criterion. In aspects of these embodiments, the combined episodic memory and working memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0083] In some embodiments, the predefined threshold criterion that identifies or confirms that an individual has PVCI is determined by the presence of an episodic memory criterion and two or more factors, one factor being a viral infection criterion and another factor being an antiviral drug use criterion. In aspects of these embodiments, the episodic memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, and the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks.

[0084] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by the presence of a working memory criterion and two or more factors, one factor being a viral infection criterion and another factor being an antiviral drug use criterion. In aspects of these embodiments, the working memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, and the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks.

[0085] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by the presence of a combined episodic memory and working memory criterion and two or more factors, one factor being a viral infection criterion and another factor being an antiviral drug use criterion. In aspects of these embodiments, the combined episodic memory and working memory criterion comprises a score one or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion is at least one viral infection in the past 10 years, and the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks.

[0086] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by the presence of an episodic memory criterion and three or more factors, one factor being an inflammation criterion, another factor being a viral infection criterion, and a third factor being an antiviral drug use criterion. In aspects of these embodiments, the episodic memory criterion comprises a score 1 or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0087] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by the working memory criterion and the presence of three or more factors, one factor being an inflammation criterion, another factor being a viral infection criterion, and a third factor being an antiviral drug use criterion. In aspects of these embodiments, the working memory criterion comprises a score of 1 or more standard deviations below the normative mean (Z-score transformation of -1 or less), the viral infection criterion comprises at least one viral infection in the past 10 years, the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or more.

[0088] In some embodiments, the predefined threshold criterion for identifying or confirming that an individual has PVCI is determined by a combined episodic memory and working memory criterion and the presence of three or more factors, one factor being an inflammation criterion, another factor being a viral infection criterion, and a third factor being an antiviral drug use criterion. In aspects of these embodiments, the combined episodic memory and working memory criterion comprises a score one or more standard deviations below the normative mean (Z-score transformation less than or equal to -1), the viral infection criterion comprises at least one viral infection in the past 10 years, the antiviral drug use criterion comprises use of an antiviral drug in the past 8 weeks, and the inflammation criterion comprises the presence of a CRP blood level of 10 mg / L or greater.

[0089] In addition, the risk stratification matrix can further stratify an individual's PVCI diagnostic score to identify or confirm the presence of a PVCI. In some embodiments, the risk stratification matrix disclosed herein can apply a weighted score to each threshold criterion value assigned to the episodic memory score, the working memory score, the combined episodic and working memory score, each additional risk-related factor, or any combination thereof. In some embodiments, the weighted score assigned to each threshold criterion value by the risk stratification matrix is ​​developed from data obtained from information compiled on the PVCI, such as information obtained from observational studies, interventional studies, and clinical studies.

[0090] If an individual's PVCI diagnostic score meets certain predefined threshold criteria, the risk stratification matrix disclosed herein indicates that the individual has PVCI. In addition, depending on which predefined threshold criteria are met, the risk stratification matrix disclosed herein can identify the degree of cognitive impairment.

[0091] In some embodiments, the weighted scores assigned to each threshold criterion value by the risk stratification matrix for the episodic memory score, working memory score, combined episodic and working memory score, and each additional risk-related factor to arrive at a PVCI diagnostic score that identifies or confirms the presence of PVCI in an individual are based on Table 2.

[0092] [Table 2] TIFF2024504116000009.tif167169

[0093] As described in Tables 1 and 2, the disclosed system, method, and use may therefore apply weights or weighted scores based on the baseline values ​​of the risk stratification matrix. This includes matrices performed in conjunction with and evaluated against one or both of the episodic memory score and the working memory score to determine a PND risk score for determining an individual's risk status susceptibility to PND, and a PVCI diagnostic score for determining or confirming an individual's diagnosis of PVCI. In the case of PND, criteria such as inflammation level, age, BMI, education, drug use, and disease diagnosis are variables that include a clinical or patient-based approach to determining a PND risk score. In the case of PVCI, criteria such as inflammation level, use of antiviral drugs, and diagnosis or history of viral infection are variables that include a clinical or patient-based approach to determining a PVCI diagnostic score. In either case, these variables are predictors, and once weights or weighted scores are assigned based on baseline values, they become indices that allow a mathematical function including risk stratification to model the risk score for each patient.

[0094] It is understood that other predictor variables can be utilized instead of or in addition to the variables listed herein, and thus the present invention is not limited to any particular predictor variable or set of predictor variables mentioned herein. For example, other medications and other disease diagnoses can be associated with the PND risk score or PVCI diagnostic score and can be modeled in the risk stratification matrix and as such can be assigned different weighted scores based on their particular characteristics. Non-limiting predictor variables include additional or alternative cognitive domains including memory, psychomotor speed, attention, executive function, social and emotional cognition, preoperative delirium, depression scale, anxiety scale, pain scale, sedation scale, general health scale, type of surgery, length of surgery, type of anesthesia, length of anesthesia, medication scale, medication scale, one or more neuroimaging parameters, one or more inflammatory cytokines, quality of life assessment, disability (ADL / IADL), demographic information, socioeconomic information, one or more comorbidities, one or more lifestyle risks, frailty, hypotension, respiratory complications, and subdomains of IQ. In any case, the matrices for the episodic memory scores and working memory scores may include other variables and have other associated weighted scores.

[0095] A risk stratification matrix is ​​an approach to model such variables, which is the application of mathematical functions that assess the importance of clinical characteristics associated with PND and PCVI, such as, for example, episodic memory score, working memory score, episodic memory and working memory combined score, one or more risk-related factors, or a combination thereof. These mathematical functions are used to determine the associated weighted score of each variable. However, it should be understood that such weighted scores may be adjusted according to different reference values, and thus the mathematical function may include one or more techniques for evaluating the associated weighted score based on the variance within each variable. Other mathematical functions may also be used to evaluate such associated weighted scores, such as functions that take into account the time changes in variables that may be related to the overall assessment of PND or PCCI, such as, for example, the variability of a patient's BMI or drug dose. Furthermore, other mathematical approaches may be utilized, such as regression models to estimate relationships between variables, Bayesian models to update weights or weighted scores as more clinical data becomes available from more patients, and any other approach that improves the ability to determine the relevance of variables and the process of weighting their importance to achieve a more accurate risk score, as well as the ability to assess episodic and / or working memory scores for a matrix of such variables.

[0096] Mathematical functions such as regression and Bayesian analysis are machine learning techniques that computer systems can apply to improve the process of determining the relevance of variables and weighting their importance. Thus, the present invention can include the application of machine learning and artificial intelligence to assess risk scores for PND and PVCI. Such application of machine learning and artificial intelligence can be represented in the machine learning modeling layer in conjunction with the risk stratification matrix.

[0097] The machine learning modeling layer may be composed of one or more neural networks that further evaluate the variables to execute risk stratification matrices and other specific algorithms to derive PND or PVCI risk scores. A neural network is composed of nodes, which are computational units with one or more biased input / output connections and output connections, which are transfer (or activation) functions that combine the inputs in some way, and variables may be assigned. The nodes are then organized into layers that form a neural network. There are many types of neural networks, which are computational systems that "learn" to perform tasks without being programmed with rules specific to the task, based on the example. A neural network is based on an array of connected aggregate nodes (or "neurons") that send signals to each other in multiple layers through connections. As mentioned above, the connections are activation or transfer functions that "fire" these nodes and combine the inputs according to a mathematical formula or formula. Different types of neural networks generally have different configurations of these layers of connected and aggregated nodes, but they may generally be described as an input layer, an intermediate layer or "hidden layer", and an output layer. These layers may perform different transformations on their various inputs using different mathematical calculations or functions. Signals travel between these layers, from the input layer through the hidden layers to the output layer, and may traverse layers and nodes multiple times. Signals are sent between nodes via connections, and the output of each node is calculated with a nonlinear function that sums all the inputs to that node. Weight matrices and biases are typically applied to each node and each connection, and these weights and biases are adjusted as the neural network processes the inputs and sends them across the nodes and connections. These weights represent the increase or decrease in the strength of the signal at a particular connection. Additionally, nodes may have thresholds, so that a signal is sent only if the aggregated output at that node exceeds that threshold. The weights represent the time it takes for the activation function to take place, and the bias represents when in time such a function begins, and together these functions serve to minimize the gradient over time.At least in the case of weights, the weights can be initialized and changed (i.e., decayed) over time as the system learns what the weights should be and how they should be adjusted, for example, based on particular values ​​of variables. In other words, neural networks evolve as they learn, and the mathematical formulas and functions that comprise the neural network design can change over time as the system itself improves.

[0098] Aspects of the present disclosure disclose providing treatment recommendations based on an individual's risk status susceptibility to PND. Both preclinical and clinical studies suggest that immune activation and neuroinflammation play a fundamental role in the pathogenesis of PND. For example, these studies have repeatedly demonstrated that there is a direct correlation between inflammatory responses and cognitive function after surgery, and that individuals with higher inflammatory cytokines after surgery are at higher risk for PND. Mechanistically, surgery itself may be a trigger for PND, as the resulting tissue damage induces an inflammatory process, triggering the release of IL-1 and TNF-a from endothelial cells and phagocytes, triggering a cascade of downstream signaling events. Although the blood-brain barrier (BBB) ​​tightly regulates the passage of inflammatory factors into the CNS, peripheral inflammatory conditions may compromise the integrity of the BBB. Such a compromise allows the CNS to gain access to peripheral inflammatory factors, causing neuroinflammation, which in turn triggers the expression of inflammatory cytokines in the CNS, causing further neuroinflammation within the CNS. The hippocampus contains the highest density of cytokine (inflammatory) receptors and is particularly vulnerable to the harmful effects of inflammation. This brain region is well established for its role in learning and memory formation. Therefore, increased brain inflammation levels can negatively affect the hippocampus and cause the decline of these cognitive processes.

