Diagnostic method

Abstract

Cognitive impairment in a subject (such as dementia or Alzheimer’s Disease) is detected by analysing one or more ocular microtremor (OMT) measurements obtained from the subject 202, and diagnosing cognitive impairment based on the OMT measurements 204. OMT measurements may be the mean OMT frequency. OMT measurements may be correlated with standard cognitive impairment test scores. The mean OMT frequency may be compared to a threshold to diagnose cognitive impairment (e.g. below a threshold value of about 65Hz dementia is diagnosed, and below 69Hz mild cognitive impairment is diagnosed). Progression of cognitive impairment is monitored by comparing OMT measurements obtained from the subject at a first time and at a second later time, where a change in OMT measurement is indicative of a change in cognitive impairment. Therapeutic effect of a treatment is determined by comparing OMT frequency measurements obtained before and after treatment, where an increase in OMT frequency indicates a therapeutic effect and a decrease in OMT frequency indicates no such effect.

Description

Field of the Invention The present invention relates to a method for detecting cognitive impairment and a method for diagnosing dementia. The invention also relates to a method for monitoring cognitive impairment progression and a method of determining the therapeutic effect of a treatment regimen for cognitive impairment. The invention also relates to a computer program or computer-storage medium comprising instructions to perform the methods; and a kit, an apparatus and a system for performing the methods. The invention also relates to use of OMT as a biomarker for detecting cognitive impairment or for diagnosing dementia. Background Diagnosis of cognitive impairment such as dementia, particularly in the early stages, is difficult. This is due to the person having fewer symptoms as only a small part of the brain is damaged. However, treatment is typically most effective when started early in the disease process. Summary of the Invention The inventors have found that OMT measurements can be used to indicate cognitive impairment. This provides an objective test for cognitive impairment, for example dementia. They further show in the examples that OMT measurements correlate with a proxy for cognitive impairment (MoCA). This allows the prioritisation of patients according to disease severity. Therefore, in a first aspect the invention provides a method of diagnosing dementia in a subject comprising: a) analysing one or more ocular microtremor (OMT) measurements obtained for the subject; and b) based on the one or more OMT measurements, diagnosing dementia in the subject. In a further aspect the invention provides a method of detecting cognitive impairment in a subject comprising: a) analysing one or more OMT measurements from the subject; and b) based on the one or more OMT measurements, detecting cognitive impairment. In a further aspect the invention provides a method of monitoring cognitive impairment progression in a subject comprising: a) analysing one or more OMT measurements obtained for the subject at a first time point; b) analysing one or more OMT measurements obtained for the subject at a second later time point; and c) comparing the one or more measurements obtained in a) with those obtained in b), wherein a change in the one or more OMT measurements from a) to b) is indicative of a change in cognitive impairment in the subject. In a further aspect the invention provides a method of determining the therapeutic effect of a treatment regimen for cognitive impairment in a subject comprising: a) analysing one or more OMT measurements obtained for the subject, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean OMT frequency; b) repeating step a) after treatment; and c) comparing the OMT frequency obtained in a) with the OMT frequency obtained in b), wherein: i) an increase in the OMT frequency indicates that the treatment has a therapeutic effect; or ii) a decrease or no change in the OMT frequency indicates that the treatment is not having a therapeutic effect. In a further aspect the invention provides a computer-readable storage medium or a computer program comprising computer-executable instructions, which when executed by a computing system, are capable of causing the computing system to perform the method. In a further aspect, the invention provides a kit comprising: a) an OMT device for obtaining OMT data from a subject; and b) the computer-readable storage media; or computer program described above. In a further aspect, the invention provides an apparatus comprising processing circuitry configured to perform the methods described herein, optionally wherein the apparatus is an OMT device configured to obtain OMT data from the subject. In a further aspect, the invention provides a system comprising: a) an OMT device for obtaining OMT data from a subject; and b) an electronic device operably connected to the OMT device; wherein the OMT device and electronic device are configured to perform any of the methods described herein. In a further aspect, the invention provides use of OMT measurements obtained from a subject to detect cognitive impairment. In a further aspect, the invention provides use of OMT measurements obtained from a subject to diagnose dementia. Detailed description General OMT There are three different types of involuntary fixational human eye movements: drift, microsaccades, and ocular microtremor (OMT). OMT is the smallest of the involuntary eye movements. It is present in all subjects, even when the eye appears to be at rest. Various types of measurements can be taken in relation to