[0099] In addition to neuroinflammation as a result of surgical procedures, the use of anesthetics before surgery is also thought to contribute to the development of PND because anesthetics penetrate the CNS and directly affect neuronal signaling and activity. Anesthesia exhibits time- and dose-dependent neurotoxicity, causing clinically significant neuronal damage. In addition, perioperative immunosuppression is due to anesthesia and neuroendocrine stress exerted through activation of the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Thus, the use of anesthetics during surgery also appears to cause neuroinflammation.

[0100] Although PND may accelerate the development of existing neurodegenerative diseases, it is not itself a neurodegenerative disease such as Alzheimer's or Parkinson's. As mentioned above, PND appears to be caused via surgical or anesthetic-induced injury that triggers a neuroinflammatory response in the brain that affects hippocampal learning and memory function. The cognitive impairment associated with PND is either transient or chronic. On the other hand, neurodegenerative diseases are not temporary, and the chronic cognitive impairment seen in some PND individuals does not coincide with a degenerative process in nature. Therefore, PND is not a neurodegenerative disease.

[0101] Fibrates are a type of amphipathic carboxylic acid that has the property of modifying lipid levels. Non-limiting examples of fibrates include bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, and simfibrate. These drugs are considered hypolipidemic drugs because they are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol). Fibrates activate peroxisome proliferator-activated receptors (PPARs), especially PPARα. PPARs are a type of intracellular receptor that regulates carbohydrate and fat metabolism, as well as the differentiation of adipose tissue.

[0102] Besides PPAR agonism, the anti-inflammatory effects of fibrates are influenced by their ability to selectively inhibit cyclooxygenase 2 (COX2) activity, as well as the nonsteroidal anti-inflammatory drug (NSAIDs) effects through cannabinoid receptor type 2 (CB2) agonism. CB2 is expressed in peripheral immune cells such as monocytes, macrophages, B cells, and T cells, as well as microglia in the brain. The combination of these three complementary pharmacological actions has been proposed for complete resolution of inflammation, without the possibility of gastric mucosal erosions and cardiac damage.

[0103] Two examples of fibrates include fenofibrate and fenofibric acid. Fenofibrate is a fibric acid derivative that contains fenofibric acid bound to an isopropyl ester. Therefore, fenofibrate can be considered a prodrug of fenofibric acid. Fenofibrate has a logP of 5.2, whereas fenofibric acid has a logP of 3.9. The chemical structures of these two compounds are shown below. Tricor, a commercially available compound, is a fenofibrate approved for the treatment of abnormal blood lipid levels and has marketing authorization to aid in the use of it to extend the life expectancy of myocardial infarction patients. [ka]

[0104] In some embodiments, providing a treatment recommendation based on the individual's risk status susceptibility to PND includes i) no treatment recommendation, or ii) treatment with a fibrate. In aspects of these embodiments, in a risk status PND assessment that indicates the individual meets the threshold criteria matrix of Table 1, the treatment recommendation includes treatment with a fibrate. In other aspects of these embodiments, in a risk status PND assessment that indicates the individual meets the threshold criteria matrix of Table 2, the treatment recommendation includes treatment with a fibrate.

[0105] In other aspects of these embodiments, in a risk status PND assessment indicating that an individual is classified as having preoperative neurocognitive impairment, the treatment recommendation comprises treatment with a fibrate. In yet other aspects of these embodiments, in a risk status PND assessment indicating that an individual is classified as having delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), the treatment recommendation comprises treatment with a fibrate. In yet other aspects of these embodiments, in a risk status PND assessment indicating that an individual is classified as having mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), the treatment recommendation comprises treatment with a fibrate. In other aspects of these embodiments, in a risk status PND assessment indicating that an individual is classified as having severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), the treatment recommendation comprises treatment with a fibrate. In yet other aspects of these embodiments, in a risk status PND assessment indicating that an individual is classified as having mild neurocognitive impairment (or long-term postoperative cognitive impairment), the treatment recommendation comprises treatment with a fibrate. In still other aspects of these embodiments, in a risk status PND assessment that indicates the individual is classified as having severe neurocognitive impairment (or long-term post-operative cognitive impairment), the treatment recommendation includes treatment with a fibrate.

[0106] Aspects of the present disclosure disclose methods of treating individuals at risk of or suffering from PND or PVCI. In some embodiments, the disclosed methods comprise, consist essentially of, or consist of administering to an individual at risk of or suffering from PND or PVCI an effective amount of a composition comprising a fibrate. In some embodiments, the compositions disclosed herein comprise, consist essentially of, or consist of bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibrate acid, gemfibrozil, lonifibrate, or simfibrate. In a preferred embodiment, the compositions disclosed herein are fenofibrate or fenofibric acid.

[0107] Aspects of the present disclosure disclose an effective amount of a fibrate for use in treating individuals at risk for or suffering from PND or PVCI. In some embodiments, the compositions disclosed herein comprise, consist essentially of, or consist of bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibrate acid, gemfibrozil, lonifibrate, or simfibrate. In a preferred embodiment, the compositions disclosed herein are fenofibrate or fenofibric acid.

[0108] Aspects of the present specification disclose the use of a fibrate in the manufacture of a medicament for treating an individual at risk for or suffering from PND or PVCI. In some embodiments, the composition disclosed herein comprises, consists essentially of, or consists of bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibrate acid, gemfibrozil, lonifibrate, or simfibrate. In a preferred embodiment, the composition disclosed herein is fenofibrate or fenofibric acid.

[0109] The compositions or medicaments disclosed herein refer to compositions or medicaments that contain an effective concentration of the fibrates disclosed herein. Preferably, the compositions or medicaments disclosed herein do not cause adverse, allergic, or other unexpected or undesirable reactions when administered to an individual. The compositions or medicaments disclosed herein are useful for medical and veterinary applications. The compositions or medicaments disclosed herein can be formulated into any form that allows for administration of the compositions or medicaments disclosed herein in a manner that achieves the desired beneficial effect. In one embodiment, the compositions or medicaments disclosed herein can be formulated into, for example, a single-phase formulation, a two-phase formulation that includes a middle phase and a dispersed phase, or a multi-phase formulation. In another embodiment, the compositions or medicaments disclosed herein can be formulated into, for example, a liquid composition or medicament, a colloid composition or medicament, a semi-solid composition or medicament, or a solid composition or medicament. In another embodiment, the compositions or medicaments disclosed herein can be formulated into, for example, a liquid aerosol, a foam, an emulsion, a gel, a sol, or a solid sol. The compositions or medicaments disclosed herein may be formulated as immediate release or controlled release formulations. The compositions or medicaments disclosed herein may be administered to an individual alone, or in combination with other supplementary active compounds, drugs, agents or hormones.

[0110] The present specification partially discloses an effective amount. For the method or use disclosed herein, the fibrate disclosed herein is used or administered in an effective amount. The effective amount of the fibrate disclosed herein is an amount sufficient to treat PND or pathology, or PVCI or pathology. In an aspect of this embodiment, the effective amount of the fibrate disclosed herein is an amount sufficient to reduce one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology, or an amount sufficient to protect an individual from one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology. As used herein, the term "effective amount" includes the terms "sufficient amount", "therapeutically sufficient amount", "therapeutically effective amount", "effective amount", or "therapeutically effective dose", and refers to the minimum amount of the fibrate disclosed herein required to achieve a desired therapeutic effect, including an amount sufficient to reduce or inhibit one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology.

[0111] In aspects of this embodiment, an effective amount of a fibrate disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology, by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, an effective amount of a fibrate disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology, by, for example, up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100%. In yet another aspect of this embodiment, an effective amount of a fibrate disclosed herein can provide a therapeutic effect against one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology, for example, by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about Reduces or inhibits by 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. In yet another aspect of this embodiment, an effective amount of a fibrate disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with PND or pathology, or PVCI or pathology, for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0112] The actual effective amount of a fibrate disclosed herein to be used or administered to an individual can be determined by one of skill in the art by considering factors including, but not limited to, the type of PND or pathology or PVCI or pathology, the specific physiological condition or symptom associated with the PND or pathology or PVCI or pathology, the cause of the PND or pathology or PVCI or pathology, the severity of the PND or pathology or PVCI or pathology, the degree of relief desired of the PND or pathology or PVCI or pathology, the duration of relief desired of the PND or pathology or PVCI or pathology, the particular fibrate used in the disclosed methods or uses, the excretion rate of the particular fibrate used in the disclosed methods or uses, the efficacy of the particular fibrate used in the disclosed methods or uses, the nature of other compounds included in the disclosed methods or uses, the particular route of administration used in the disclosed methods or uses, the particular characteristics, medical history and risk factors of the individual, such as age, weight, general health and the like, or a combination thereof. Furthermore, when repeated administration of the disclosed methods or uses is employed, the actual effective amount will further depend on factors including, but not limited to, the frequency of administration, the half-life of the fibrate disclosed herein used in the disclosed methods or uses, or any combination thereof.

[0113] The actual effective amount of the fibrates disclosed herein is determined by routine screening procedures used to evaluate the activity and efficacy of the fibrates disclosed herein. Such screening procedures are well known to those skilled in the art. For example, those skilled in the art know that the effective amount of the fibrates disclosed herein can be estimated from in vitro assays and in vivo administration studies using animal models before administration to humans. Due to differences in the efficiency of various administration routes, it should be expected that there will be a large variation in the effective amount required. For example, oral use or administration will generally be expected to require higher dosage levels than use or administration by intravenous or intravitreal injection. Variations in these dosage levels can be adjusted using standard empirical optimization routines that are well known to those skilled in the art. In addition, variations in dosage levels can be adjusted using standard empirical optimization routines that are well known to those skilled in the art. Fibrates disclosed herein that have a higher level of activity and / or efficacy can be used in a smaller effective amount, while fibrates that have a lower level of activity and / or efficacy may require a larger effective amount to achieve the same control effect. Such effective amounts can be determined by routine assays / measurements of the activity and / or efficacy of the fibrates disclosed herein. The exact therapeutically effective dose levels and patterns are preferably determined by the attending medical professional, taking into account the factors identified above.

[0114] Dosing can be a single dose or cumulative (continuous dosing), as can be easily determined by one of skill in the art. For example, the treatment of PND or pathology, or PVCI or pathology, can include a one-time administration of the fibrate used in the disclosed methods or uses. As a non-limiting example, the fibrate used in the disclosed methods or uses can be administered to an individual once, for example, as a single injection or deposition. Alternatively, the treatment of PND or pathology, or PVCI or pathology can include multiple administrations of the fibrate used in the disclosed methods or uses administered over a wide range of time periods, for example, daily, every other day, every third day, once a week, multiple times a week, once a month, multiple times a month, once a year, or multiple times a year. As a non-limiting example, the fibrate used in the disclosed methods or uses can be administered to an individual once. The timing of administration can vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, a fibrate used in the disclosed methods or uses can be administered to an individual daily, every other day, every three days, once a week, multiple times a week, once a month, multiple times a month, once a year, or multiple times a year for an indefinite period of time, or until the individual no longer requires treatment for the PND or pathology, or PVCI or pathology. One of skill in the art will recognize that an individual's condition can be monitored throughout the course of treatment, and that the use or administration of a fibrate used in the disclosed methods or uses can be adjusted accordingly.

[0115] The aspects of the present specification can also be explained by the following embodiments. 1. A method for identifying an individual at risk for perioperative neurocognitive impairment, comprising: a) determining an episodic memory reference value, a working memory reference value, or a combined episodic memory and working memory reference value for the individual; b) determining a PND risk score by comparing the episodic memory reference value, the working memory reference value, or the combined episodic memory and working memory reference value to a normative mean; and c) determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PND risk score to a predefined threshold criterion. Alternatively, steps b) and c) are performed using an episodic memory reference value, a working memory reference value, or a combined episodic memory and working memory reference value already determined for the individual. Thus, a method for identifying an individual at risk for perioperative neurocognitive impairment may include: a) providing an episodic memory baseline value, a working memory baseline value, or a combined episodic memory and working memory baseline value previously determined for the individual; b) determining a PND risk score by comparing the episodic memory baseline value, the working memory baseline value, or the combined episodic memory and working memory baseline value to a normative mean; and c) determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PND risk score to a predefined threshold criteria. 2. The method of embodiment 1, wherein the episodic memory baseline is obtained by measuring the individual's episodic memory using an episodic memory test. 3. The method of embodiment 1, wherein the working memory baseline is obtained by measuring the individual's working memory using a working memory test. 4. The method of embodiment 1, wherein the combined episodic memory and working memory baseline is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test. 5. The method of embodiment 2 or 4, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test. 6. The method of embodiment 3 or 4, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test. 7. The method of any one of the preceding embodiments, further comprising, prior to step (b), determining a weighted score for the episodic memory metric, the working memory metric, or the combined episodic memory and working memory metric. 8. The method of any one of embodiments 1-7, wherein the individual's risk state susceptibility is identified as being at high risk for PND when a) the episodic memory criterion is more than one standard deviation below the normative mean, or b) the working memory criterion is more than one standard deviation below the normative mean, or c) the combined episodic memory and working memory criterion is more than one standard deviation below the normative mean. 9. The method of any one of embodiments 1-7, wherein the individual's risk state susceptibility is identified as being at moderate risk for PND when a) the episodic memory criterion is below the normative mean but less than one standard deviation below the normative mean, or b) the working memory criterion is below the normative mean but less than one standard deviation below the normative mean, or c) the combined episodic memory and working memory criterion is below the normative mean but less than one standard deviation below the normative mean. 10. The method of any one of embodiments 1 to 9, further comprising, prior to step (b), determining a baseline value of one or more risk-associated factors for perioperative neurocognitive impairment in the individual. 11. The method of embodiment 10, wherein determining the PND risk score is performed in conjunction with comparing the reference values ​​of each of one or more risk-associated factors to normative means. 12. The method of embodiment 10 or 11, wherein the one or more risk-associated factors include inflammation criteria, age criteria, body mass index (BMI) criteria, education criteria, drug use criteria, disease diagnosis or medical history criteria, or any combination thereof. 13. The method of any one of embodiments 10-12, further comprising determining a weighted score for each of the reference values ​​of one or more risk-related factors. 14. The method of any one of embodiments 1-13, wherein the PND risk score is determined using the predefined threshold criteria in Table 1. 15. An individual's risk state susceptibility is determined by: a) an episodic memory baseline that is ≥1 standard deviation below the normative mean; baseline values ​​for one or more risk factors that are indicative of high inflammation; an age baseline of ≥60 years; a BMI baseline of ≥30; an education baseline of ≤12 years of formal education; a medication use baseline of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic-based medications in the past 8 weeks; and a history of psychiatric, neurological, diabetes, or mental disorders. or b) a working memory baseline more than one standard deviation below the normative mean and baseline values ​​for one or more risk factors including inflammation baseline indicating high inflammation, age baseline 60 years or older, BMI baseline 30 or higher, education baseline 12 years or less of formal education, use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antidysrhythmics, antidepressants, antimuscarinics, antidepressants, antimuscarinics, antidysrhythmics, antihypertensive ... or c) a combined episodic and working memory measure is more than one standard deviation below the normative mean and the measures for one or more risk factors include an inflammation measure indicating high inflammation, an age measure 60 years or older, a BMI measure 30 or higher, an education measure of 12 years or less of formal education, or a medication use measure for use of antihypertensives, antiparkinsonians, or anticholinergic-based medications, and a disease diagnosis or medical history measure for the presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune diseases, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse; or 15. The method of any one of embodiments 10-14, wherein the patient is identified as at very high risk for PND when the patient's clinical profile includes a baseline value of 100 mg / kg / day, a baseline value of medication use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and a baseline value of disease diagnosis or medical history of presence of psychiatric disorder, neurological disease, diabetes, metabolic syndrome, autoimmune disease, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse. 16. The method of any one of embodiments 10-14, wherein the individual's risk state susceptibility is identified as being at high risk for PND when: a) the episodic memory reference value is more than one standard deviation below the normative mean and the inflammation reference value of a blood level of CRP of 10 mg / L or more; or b) the working memory reference value is more than one standard deviation below the normative mean and the inflammation reference value of a blood level of CRP of 10 mg / L or more; or c) the combined episodic memory and working memory reference value is more than one standard deviation below the normative mean and the inflammation reference value of a blood level of CRP of 10 mg / L or more; or d) the episodic memory reference value is more than one standard deviation below the normative mean and the reference value for age 60 years or older; or e) the working memory reference value is more than one standard deviation below the normative mean and the reference value for age 60 years or older; or f) the combined episodic memory and working memory reference value is more than one standard deviation below the normative mean and the reference value for age 60 years or older. 17. An individual's risk state sensitivity is when: a) the episodic memory measure is below the normative mean but less than one standard deviation below the normative mean and the inflammatory measure for a blood level of CRP ≥10 mg / L; or b) the working memory measure is below the normative mean but less than one standard deviation below the normative mean and the inflammatory measure for a blood level of CRP ≥10 mg / L; or c) the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean and the inflammatory measure for a blood level of CRP ≥10 mg / L. or d) the episodic memory measure is below the normative mean but less than one standard deviation below the normative mean and age 60 years or older; or e) the working memory measure is below the normative mean but less than one standard deviation below the normative mean and age 60 years or older; or f) the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean and age 60 years or older. 18. An individual's risk status susceptibility is determined when: a) the episodic memory baseline exceeds the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline of CRP blood levels less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, an education baseline of 12 or more years of formal education, a substance use baseline of no substance use for a risk status, and a disease diagnosis or medical history baseline of no disease diagnosis or medical history for a risk status; or b) the working memory baseline exceeds the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline of CRP blood levels less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, and an education baseline of 12 or more years of formal education. , or c) when the episodic memory and working memory combined criteria are above the normative mean and the criteria for one or more risk associated factors include an inflammation criteria for blood levels of CRP less than 10 mg / L, an age criteria for age less than 60 years, a BMI criteria for BMI less than 30, an education criteria for 12 or more years of formal education, a drug use criteria for no risk condition drug use, and a disease diagnosis or history criteria for no risk condition disease diagnosis or history. 19. The method of any one of embodiments 1-18, wherein the individual's risk status susceptibility classifies the individual as one for which additional monitoring is recommended, treatment of PND is recommended prior to surgery, and / or treatment of PND is recommended following surgery. 20. The method of any one of embodiments 1-19, wherein the risk status severity classifies the individual as having preoperative neurocognitive impairment, postoperative delirium, delayed postoperative neurocognitive recovery, mild postoperative neurocognitive impairment, severe postoperative neurocognitive impairment, mild neurocognitive impairment, or severe neurocognitive impairment. 21. The method of any one of embodiments 1-20, further providing a treatment recommendation based on the individual's risk status susceptibility. 22. The method of embodiment 21, wherein the treatment recommendation comprises no treatment recommendation or treatment with a fibrate. 23. The method of embodiment 21, wherein when the individual's risk status susceptibility is identified as being at very high risk for PND, at high risk for PND, or at moderate risk for PND, the treatment recommendation comprises treatment with one or more fibrates. 24. The method of embodiment 19, wherein a) when the individual's risk status susceptibility indicates that the individual has preoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or b) when the individual's risk status susceptibility indicates that the individual has delayed postoperative neurocognitive recovery, the treatment recommendation comprises treatment with one or more fibrates; or c) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or d) when the individual's risk status susceptibility indicates that the individual has severe postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or e) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or f) when the individual's risk status susceptibility indicates that the individual has severe postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates. 25. The method of embodiment 19, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. 26. A method for identifying and / or confirming an individual at risk for post-viral cognitive impairment (PVCI), comprising: a) determining an episodic memory reference value, a working memory reference value, or a combined episodic memory and working memory reference value for the individual; b) determining a PVCI diagnostic score by comparing the episodic memory score, the working memory score, or the combined episodic memory and working memory reference value to a normative mean; and c) identifying or confirming a diagnosis in the individual of PVCI by comparing the PVCI diagnostic score to a predefined threshold criterion. Alternatively, steps b) and c) are performed using an episodic memory reference value, a working memory reference value, or a combined episodic memory and working memory reference value already determined for the individual. Thus, a method for identifying and / or confirming an individual at risk for post-viral cognitive impairment (PVCI) may include: a) determining an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline previously determined for the individual; b) determining a PVCI diagnostic score by comparing the episodic memory score, the working memory score, or the combined episodic memory and working memory baseline to a normative mean; and c) identifying or confirming a diagnosis of PVCI in the individual by comparing the PVCI diagnostic score to a predefined threshold criteria. 27. The method of embodiment 26, wherein the episodic memory baseline is obtained by measuring the individual's episodic memory using an episodic memory test. 28. The method of embodiment 26, wherein the working memory baseline is obtained by measuring the individual's working memory using a working memory test. 29. The method of embodiment 26, wherein the combined episodic memory and working memory baseline is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test. 30. The method of embodiment 27 or 29, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test. 31. The method of embodiment 28 or 29, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test. 32. The method of any one of embodiments 26-31, further comprising, prior to step (b), determining a weighted score for the episodic memory metric, the working memory metric, or the combined episodic memory and working memory metric. 33. The method of any one of embodiments 26-32, wherein a PVCI diagnosis is identified or confirmed when a) the episodic memory criterion is more than one standard deviation below the normative mean, or b) the working memory criterion is more than one standard deviation below the normative mean, or c) the combined episodic memory and working memory criterion is more than one standard deviation below the normative mean. 34. The method of any one of embodiments 26-33, further comprising, prior to step (b), determining a baseline value of one or more risk-related factors for PVCI in the individual. 35. The method of embodiment 34, wherein determining the PVCI diagnostic score is performed in conjunction with comparing the reference values ​​of each of one or more risk-related factors to normative means. 36. The method of embodiment 34 or 35, wherein the one or more risk-associated factors include inflammation baseline, antiviral drug use baseline, viral infection diagnosis or medical history baseline, or any combination thereof. 37. The method of any one of embodiments 34-36, further comprising determining a weighted score for each of the reference values ​​of one or more risk-associated factors. 38. The method of any one of embodiments 26-37, wherein the PVCI diagnostic score is determined using the predefined threshold criteria of Table 2. 39. The method of any one of embodiments 20-27, wherein a PVCI diagnosis is identified or confirmed when a) the episodic memory criterion is more than one standard deviation below the normative mean and one or more risk status factors are present, or b) the working memory criterion is more than one standard deviation below the normative mean and one or more risk status factors are present, or c) the combined episodic memory and working memory criterion is more than one standard deviation below the normative mean and one or more risk status factors are present, or d) the episodic memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present, or e) the working memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present, or f) the combined episodic memory and working memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present. 40. The method of any one of embodiments 26-39, wherein the PVCI diagnostic score classifies the individual as recommending additional monitoring and / or treatment of a post-infection PVCI. 41. The method of any one of embodiments 26-40, further providing a treatment recommendation based on the individual's risk status susceptibility. 42. The method of embodiment 41, wherein the treatment recommendation comprises no treatment recommendation or treatment with a fibrate. 43. The method of embodiment 42, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