OMT. One or more of these OMT measurements may be used. For example, the OMT frequency. Cognitive impairment By cognitive impairment is meant a decline in mental abilities. These may include problems with memory, language or judgement. Mild cognitive impairment is when there is a small decline in mental abilities. Cognitive impairment includes dementia which is a specific level of cognitive impairment. Dementia Dementia is a syndrome associated with an ongoing decline of brain functioning. There are different clinical stages of dementia: early, middle and late (also referred to as mild, moderate and severe). The diagnosis by the present method may be at the early stage of the disease. Forms of dementia include Alzheimer’s disease. Cognitive Impairment Test Score To aid clinicians, the OMT measurement may be correlated to a cognitive impairment test score. Clinicians are familiar with the meaning of cognitive test scores. They are the output of cognitive impairment tests. There are various tests that are used. For example the Montreal Cognitive Assessment (MoCA). MoCA is a widely used screening assessment for detecting cognitive impairment. MoCA scores range between 0 and 30. The following ranges may be used to indicate cognitive health: • A score of 26 or above is considered normal • A score of 18-25 indicates mild cognitive impairment • A score of 10-17 indicates moderate cognitive impairment • A score of less than 10 indicates severe cognitive impairment By correlating the OMT measurement with a cognitive test score, the clinician is provided with a familiar clinical grading of the cognitive impairment. Subject By subject is meant human. Diagnosis The OMT measurements are a tool to aid diagnosis as part of a multi-modal approach. A multi-modal approach is where multiple different data points are collected from various data analyses to aid diagnosis. Therefore, the subject may be one suspected of having cognitive impairment. That is, the subject may have shown symptoms indicative of cognitive impairment. Where the diagnosis is of dementia, the subject may be one suspected of having dementia or have shown symptoms indicative of dementia. As an example of a multimodal approach, diagnosis may involve determining the OMT frequency, for example the mean OMT frequency, for the subject, and comparing this with a threshold OMT frequency. This analysis obtained for the subject may then be combined with other data to allow a diagnosis to be made. For example, the results of a cognitive test or other assessments. As a result, diagnosis herein may be substituted by “screening”, i.e. OMT is useful as a screening tool for detecting cognitive impairment. It may be a screening tool for detecting Alzheimer’s disease. Threshold value By threshold value is meant a cutoff which distinguishes healthy subjects from subjects with a higher probability of having a disease. Frequency OMT is a small, high frequency tremor of the eyes. The mean OMT frequency is typically 70-90Hz in healthy adults. The OMT frequency may be calculated in a number of ways. For example, the OMT frequency can be calculated by counting the number of times that the eye changes direction on one axis. This can be done by counting the peaks and troughs on the time series waveform that represents the eye position along an axis, for example the horizontal axis. The mean frequency can be calculated by dividing the frequency counted by the duration of the measurement to arrive at a mean frequency. For example, counting the number of peak trough pairs of the waveform over a specific duration then dividing the number counted by the duration which is typically between 2 and 5 seconds. An example OMT waveform is shown in Figure 7 Figure 7 shows the peaks and troughs as counted. One peak and one trough together can be used as 1 measurement How many of these peak-troughs are in a second can be measured for the frequency, For example, if 75 peak-troughs are present in 1 second, then the frequency is 75 Hz. Frequency calculations over several seconds can be used to measure the mean frequency. For example, if 63 Hz is measured for the first second; 62 for the second second, and 61 Hz for the third second, then the mean frequency can be calculated as 63+62+61 / 3 = 62 Hz. One peak and one trough may be counted together as 1 measurement as some peaks or troughs can fall below the threshold value to be counted, so allowing both to count as 1 measurement avoids the issue that a count could be missed simply because the peak did not reach a certain value (and the same for trough measurements, if they fall outside the threshold value, the peak may be of sufficient value to be counted and not be incorrectly disregarded as noise). However, it is also possible to measure the frequency counting peaks or troughs as an alternative. The peaks and troughs in the waveform may vary in magnitude. If a peak or trough is arbitrarily small, it could be considered data or signal noise from the instrument and may be ignored from the calculation. A minimum magnitude threshold can be used to include or exclude a peak or trough from being counted to remove noise from the waveform. The frequency, for example the mean frequency, for diagnosing dementia may be below about 65Hz. For example, the frequency or mean frequency may be below 68 Hz, 67 Hz, 66 Hz, 65 Hz, 64 Hz, 63Hz or 62 Hz. The frequency, for example the mean frequency, for diagnosing mild cognitive impairment, may be below about 69Hz. For example, the frequency or mean frequency may be below 69 Hz, 68 Hz, 67 Hz, 66 Hz. For example, the frequency or mean frequency may be in a range from 65-69Hz. OMT data By OMT data is meant the data collected from