[0116] Aspects of the present specification can also be described by the following embodiments. 1. A method for identifying an individual at risk of perioperative neurocognitive impairment, comprising: a) determining an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline for the individual; b) determining baseline values ​​of one or more risk-related factors for perioperative neurocognitive impairment in the individual; c) determining a PND risk score by i) comparing the episodic memory baseline, the working memory baseline, or the combined episodic memory and working memory baseline with a normative mean, and ii) comparing the baseline values ​​of each of the one or more risk-related factors with the normative mean; and d) determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PND risk score with a predefined threshold criterion. Alternatively, steps b), c), and d) are performed using the episodic memory baseline, the working memory baseline, or the combined episodic memory and working memory baseline already determined for the individual. Thus, a method for identifying an individual at risk of perioperative neurocognitive impairment may include: a) providing an episodic memory baseline value, a working memory baseline value, or a combined episodic memory and working memory baseline value determined for the individual; b) determining baseline values ​​of one or more risk associated factors for perioperative neurocognitive impairment in the individual; c) determining a PND risk score by i) comparing the episodic memory baseline value, the working memory baseline value, or the combined episodic memory and working memory baseline value to a normative mean, and ii) comparing the baseline value of each of the one or more risk associated factors to the normative mean; and d) determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PND risk score to a predefined threshold criteria. 2. The method of embodiment 1, wherein the episodic memory baseline is obtained by measuring the individual's episodic memory using an episodic memory test. 3. The method of embodiment 1, wherein the working memory baseline is obtained by measuring the individual's working memory using a working memory test. 4. The method of embodiment 1, wherein the combined episodic memory and working memory baseline is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test. 5. The method of embodiment 2 or 4, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test. 6. The method of embodiment 3 or 4, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test. 7. The method of any one of embodiments 1-6, wherein the one or more risk-associated factors include inflammation criteria, age criteria, body mass index (BMI) criteria, education criteria, drug use criteria, disease diagnosis or medical history criteria, or any combination thereof. 8. The method of any one of embodiments 1-7, further comprising determining a weighted score for the episodic memory baseline, the working memory baseline, the combined episodic memory and working memory baseline, the baseline for each of the one or more risk-related factors, or any combination thereof. 9. The method of any one of embodiments 1-8, wherein the PND risk score is determined using the predefined threshold criteria in Table 1. 10. An individual's risk state susceptibility is determined to be: a) an episodic memory baseline ≥ 1 standard deviation below the normative mean; baseline values ​​for one or more risk factors including inflammation baseline indicating high inflammation; age baseline ≥ 60 years; BMI baseline ≥ 30; education baseline ≤ 12 years of formal education; medication use baseline for use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic-based medications in the past 8 weeks; and no psychiatric, neurological, diabetic, or mental disorders. or b) a working memory baseline more than one standard deviation below the normative mean and baseline values ​​for one or more risk factors including inflammation baseline indicating high inflammation, age baseline 60 years or older, BMI baseline 30 or higher, education baseline 12 years or less of formal education, use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antidepressants, antianxiety medications, antidepressants, antimuscarinics ... or c) a combined episodic and working memory measure is more than one standard deviation below the normative mean and the measures for one or more risk factors include an inflammation measure indicating high inflammation, an age measure 60 years or older, a BMI measure 30 or higher, and 12 years or less of formal education. The method of any one of embodiments 1-9, wherein the patient is identified as being at very high risk for PND when the baseline includes a medication use baseline of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and a disease diagnosis or history of presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune diseases, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse. 11. An individual's risk state susceptibility is determined to be: a) when the episodic memory baseline is more than one standard deviation below the normative mean; or b) when the working memory baseline is more than one standard deviation below the normative mean; or c) when the combined episodic memory and working memory baseline is more than one standard deviation below the normative mean; or d) when the episodic memory baseline is more than one standard deviation below the normative mean and an inflammation baseline of 10 mg / L blood level of CRP; or e) when the working memory baseline is more than one standard deviation below the normative mean and an inflammation baseline of 10 mg / L blood level of CRP; or f) when the episodic memory baseline is more than one standard deviation below the normative mean and an inflammation baseline of 10 mg / L blood level of CRP; The method of any one of embodiments 1-9, wherein the subject is identified as being at high risk for PND when the combined memory and working memory reference value is more than one standard deviation below the normative mean and an inflammation reference value of 10 mg / L blood levels of CRP, or g) the episodic memory reference value is more than one standard deviation below the normative mean and an inflammation reference value for age 60 years or older, or h) the working memory reference value is more than one standard deviation below the normative mean and an inflammation reference value for age 60 years or older, or i) the combined episodic memory and working memory reference value is more than one standard deviation below the normative mean and an inflammation reference value for age 60 years or older. 12. An individual's risk state susceptibility is determined to be: a) when the episodic memory measure is below the normative mean but less than one standard deviation below the normative mean; or b) when the working memory measure is below the normative mean but less than one standard deviation below the normative mean; or c) when the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean; or d) when the episodic memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure with a blood level of CRP ≥ 10 mg / L; or e) when the working memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure with a blood level of CRP ≥ 10 mg / L; or f) The method of any one of embodiments 1-9, wherein the subject is identified as being at moderate risk for PND when the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure of blood levels of CRP equal to or greater than 10 mg / L; or g) the episodic memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure of blood levels of CRP equal to or greater than 10 mg / L; or h) the working memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure of age 60 years or older; or i) the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure of blood levels of CRP equal to or greater than 10 mg / L; 13. The individual's risk status susceptibility is determined to be: a) when the episodic memory baseline exceeds the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline of CRP blood levels less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, an education baseline of 12 or more years of formal education, a substance use baseline of no risk status substance use, and a disease diagnosis or medical history baseline of no risk status disease diagnosis or medical history; or b) when the working memory baseline exceeds the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline of CRP blood levels less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, and an education baseline of 12 or more years of formal education. or c) when the episodic memory and working memory combined baseline is above the normative mean and the baseline values ​​for one or more risk associated factors include an inflammation baseline value of blood levels of CRP less than 10 mg / L, an age baseline value of less than 60 years, a BMI baseline value of less than 30, an education baseline value of 12 or more years of formal education, a drug use baseline value of no drug use for a risk condition, and a disease diagnosis or history baseline value of no disease diagnosis or history for a risk condition. 14. The method of any one of embodiments 1-13, wherein the individual's risk status susceptibility classifies the individual as one for which additional monitoring is recommended, treatment of PND is recommended prior to surgery, and / or treatment of PND is recommended following surgery. 15. The method of any one of embodiments 1-14, wherein the risk status severity classifies the individual as having preoperative neurocognitive impairment, postoperative delirium, delayed postoperative neurocognitive recovery, mild postoperative neurocognitive impairment, severe postoperative neurocognitive impairment, mild neurocognitive impairment, or severe neurocognitive impairment. 16. The method of any one of embodiments 1-15, further providing a treatment recommendation based on the individual's risk status susceptibility. 17. The method of embodiment 16, wherein the treatment recommendation comprises no treatment recommendation or treatment with one or more fibrates. 18. The method of embodiment 16, wherein when the individual's risk status susceptibility is identified as being at very high risk for PND, at high risk for PND, or at moderate risk for PND, the treatment recommendation comprises treatment with one or more fibrates. 19. The method of embodiment 15, wherein a) when the individual's risk status susceptibility indicates that the individual has preoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or b) when the individual's risk status susceptibility indicates that the individual has delayed postoperative neurocognitive recovery, the treatment recommendation comprises treatment with one or more fibrates; or c) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or d) when the individual's risk status susceptibility indicates that the individual has severe postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or e) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates; or f) when the individual's risk status susceptibility indicates that the individual has severe postoperative neurocognitive impairment, the treatment recommendation comprises treatment with one or more fibrates. 20. The method of any one of embodiments 17-19, wherein the one or more fibrates comprises bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. 21. A method for identifying and / or confirming an individual at risk for post-viral cognitive impairment (PVCI), comprising: a) determining an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline for the individual; b) determining baseline values ​​of one or more risk-related factors for post-viral cognitive impairment in the individual; c) determining a PVCI diagnostic score by i) comparing the episodic memory score, the working memory score, or the combined episodic memory and working memory baseline with a normative mean, and ii) comparing the baseline values ​​of each of the one or more risk-related factors with the normative mean; and d) identifying or confirming the diagnosis of PVCI in the individual by comparing the PVCI diagnostic score with a predefined threshold criterion. Alternatively, steps b), c), and d) are performed using an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline already determined for the individual. Thus, a method for identifying and / or confirming an individual at risk for post-viral infection cognitive impairment (PVCI) may include: a) providing an episodic memory baseline value, a working memory baseline value, or a combined episodic memory and working memory baseline value determined for the individual; b) determining baseline values ​​of one or more risk-associated factors for post-viral infection cognitive impairment in the individual; c) determining a PVCI diagnostic score by i) comparing the episodic memory score, the working memory score, or the combined episodic memory and working memory baseline value to a normative mean, and ii) comparing the baseline values ​​of each of the one or more risk-associated factors to the normative mean; and d) identifying or confirming a diagnosis of PVCI in the individual by comparing the PVCI diagnostic score to a predefined threshold criteria. 22. The method of embodiment 21, wherein the episodic memory baseline is obtained by measuring the individual's episodic memory using an episodic memory test. 23. The method of embodiment 21, wherein the working memory baseline is obtained by measuring the individual's working memory using a working memory test. 24. The method of embodiment 21, wherein the combined episodic memory and working memory baseline is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test. 25. The method of embodiment 22 or 24, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test. 26. The method of embodiment 23 or 24, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test. 27. The method of any one of embodiments 21-26, wherein the one or more risk-associated factors include inflammation baseline, antiviral drug use baseline, viral infection diagnosis or medical history baseline, or any combination thereof. 28. The method of any one of embodiments 26-31, further comprising, prior to step (b), determining a weighted score for the episodic memory criterion value, the working memory criterion value, the combined episodic memory and working memory criterion value, the criterion values ​​for each of the one or more risk-related factors, or any combination thereof. 29. The method of any one of embodiments 21-28, wherein the PVCI diagnostic score is determined using the predefined threshold criteria of Table 2. 30. PVCI diagnosis is made when a) the episodic memory measure is more than one standard deviation below the normative mean, or b) the working memory measure is more than one standard deviation below the normative mean, or c) the combined episodic memory and working memory measure is more than one standard deviation below the normative mean, or d) the episodic memory measure is more than one standard deviation below the normative mean and one or more risk status factors are present, or e) the working memory measure is more than one standard deviation below the normative mean and one or more risk status factors are present, or f) the combined episodic memory and working memory measure is more than one standard deviation below the normative mean. or g) the episodic memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present; or h) the working memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present; or i) the combined episodic memory and working memory criterion is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present. 31. The method of any one of embodiments 21-30, wherein the PVCI diagnostic score classifies the individual as recommending additional monitoring and / or treatment of a post-infection PVCI. 32. The method of any one of embodiments 21-31, further providing a treatment recommendation based on the individual's risk status susceptibility. 33. The method of embodiment 32, wherein the treatment recommendation comprises no treatment recommendation or treatment with one or more fibrates. 34. The method of embodiment 33, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