the subject. The OMT data is collected from the subject and stored on a processor. The OMT data is derived by sampling the movements of the eye and processing the raw information in order to produce the OMT data that is stored on a processor. The OMT data may be the OMT time series waveform (for example where the OMT measurement is the OMT frequency). An example OMT waveform is shown in Figure 7. The OMT frequency can be calculated from the OMT waveform as described above. The methods may further comprise collection of the OMT data from the subject. For example, using the device described below. Methods The methods may be in vitro methods. The methods may be computer-implemented methods. For example one or more steps may be computer implemented. Analysing OMT measurements The methods comprise analysing OMT measurements obtained from (or for) a subject. The one or more OMT measurements may be stored on a processor. That is, the analysis of the one or more OMT measurements is in-vitro analysis. The OMT measurement is obtained (calculated) from OMT data obtained from the subject. The OMT data is stored on a processor and one or more OMT measurements are calculated from the OMT data. This analysis may be of the frequency, for example the mean OMT frequency, to detect cognitive impairment or diagnose dementia. Analysis may include determining if the frequency, for example the mean frequency is below a certain threshold as indicated above. Additionally, or alternatively analysis of the OMT measurement may comprise correlating the OMT measurement to a cognitive impairment test score, for example a MoCA score. For example, if the OMT measurement is frequency, for example mean frequency, then below a threshold value of about 65Hz a diagnosis of dementia may be made. The mean frequency may also or alternatively be correlated with a particular cognitive test score, for example MoCA score. By this is meant there is a positive correlation between OMT mean frequency and the MoCA score. For example, the lower the frequency may indicate a lower MoCA score. In this way, not only can dementia or cognitive impairment be diagnosed, but also the likely severity of the dementia or impairment by providing a cognitive impairment score, for example MoCA score, which provides a clinically relevant score. Equally a lower frequency can indicate more progressed dementia or cognitive impairment generally. Detecting cognitive impairment The methods disclosed may be used for detecting cognitive impairment. The cognitive impairment detected may be mild cognitive impairment. Alternatively the cognitive impairment may be moderate or severe cognitive impairment. Monitoring cognitive impairment progression The methods disclosed herein can also be used over time to monitor progression of cognitive impairment. Where the OMT measurement is OMT frequency, a decrease in the OMT frequency, for example the mean OMT frequency, may indicate progression of cognitive impairment, i.e. a worsening of, or increase in the severity of, cognitive impairment. Determining the therapeutic effect of a treatment regimen for cognitive impairment The methods disclosed herein may also be used to verify the utility of a treatment regimen as the OMT measurement may be taken before treatment and after treatment and any change in the OMT measurement analysed. Treatment The diagnostic method may also comprise a further step comprising treatment if the subject is diagnosed with dementia. The treatment may be a an antibody to beta-amyloid. Alternatively or additionally treatment may be with an acetyl cholinesterase inhibitor or antagonist of the N-methyl-D-aspartate receptor. For example, treatment may be with donepezil, rivastigmine, galantamine and memantine. Uses Also disclosed is the use of one or more OMT measurements as a biomarker for cognitive impairment, for example mild cognitive impairment or dementia. The dementia may be Alzheimer’s disease. The OMT measurement may be the frequency. For example, the mean OMT frequency may be used as a biomarker. The use is an in vitro use. Other methods The method may also include: As the method is used as part of a multi-modal approach, the method may instead be characterised as: A method of collecting data from a subject (or screening a subject) suspected of having cognitive impairment, optionally wherein the cognitive impairment is dementia, the method comprising: a) Obtaining (collecting) OMT data from the subject; b) Calculating one or more OMT measurements from the OMT data; and c) Analysing the one or more measurements obtained for the subject. The OMT data may be the OMT waveform. The measurement may be the frequency. The analysis may comprise determining if the OMT measurement, for example the OMT frequency, is below a threshold value. The method may additionally or alternatively comprise correlating the one or more measurements with a cognitive impairment test score. By screening a subject is meant to detect potential disease. The method may further comprise selecting the subject for further screening to diagnose dementia or cognitive impairment. For example where the OMT frequency is below the threshold value (or is in a range indicating cognitive impairment) or the clinical score is below a certain value indicating cognitive impairment. In the same way, the method of monitoring the cognitive impairment progression may be a method of collecting data from a subject, suspected of progressive cognitive impairment. The method may therefore comprise: a) obtaining (collecting) OMT data from the subject at a first time point; b) calculating one or more OMT measurements from the OMT data; and c) analysing the OMT measurement; d) repeating