[0117] Aspects of the present specification can also be described by the following embodiments. 1. A method for treating perioperative neurocognitive impairment or post-viral cognitive impairment by administering a composition comprising one or more fibrates. 2. The method of embodiment 1, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. 3. The method of embodiment 1 or 2, wherein the perioperative neurocognitive impairment is delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment). 4. A composition comprising one or more fibrates for use in the treatment of perioperative neurocognitive impairment or post-viral cognitive impairment. 5. The composition of embodiment 4, wherein the one or more fibrates comprises bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. 6. The composition of embodiment 4 or 5, wherein the perioperative neurocognitive impairment is delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment). 7. Use of one or more fibrates in the manufacture of a medicine for the treatment of perioperative neurocognitive disorder or post-viral cognitive disorder. 8. The use of embodiment 7, wherein the one or more fibrates comprises bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof. 9. The use of embodiment 7 or 8, wherein the perioperative neurocognitive impairment is delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment). EXAMPLES

[0118] The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments presently contemplated, and are not to be construed as limiting any of the embodiments described herein, including those related to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.

[0119] Example 1 A clinical study of risk predictors of POCD in an elderly cohort after elective surgery A secondary analysis was performed on a dataset collected from a prospective multicenter observational study conducted in Europe. The analysis was performed on 933 patients undergoing elective surgery with a predicted operative time of 60 minutes or more. All patients were at least 65 years old and had a Mini-Mental State Examination (MMSE) score >23. Cognitive assessments were collected before surgery (baseline), at discharge (postoperative day 7), and at a 3-month postoperative follow-up. The cognitive assessments included tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), including reaction time (RTI, a measure of simple attention), paired-associate learning (PAL, a measure of episodic memory), spatial span (SSP, a measure of working memory), and verbal recognition memory (VRM, a measure of recognition memory). Each of these cognitive tests yields multiple different outcome measures (e.g., errors, latency, span length) and allows for a statistical evaluation of the participants' performance on each of the tasks.