steps a)-c) at a second time point; and comparing the one or more OMT measurements from the first time point with the one or more OMT measurements at a second time point. The methods may also include a method of collecting data from a subject undergoing treatment for cognitive impairment The method may comprise: a) obtaining OMT data from the subject; b) calculating one or more OMT measurements from the OMT data; and c) analysing the one or more OMT measurements. That is, the methods may be data collection methods, which combined with further data points lead to a diagnosis. OMT Device The device is configured to obtain OMT data from a subject. The OMT data is stored on a processor of the OMT device. The device may also be configured to perform calculations on the OMT data and to output one or more OMT measurements. For example, the device may be configured to obtain an OMT waveform from a subject and calculate the frequency, for example the mean frequency, from the OMT waveform. The OMT data (and optionally further the calculated one or more OMT measurements from the data) may be obtained using a device comprising: • a light source for illuminating a target area of the eye with a light beam; • a detector arranged to detect scattered light from the interaction of the light beam with the target area of the eye; • a focusing lens arranged with the detector on the focal plane to resolve the angle of the scattered light for the detector; and • a port in a wall of the device through which the light beam can exit the device and / or through which the scattered light can enter the device; and • wherein the device is configured to stabilise and / or support the device on or against a patient’s head. The one or more support portions may be configured, in use, to position the port at a predetermined distance from the eye during a measurement; and optionally or preferably, within a predetermined volume of space with respect to the eye. The device may be a handheld device. System A system comprises an OMT device configured to obtain OMT data, for example the device as described above; and an electronic device operably connected to the OMT device and configured to receive OMT data from the device, wherein the OMT device and electronic device are configured to collectively perform any of the methods described herein. For example, the OMT device may be configured to obtain OMT data and perform further calculations on the OMT data. For example, where the OMT data collected is an OMT waveform, the OMT device may additionally calculate the OMT frequency, for example the mean frequency, from the OMT waveform. Alternatively, the OMT device may only obtain the OMT data and the electronic device receives the OMT data and performs the further calculations. For example, the electronic device may receive the OMT data, for example the OMT waveform from the device, and the electronic device may calculate the OMT frequency from the OMT data, e.g. waveform (as well as carry out any further analyses, for example correlating the OMT frequency with a cognitive impairment test score). By electronic device described herein includes a computing device such as a Personal Computer (PC), desktop PC, a laptop computer, or the like; a personal communication device such as a mobile phone, a tablet device or the like; and / or other electronic devices such as a mobile medical device. The electronic device may comprise one or more control systems which may in turn comprise one or more processors. The control system may comprise one or more controllers collectively comprising at least one electronic processor having an electrical input for receiving an input signal; and at least one memory device electrically coupled to the at least one electronic processor and having instructions stored therein; and wherein the at least one electronic processor is configured to access the at least one memory device and execute the instructions. The electronic device may be physically connected to the OMT device. Alternatively, the electronic device may be connected wirelessly to the OMT device. By processor as described herein is meant general purpose processors, network processors that process data communicated over a computer network, or other types of processor, including reduced instruction set computers or complex instruction set computers. Apparatus The processing circuitry may be general purpose processor circuitry configured by program code to perform specified processing functions. The circuitry may also be configured by modification to the processing hardware. The configuration of the circuitry to perform a specified function may be limited exclusively to hardware, limited exclusively to software, or a combination of hardware modification and software execution. Program instructions may be used to configure the logic gates of general purpose or special purpose processor circuitry to perform a processing function. The processing circuitry is described further below. The apparatus comprises a control system. The control system comprises one or more processors collectively configured to receive one or more ocular microtremor (OMT) measurements obtained from a subject. The control system may be configured to receive OMT data and perform further calculations on the OMT data to result in one or more OMT measurements. For example, if the OMT data is an OMT waveform, the apparatus may calculate as output an OMT frequency, optionally the mean OMT frequency, accompanied by a cognitive impairment test score which correlates to the OMT frequency. The control system may comprise one or more controllers collectively comprising at least one electronic processor having an electrical input for receiving an input signal; and at least one memory device electrically coupled to the at least one electronic processor and having instructions stored therein; and wherein the at least one electronic processor is configured to access the at least one memory device and execute the instructions. With reference to Figure 4, there is illustrated a control system 100. The control system 100 comprises a processor 102. The control system 100 is configured to receive one or more ocular microtremor (OMT) measurements or OMT data 104 obtained from a subject. Where the input is OMT data, the processor is configured to perform further calculations on the OMT data. For example, if the OMT data is a waveform, the processor may be configured to calculate the OMT frequency from the OMT waveform. The OMT measurement, e.g. the OMT frequency, may then be correlated to a cognitive impairment test score. The output 106 may be the frequency and the cognitive impairment test score correlated to that frequency. Referring now to Figure 5, there is shown a flow chart of a method according to an example of the disclosure. The method 200 comprises, at block 202, receiving one or more ocular microtremor (OMT) measurements obtained from a subject. At block 204, the method comprises determining a level of cognitive impairment of the subject. The method 200, at block 11 206, may comprise outputting the determined level. The method may be implemented by the control system 100 described herein in reference to Figure 4, but is not limited thereto. Referring now to Figure 6, there is shown a block diagram of an apparatus 300 that is a device configured to collect OMT data. The apparatus comprises the control system 100 described and a device unit 302 for obtaining OMT data from a subject. Such a device unit may comprise a housing containing light source for illuminating a target area of the eye with a light beam; a detector arranged to detect scattered light from the interaction of the light beam with the target area of the eye; a focusing lens arranged to collect the scattered light for the detector; and a port in a wall of the housing, wherein the port is configured such that at least one of: the light beam can exit the device and the scattered light can enter the device. The housing may comprise one or more support portions configured, in use, to be placed in contact with one or more locations on a patient’s head or face to stabilise and support the device on or against a patient’s head. The housing may be moveable relative to each support portion for aligning the device to the target area of the eye. The apparatus may be a handheld device. Computer program and non-transitory media By computer program is meant machine readable program instructions. These may be provided on a transitory medium such as a transmission medium or on a non-transitory medium such as a storage medium. When executed by one or more electronic processors, the instructions cause the one or more electronic processors to carry out one or more of the methods described herein. The machine-readable instructions may, for example, be executed by a general-purpose computer, a special purpose computer, an embedded processor or processors of other programmable data processing devices to realize the functions described in the description and diagrams. The term 'processor' is to be interpreted broadly to include a CPU, processing unit, ASIC, logic unit, or programmable gate array etc. The methods and functional modules may all be performed by a single processor or divided amongst several processors. Kit The components of the kit are as described above for the individual components. Throughout the specification, unless the context demands otherwise, the terms ‘comprise’ or ‘include’, or variations such as ‘comprises’ or ‘comprising’, ‘includes’ or ‘including’ will be understood to imply the method or kit includes a stated integer or group of integers, but not the exclusion of any other integer or group of integers. Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in the text is not repeated in this text is merely for reasons of conciseness. Reference to cited material or information contained in the text should not be understood as a concession that the material or information was part of the common general knowledge or was known in any country. Description of the Figures Figure 1 shows: Right eye OMT vs MoCA. Figure 2 shows: Left eye OMT vs MoCA. Figure 3 shows: Mean of right and left eye OMT vs MoCA. Figure 4 shows: a block diagram of a control system according to an embodiment of the invention; Figure 5 shows: a flow chart of a method according to an embodiment of the invention Figure 6 shows: a block diagram of an apparatus according to an embodiment of the invention. Figure 7 shows: An example waveform. The plot represents a 1 second waveform segment with peaks marked by “X” and troughs marked with “O”. Examples Aspects of the present invention will now be illustrated by way of example only and with reference to the following experimentation. Example 1: Measuring OMT in dementia patients The measurements were taken using an iTremor handheld device (for example as described in WO2020 / 043859). The device was positioned at a close proximity to the subject’s eye (approx. 