[0120] To determine preoperative cognitive impairment (i.e., to determine whether having preoperative cognitive impairment increases a person's risk susceptibility to PND), a combined (i.e., composite) risk score was calculated from the episodic memory baseline and working memory baseline using preoperative performance on the PAL task and SSP task, respectively. The outcome measures for each task used to generate this combined risk score were the adjusted total number of errors on the PAL test 8 shapes (PALTEA8) and the total number of errors on the SSP test (SSPTE). To determine whether each individual participant had preoperative cognitive impairment that could be a risk for PND, the preoperative (baseline) data for these two outcome measures (adjusted total number of errors on the PAL test 8 shapes and total number of errors on the SSP test) were pooled across both surgery and control group participants to serve as a normative data comparison against which each individual participant could be compared. The calculation of this combined episodic memory and working memory baseline was as follows: First, a Z-score for each episodic memory and working memory was created for each participant. Z PALTEA8 =-(PALTEA8 個人の参加者スコア -PALTEA8 規範平均 ) / PALTEA8 規範SD、 and Z SSPTE =-(SSPTE 個人の参加者スコア -SSPTE 規範平均 ) / SSPTE 規範SD These scores were then calculated together to create a combined risk score for memory function. Combined risk score = (Z PALTEA8 +Z SSPTE ) / 2. Here, a negative risk score could mean that an individual participant performed worse than the normative mean.

[0121] Overall preoperative cognitive impairment for each participant was classified as cognitive test performance (on adjusted total errors on the PAL test 8 shapes and total errors on the SSP test) below the mean of the normative comparison (i.e., poor). Mild to moderate preoperative impairment was classified as cognitive test performance less than 1 SD below the mean of the normative comparison (i.e., more than 1 SD worse).

[0122] To assess whether preoperative cognitive impairment (either preoperative global impairment or preoperative mild to moderate impairment) puts individuals at risk for PND, changes in cognitive performance after surgery were statistically evaluated. To assess postoperative changes in cognitive performance, and finally to determine whether participants had PND, a reliable change index (RCI) score was calculated using one outcome measure from each of the CANTAB tasks used in the European study. For the RTI task, the correct latency outcome measure was used. For the PAL task, the adjusted total number of errors outcome measure was used. For the SSP task, the degree of span length outcome measure was used. For the VRM task, the immediate free recall of words outcome measure was used. For each of the described cognitive outcome measures, the corresponding RCI was calculated. RCI=(ΔX-ΔXc) / SD(ΔXc), where ΔX refers to the difference in postoperative test scores compared to preoperative (baseline) and ΔXc refers to the mean test score difference between the corresponding measurement time points in the non-operative control group (n=114) to correct for learning effects and variability in repeated cognitive testing. The RCI was then normalized to the standard deviation (SD) of the mean difference between the control group SD (ΔXc). The overall RCI score for each participant was defined as the sum of all RCI scores for each cognitive outcome measure, Σ(RCI), relative to the standard deviation SD of the sum of the RCI scores for the control group (Σ(RCIc)) using the formula: Composite RCI:Σ(RCI) / SD(Σ(RCIc)). An individual was defined as having PND if 1) the total RCI score was a negative value (indicating cognitive decline after surgery) or 2) the total RCI score represented a decline of more than 0.5 SD (indicating at least half a SD decline in cognitive performance after surgery).

[0123] To generate an overview of cognitive performance on the CANTAB task at both preoperative (baseline) and postoperative (3-month follow-up) time points, summary descriptive statistics for each of the study outcome measurement variables for surgical and control participants are presented in Table 3 .

[0124] [Table 3] To generate an overview of cognitive performance in relation to the pre-operative "risk" combined scores (minus RCI score and RCI score >0.5SD) of episodic memory and working memory for each of the different classifications of PND, summary descriptive statistics are provided below in Table 4. In addition to the combined scores, descriptive statistics are also provided separately for both episodic memory and working memory.

[0125] [Table 4]

[0126] Pearson correlation coefficients were calculated to assess the linear relationship between the episodic and working memory combined risk score (preoperative) and the PND RCI outcome score at 3 months: r=1.54, p<.001 value. The direction of the results indicates that poorer performance on the episodic and working memory combined risk score at baseline was significantly associated with a more negative change from baseline RCI score at 3 months postoperatively. The direction of the results indicates that poorer performance on the episodic and working memory combined risk score was associated with poorer postoperative cognitive performance. To further explore this association, binary logistic regression was performed and confirmed that poorer baseline performance (i.e., preoperative cognitive impairment relative to the normative mean) was a significant predictor of risk for developing PND.

[0127] Binary logistic regression indicates that on the episodic + working memory combined risk score, overall preoperative cognitive impairment (i.e., cognitive test performance below the normative comparison mean) was a significant predictor of PND (negative RCI score) when controlling for age; Wald = 11.472, P < .001. The odds ratio for the combined risk score was 1.764 (95% Cl 1.270 to 2.450), indicating that the odds of having PND at 3 months were = 100(1.764-1) = 76% higher for those with preoperative performance worse than the normative mean on the combined risk score than for those with preoperative performance better than the normative mean.

[0128] Binary logistic regression indicates that overall preoperative cognitive impairment (i.e., cognitive test performance below the normative comparison mean) on the episodic + working memory combined risk score was a trendwise significant predictor of PND (RCI score >0.5 SD) when controlling for age; Wald = 3.114, P = .078. The odds ratio for the risk score was 1.379 (95% Cl. 965 to 1.971), indicating that the odds of having PND at 3 months were = 100(2.064-1) = 38% higher in those with preoperative performance worse than the normative mean on the combined risk score than in those with preoperative performance better than the normative mean. The proportion of participants meeting PND, defined as a decline in RCI score >0.5 SD from baseline, was 30%.

[0129] Of the patients tested, 6% had mild to moderate preoperative impairment defined by performance >1 SD below the normative comparison on the episodic + working memory combined risk score. Binary logistic regression indicates that a preoperative deficit of >1 SD below the normative comparison mean on the episodic + working memory combined risk score tends to be a significant predictor of PND (negative RCI score) when controlling for age. Wald = 3.048, P = .081. The odds ratio for the risk score was 1.877 (95% Cl. 926 to 3.805), indicating that the odds of having PND at 3 months were = 100 (1.877-1) = 88% higher in those with a preoperative deficit of >1 SD on the combined risk score compared with those without a preoperative deficit. Binary logistic regression indicates that a preoperative deficit >1 SD below the normative comparison mean in the episodic + working memory combined risk score was a significant predictor of PND (RCI score >0.5 SD) when controlling for age. Wald = 4.231, P = .040. The odds ratio for the risk score was 2.064 (95% Cl 1.035 to 4.118), indicating that the odds of having PND at 3 months were = 100 (2.064-1) = 106% higher in those with a preoperative deficit >1 SD in the combined risk score compared with those without a preoperative deficit. The proportion of participants meeting PND, defined as a decline in RCI score >0.5 SD from baseline, was 30%.

[0130] A secondary analysis of a large European dataset successfully identified cognitive risk factors (episodic and working memory) for determining PND outcome, controlling for age. The results of this analysis support the development of standardized prediction tools to measure key factors associated with PND risk, providing a major medical advance in this field.

[0131] Finally, the foregoing description of the embodiments of the present invention has been presented for purposes of illustration and description. Although aspects of the present invention are highlighted by reference to specific embodiments, those skilled in the art will readily appreciate that these described embodiments are merely illustrative of the principles encompassing the present invention. As such, the specific embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Thus, it is to be understood that embodiments of the subject matter of the present disclosure are in no way limited to the specific elements, compounds, compositions, components, articles, devices, methodologies, uses, protocols, steps, and / or limitations described herein, unless expressly stated as such.

[0132] In addition, groupings of alternative embodiments, elements, steps and / or limitations of the invention should not be construed as limitations. Each such grouping may be referenced and claimed individually or in any combination with other groupings disclosed herein. It is anticipated that one or more of the alternative embodiments, elements, steps and / or limitations of a grouping may be included in or deleted from a grouping for reasons of convenience and / or patentability. When such inclusion or deletion is made, the specification is deemed to include the modified grouping and will satisfy all Markush group descriptions used in the appended claims.

[0133] Moreover, those skilled in the art will recognize that certain changes, modifications, permutations, alterations, additions, subtractions, and subcombinations thereof may be made in accordance with the teachings herein without departing from the spirit of the invention. Moreover, it is intended that the following appended claims and any claims thereafter introduced be interpreted to include all such changes, modifications, permutations, alterations, additions, subtractions, and subcombinations that are within their true spirit and scope. Accordingly, the scope of the invention is not limited to that precisely as shown and described herein.

[0134] Certain embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that such variations will be adopted by those skilled in the art as appropriate, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of all possible variations of the above-described embodiments is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0135] The words, phrases, and terms used in this specification are used for the purpose of describing only certain embodiments, elements, steps, and / or limitations, and are not intended to limit the scope of the present invention, which is defined solely by the claims. In addition, such words, phrases, and terms are not to be understood only in their generally defined meanings, but also to include structures, materials, and acts that go beyond the scope of their generally defined meanings, as specifically defined herein. Thus, if an element, step, or limitation can be understood in the context of this specification as including multiple meanings, its use in the claims should be understood to be general to all possible meanings supported by this specification and by the term itself.

[0136] Thus, the definitions and meanings of the elements, steps, or limitations recited in the claims set forth below are defined herein to include not only the literally recited combinations of elements, steps, or limitations, but also all equivalent structures, materials, or acts for performing substantially the same function in substantially the same way to achieve substantially the same results. Thus, in this sense, it is contemplated that equivalent replacements of two or more elements, steps, and / or limitations may be equivalently substituted for any one of the elements, steps, or limitations in the claims set forth below, or that a single element, step, or limitation may be substituted for two or more elements, steps, and / or limitations in such claims. Although elements, steps, or limitations may be described above as acting in a particular combination and may initially be claimed as such, it should be expressly understood that one or more elements, steps, and / or limitations from a claimed combination may, in some cases, be deleted from the combination, and the claimed combination may be directed to a subcombination or a variation of the subcombination. Thus, notwithstanding the fact that elements, steps and / or limitations of the claims are described below in a particular combination, the invention should be expressly understood to include other combinations of fewer, more, or different elements, steps and / or limitations disclosed in the above combinations, even if not originally claimed in such combination. Moreover, slight variations from the claimed subject matter, now known or later devised, as viewed by one of ordinary skill in the art, are expressly contemplated to be equivalently within the scope of the claims. Thus, obvious alternatives now or later known to those of ordinary skill in the art are defined to be within the scope of the defined elements. Thus, the claims are understood to include what is specifically illustrated and described above, what is conceptually equivalent, what is obviously a substitute, and also what essentially embraces the essential idea of ​​the invention.

[0137] Unless otherwise indicated, all numbers expressing properties, items, quantities, parameters, properties, terms, etc. used in the specification and claims should be understood to be modified in all cases by the term "about". As used herein, the term "about" means that the property, item, quantity, parameter, property, or term encompasses a range of plus or minus 10% above and below the value of the stated property, item, quantity, parameter, property, or term. Thus, unless indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximations that may vary. For example, the term "about" in the context of the mass of an ion or the mass / charge ratio of an ion refers to + / - 0.50 atomic mass units, since mass spectrometers may vary slightly in determining the mass of a given analyte. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical designation should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques.

[0138] Although the numerical ranges and values ​​setting forth the broad scope of the present invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in each testing measurement. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate numerical value falling within the range. Unless otherwise stated herein, each individual value in a numerical range is incorporated herein as if it were individually recited herein.

[0139] Use of the terms "may" or "can" in connection with an embodiment or an aspect of an embodiment also entails the alternative meanings "may not" or "cannot." Thus, when the specification discloses that an embodiment or an aspect of an embodiment may or may not be included as part of the inventive subject matter, a negative limitation or exclusionary proviso is also expressly implied, i.e., means that an embodiment or an aspect of an embodiment may or may not be included as part of the inventive subject matter. Similarly, use of the term "optionally" in connection with an embodiment or an aspect of an embodiment means that such embodiment or aspect of an embodiment may or may not be included as part of the inventive subject matter. Whether such a negative limitation or exclusionary proviso applies is based on whether a negative limitation or exclusionary proviso is recited in the claimed subject matter.

[0140] The terms "a," "an," "the," and similar references used in the context of describing the present invention (particularly in the context of the claims below) shall be construed as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Furthermore, ordinal designations of identified elements, such as "first," "second," "third," etc., are used to distinguish elements, and do not indicate or imply a required or limited number of such elements, nor do they indicate a particular location or order of such elements, unless specifically stated otherwise. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely to better illuminate the invention and does not limit the scope of the invention as otherwise claimed. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0141] When used in the claims, whether as filed or added by amendment, the open-ended transitional phrase "comprising," and variations thereof, such as "comprise" and "comprises," and equivalent open-ended transitional phrases such as "including," "containing," and "having," include all explicitly recited elements, limitations, steps, integers, and / or features, either alone or in combination with unrecited subject matter, such that the named elements, limitations, steps, integers, and / or features are essential, but other unnamed elements, limitations, steps, integers, and / or features may be added to form a structure within the scope of the claim. Specific embodiments disclosed herein may be further limited in the claims using the open-ended transitional phrase "consisting of" or "consisting essentially of" (or variations thereof, e.g., "consist of," "consists of," "consist essentially of," and "consists essentially of") in place of "comprising" or as an amendment to "comprising essentially of." When used in the claims, whether as filed or added by amendment, the open-ended transitional phrase "consisting of" excludes any element, limitation, step, integer, or feature not expressly recited in the claim. The open-ended transitional phrase "consisting essentially of" limits the claim to the elements, limitations, steps, integers, and / or features expressly recited, as well as any other elements, limitations, steps, integers, and / or features that do not materially affect the basic and novel characteristics of the claimed subject matter.The meaning of the open-ended transitional phrase "comprising" is therefore defined to include all elements, limitations, steps and / or features specifically recited, as well as any optional additional unspecified ones. The meaning of the open-ended transitional phrase "consisting of" is defined to include only those elements, limitations, steps, integers, and / or features specifically recited in the claim, whereas the meaning of the open-ended transitional phrase "consisting essentially of" is defined to include only those elements, limitations, steps, integers, and / or features specifically recited in the claim, as well as those elements, limitations, steps, integers, and / or features that do not materially affect the basic and novel characteristics of the claimed subject matter. Thus, the open-ended transitional phrase "comprising" (and its equivalents) includes, by way of limitation, within its meaning, the claimed subject matter specified by the open-ended transitional phrase "consisting of" or "consisting essentially of." As such, the embodiments described herein or claimed with the term "comprising" explicitly and unambiguously provide explanation, validity, and support for the phrases "consisting essentially of" and "consisting of."

[0142] Finally, all patents, patent publications, and other references cited and identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. No admission is made, and should be made, in this regard that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to dates or representations of such documents are based on the information available to the applicant and do not constitute an admission that the dates or representations of such documents are correct.

Claims

1. 1. A test method for identifying individuals at risk for perioperative neurocognitive impairment using a computer system, comprising: a) obtaining an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline for the individual; b) obtaining a PND risk score by comparing the episodic memory measure, the working memory measure, or the combined episodic memory and working memory measure to a normative mean; and c) determining the individual's risk status susceptibility to perioperative neurocognitive impairment by comparing the PND risk score with a predefined threshold criterion.

2. The method of claim 1 , wherein the episodic memory baseline value is obtained by measuring the episodic memory of an individual using an episodic memory test.

3. The method of claim 1 , wherein the working memory baseline value is obtained by measuring the working memory of the individual using a working memory test.

4. 2. The method of claim 1, wherein the combined episodic memory and working memory baseline is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test.

5. 5. The method of claim 2 or 4, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test.

6. 5. The method of claim 3 or 4, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test.

7. 7. The method of claim 1, further comprising, prior to step (b), obtaining a weighted score for the episodic memory metric, the working memory metric, or the combined episodic memory and working memory metric.

8. The risk state susceptibility of the individual is a) the episodic memory reference value is more than one standard deviation below the normative mean; or b) the working memory measure is more than one standard deviation below the normative mean; or c) identifying a subject as being at high risk for PND when the combined episodic memory and working memory criterion is more than one standard deviation below the normative mean;

9. The risk state susceptibility of the individual is a) the episodic memory reference value is below the normative mean but less than one standard deviation below the normative mean; or b) the working memory measure is below the normative mean but less than one standard deviation below the normative mean; or c) identifying a subject as being at moderate risk for PND when the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean.

10. 10. The method of claim 1, further comprising, prior to step (b), obtaining baseline values ​​of one or more risk associated factors for said perioperative neurocognitive impairment in said individual.

11. The method of claim 10 , wherein obtaining a PND risk score is performed in conjunction with comparing the reference value for each of the one or more risk-associated factors to a normative mean.

12. 12. The method of claim 10 or 11, wherein the one or more risk-related factors comprise inflammation baselines, age baselines, body mass index (BMI) baselines, education baselines, medication use baselines, disease diagnosis or history baselines, or any combination thereof.

13. The method of any one of claims 10 to 12, further comprising obtaining a weighted score for said reference value of each of said one or more risk-related factors.

14. The method of any one of claims 1 to 13, wherein the PND risk score is obtained using predefined threshold criteria in Table 1.

15. The risk state susceptibility of the individual is a) the episodic memory baseline is more than one standard deviation below the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline indicative of high inflammation, an age baseline of 60 years or greater, a BMI baseline of 30 or greater, an education baseline of 12 years or less of formal education, a medication use baseline of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and a disease diagnosis or history of the presence of a psychiatric disorder, neurological disease, diabetes, metabolic syndrome, autoimmune disease, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse; or b) the working memory baseline is more than one standard deviation below the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline indicative of high inflammation, an age baseline of 60 years or more, a BMI baseline of 30 or more, an education baseline of 12 years or less of formal education, a medication use baseline of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic-based medications in the past 8 weeks, and a disease diagnosis or history of the presence of a psychiatric disorder, neurological disease, diabetes, metabolic syndrome, autoimmune disease, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse; or 15. The method of any one of claims 10-14, wherein a subject is identified as being at very high risk for PND when the combined episodic memory and working memory baseline is more than one standard deviation below the normative mean and the baseline values ​​for one or more risk factors include an inflammation baseline indicative of high inflammation, an age baseline of 60 years or older, a BMI baseline of 30 or greater, an education baseline of 12 years or less of formal education, a medication use baseline of use of antihistamines, gastrointestinal antispasmodics, antivertigo / antiemetics, antidepressants, bladder antimuscarinics, skeletal muscle relaxants, antipsychotics, antiarrhythmics, antiparkinsonians, or anticholinergic based medications in the past 8 weeks, and a disease diagnosis or history of the presence of psychiatric disorders, neurological disorders, diabetes, metabolic syndrome, autoimmune disorders, heart disease, vascular disease, stroke, infection, injury, asthma, or alcohol abuse.

16. The risk state susceptibility of the individual is a) the episodic memory baseline is more than one standard deviation below the normative mean and inflammation baseline of 10 mg / L or greater blood level of CRP; or b) the working memory baseline is more than one standard deviation below the normative mean and inflammation baseline of 10 mg / L or greater blood level of CRP; or c) the combined episodic memory and working memory measure is more than one standard deviation below the normative mean and inflammation measure of blood levels of CRP of 10 mg / L or more; or d) the episodic memory reference value is more than one standard deviation below the normative mean and below the reference value for age 60 years or older; or e) the working memory measure is more than one standard deviation below the normative mean and below the age measure for people 60 years or older; or f) the subject is identified as being at high risk for PND when the combined episodic memory and working memory reference value is more than one standard deviation below the normative mean and the reference value for age 60 years or older.

17. The risk state susceptibility of the individual is a) the episodic memory baseline is below the normative mean but less than one standard deviation below the normative mean and an inflammation baseline of 10 mg / L or greater blood levels of CRP; or b) the working memory criterion is below the normative mean but less than one standard deviation below the normative mean and an inflammation criterion of 10 mg / L or greater blood levels of CRP; or c) the combined episodic and working memory measure is below the normative mean but less than one standard deviation below the normative mean and an inflammation measure of 10 mg / L or greater blood levels of CRP; or d) the episodic memory reference value is below the normative mean but less than one standard deviation below the normative mean and below the reference value for age 60 years or older; or e) the working memory measure is below the normative mean but less than one standard deviation below the normative mean and below the normative mean for age 60 years or older; or f) identifying a subject as being at moderate risk for PND when the combined episodic and working memory reference value is below the normative mean but less than one standard deviation below the normative mean and below the reference value for age 60 years or older.

18. The risk state susceptibility of the individual is a) when the episodic memory baseline exceeds the normative mean and the baseline values ​​for one or more risk-related factors include an inflammation baseline of blood levels of CRP less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, an education baseline of 12 years or more of formal education, a medication use baseline of no medication use for risk conditions, and a disease diagnosis or medical history baseline of no disease diagnosis or medical history for risk conditions; or b) the working memory baseline exceeds the normative mean and the baseline values ​​for one or more risk-related factors include an inflammation baseline of blood levels of CRP less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, an education baseline of 12 years or more of formal education, a medication use baseline of no medication use for risk conditions, and a disease diagnosis or medical history baseline of no disease diagnosis or medical history for risk conditions; or c) identifying a patient as being at low risk for PND when the combined episodic memory and working memory baseline exceeds the normative mean and the baseline values ​​for one or more risk-related factors include an inflammation baseline of blood levels of CRP less than 10 mg / L, an age baseline of less than 60 years, a BMI baseline of less than 30, an education baseline of 12 years or more of formal education, a medication use baseline of no medication use for risk conditions, and a disease diagnosis or history baseline of no disease diagnosis or history for risk conditions.

19. The method of any one of claims 1 to 18, wherein the individual's risk status susceptibility classifies the individual as one for which additional monitoring is recommended, treatment of the PND is recommended prior to surgery, and / or treatment of the PND is recommended following surgery.

20. 20. The method of any one of claims 1-19, wherein the risk status severity classifies the individual as having preoperative neurocognitive impairment, postoperative delirium, delayed postoperative neurocognitive recovery, mild postoperative neurocognitive impairment, severe postoperative neurocognitive impairment, mild neurocognitive impairment, or severe neurocognitive impairment.

21. The method of any one of claims 1 to 20, further comprising providing a treatment recommendation based on said risk state susceptibility of said individual.

22. 22. The method of claim 21, wherein the treatment recommendation comprises no treatment recommendation or treatment with one or more fibrates.

23. 22. The method of claim 21, wherein when the risk state susceptibility of the individual is identified as being at very high risk for PND, at high risk for PND, or at moderate risk for PND, the treatment recommendation comprises treatment with one or more fibrates.

24. a) when the individual's risk status susceptibility indicates that the individual has pre-operative neurocognitive impairment, a treatment recommendation comprises treatment with one or more fibrates; or b) when the individual's risk status susceptibility indicates that the individual will have delayed post-operative neurocognitive recovery, a treatment recommendation comprises treatment with one or more fibrates; or c) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, a treatment recommendation comprises treatment with one or more fibrates; or d) when the individual's risk status susceptibility indicates that the individual has severe post-operative neurocognitive impairment, a treatment recommendation comprises treatment with one or more fibrates; or e) when the individual's risk status susceptibility indicates that the individual has mild postoperative neurocognitive impairment, a treatment recommendation comprises treatment with one or more fibrates; or f) when the individual's risk status susceptibility indicates that the individual has severe post-operative neurocognitive impairment, a treatment recommendation comprises treatment with one or more fibrates.

25. 25. The method of any one of claims 22-24, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibrate, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

26. 1. A test method for identifying individuals at risk for Post Viral Cognitive Impairment (PVCI) using a computer system, comprising: a) obtaining an episodic memory baseline, a working memory baseline, or a combined episodic memory and working memory baseline for the individual; b) obtaining a PVCI diagnostic score by comparing the episodic memory score, the working memory score, or the combined episodic memory and working memory standard score to a normative mean; and c) identifying the risk of PVCI in the individual by comparing the PVCI diagnostic score with a predefined threshold criterion.

27. 27. The method of claim 26, wherein the episodic memory baseline value is obtained by measuring the episodic memory of an individual using an episodic memory test.

28. 27. The method of claim 26, wherein the working memory baseline value is obtained by measuring the working memory of the individual using a working memory test.

29. 27. The method of claim 26, wherein the combined episodic memory and working memory measure is obtained by measuring both the individual's episodic memory using an episodic memory test and the individual's working memory using a working memory test.

30. 30. The method of claim 27 or 29, wherein the episodic memory test comprises a list learning test, a recognition memory test, or a paired-associate learning test.

31. 30. The method of claim 28 or 29, wherein the working memory test comprises a spatial working memory test, a spatial span test, a digit permutation test, or an N-back test.

32. 32. The method of any one of claims 26 to 31, further comprising, prior to step (b), obtaining a weighted score for the episodic memory metric, the working memory metric, or the combined episodic memory and working memory metric.

33. The risk of the PVCI is a) the episodic memory reference value is more than one standard deviation below the normative mean; or b) the working memory measure is more than one standard deviation below the normative mean; or c) the combined episodic memory and working memory criterion value is identified when it is more than one standard deviation below the normative mean.

34. 34. The method of any one of claims 26 to 33, further comprising, prior to step (b), obtaining baseline values ​​of one or more risk-associated factors for said PVCI in said individual.

35. 35. The method of claim 34, wherein obtaining the PVCI diagnostic score is performed in conjunction with comparing the reference value for each of the one or more risk-associated factors to a normative mean.

36. 36. The method of claim 34 or 35, wherein the one or more risk-associated factors comprise inflammation baseline, antiviral medication usage baseline, viral infection diagnosis or medical history baseline, or any combination thereof.

37. The method of any one of claims 34 to 36, further comprising obtaining a weighted score for said reference value of each of said one or more risk-related factors.

38. 38. The method of any one of claims 26 to 37, wherein the PVCI diagnostic score is obtained using predefined threshold criteria in Table 2.

39. The risk of the PVCI is a) the episodic memory baseline is more than one standard deviation below the normative mean and one or more risk status factors are present; or b) the working memory measure is more than one standard deviation below the normative mean and one or more risk status factors are present; or c) the combined episodic memory and working memory measure is more than one standard deviation below the normative mean and one or more risk status factors are present; or d) the episodic memory baseline is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present; or e) the working memory measure is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present; or f) identifying when the combined episodic memory and working memory measure is below the normative mean but less than one standard deviation below the normative mean and one or more risk status factors are present.

40. 40. The method of any one of claims 26 to 39, wherein the PVCI diagnostic score classifies the individual as recommending additional monitoring and / or treatment of the PVCI following infection.

41. 41. The method of any one of claims 26 to 40, further comprising providing a treatment recommendation based on the individual's risk of PVCI.

42. 42. The method of claim 41, wherein the treatment recommendation comprises no treatment recommendation or treatment with one or more fibrates.

43. 43. The method of claim 42, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibride, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

44. A composition comprising one or more fibrates for use in the treatment of perioperative neurocognitive impairment or post-viral cognitive impairment.

45. 45. The composition of claim 44, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibride, fenofibrate, fenofibric acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

46. 46. ​​The composition of claim 44 or 45, wherein the perioperative neurocognitive impairment is delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment).

47. 13. Use of one or more fibrates in the manufacture of a medicament for the treatment of perioperative neurocognitive impairment or post-viral cognitive impairment.

48. 48. The use of claim 47, wherein the one or more fibrates comprise bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, clofibride, fenofibrate, fenofibrate acid, gemfibrozil, lonifibrate, simfibrate, or any combination thereof.

49. 49. The use according to claim 47 or 48, wherein the perioperative neurocognitive impairment is delayed postoperative neurocognitive recovery (or early postoperative cognitive impairment), mild postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), severe postoperative neurocognitive impairment (or long-term postoperative cognitive impairment), mild neurocognitive impairment (or long-term postoperative cognitive impairment), or severe neurocognitive impairment (or long-term postoperative cognitive impairment).