2-5 cm away) so that an unobstructed view of the lateral eye sclera (the white part of the eye) falls in the view field of the device. The support portion of the device was rested on the subjects eyebrow and cheek areas for stability. A short (several second) measurement was captured by the device while the participant maintained a steady and neutrally fixated eye gaze. Typically, the subjects were in a seated position; however the measurement can also be recorded with participants in a supine position. The / Tremor device uses non-invasive optical method to direct coherent light to the eye surface (but not directly into the pupil) at an eye-safe intensity for use with human eyes. The reflected scattered light was captured by the device on to an imaging sensor. Digital image processing techniques were used to extract the OMT waveform. The waveform was then characterised by summary parameters such as mean frequency, amplitude and timevarying patterns (such as bursts). As the sequence of high frame rate video of the angle resolved speckle images are captured on the imaging sensor, a hardware accelerated 2D image convolver performs cross correlation on adjacent frames in order to produce a frame sequence of correlation peaks whose position represents the average velocity of the speckle between adjacent frames. The velocity vectors that are derived from the peaks of the HW accelerated correlation function are then integrated to produce position vectors that are then passed through a digital filter to remove low frequency movements, eye drift and offsets and instrument movement due to hand tremor. The result is a set of time series data that represents the horizontal and vertical position of the eye in the frequency band of interest which is between approximately 30Hz and 230Hz. This waveform contains peaks and troughs that represent a change in direction of the eye and they are counted in order to arrive at a mean frequency. But unlike a periodic oscillating body such as a pendulum, OMT produces peaks and troughs of varying magnitude therefore a thresholding function is used to eliminate peaks and troughs that fall below a certain small magnitude that could be construed as noise. The thresholding function is dynamic and is based on the overall magnitude of the waveform signal. The mean frequency is calculated as the number of peak trough pairs that are counted over the duration of the measurement divided by the duration which is typically between 2 and 5 seconds. The OMT frequency represents a point-in-time measure. It can be repeated on demand to account for natural diurnal variation or influence of external factors such as caffeine intake. An average of several (typically 3) point-in-time measurements can be used for improved accuracy of the OMT mean frequency in a particular subject Example 2: OMT correlates with MoCA The mean frequency of OMT waveform measured in Hertz (Hz) has so far been identified as a potential neurophysiological biomarker for physical impairment. However, previously reported findings did not make associations between OMT and cognitive decline such as seen in Alzheimer’s Disease (AD). The Montreal Cognitive Assessment (MoCA) is a screening tool for cognitive function and assesses domains such as attention, concentration, memory, visuospatial skill, abstract thinking, and calculation. The MoCA consists of several tasks, such as drawing a clock, recalling a list of words, naming animals, and performing serial subtractions. The MoCA score is based on a clinical assessment and scoring system to measure cognitive decline. A score of less than 26 is generally considered to show cognitive impairment and the lower the score, the more severe the impairment. Each task is scored, and the total score ranges from 0 to 30, with a score of 26 or above generally considered normal. It is used to help identify people with Alzheimer’s disease. In a study involving n=20 participants, measurements of OMT were taken and the MoCA assessments were carried out. A scatter plot of OMT frequency and the MoCA score was generated and a least-squares linear model was fitted to quantify the association. The dataset included n=16 participants who scored 26 or more on the MoCA scale, hence would be considered as showing normal cognitive function. The remaining n=4 participants scored 25 or less on the MoCA scale, hence would be considered as showing signs of cognitive decline. Results: The results are shown in Figures 1-3. Figure 1 shows: Right eye OMT vs MoCA. Figure 2 shows: Left eye OMT vs MoCA. Figure 3 shows: Mean of right and left eye OMT vs MoCA. OMT frequency (Hz) in the right, left, and both eyes positively correlated with the total MoCA score (r= 0.569, p= .006; r= 0.687, p= .001; r= 0.657, p= .001 respectively). This shows that OMT frequency correlates with cognitive decline. While MoCA is a widely recognised and frequently used tool for Alzheimer’s diagnosis and management, it has known limitations. These include (i) time needed for test administration, which typically ranges from 10 to 15 minutes, and (ii) the learning effect (improvement in performance) attributed to familiarity with the tasks, instructions, and format of the assessment rather than a genuine change in cognitive function. The use of OMT as a proxy (or surrogate) to MoCA in cognitive assessment and Alzheimer’s can overcome these limitations since (i) OMT measurement can be completed in under 1 5 minute with the iTremor device, and (ii) OMT is objective intrinsic neurophysiological measure that cannot be consciously controlled by the subject. As such, it can provide a substantial value over a traditional neurocognitive assessment. Any outliers were found likely to be due to other underlying conditions as after running a partial correlation analysis, controlling for other symptoms / disease severity the association 10 remained significant between OMT and MoCA. Thus, even when we account for other diseases being present, the association between cognitive decline and OMT remains significant.

Claims

1. A method of diagnosing dementia in a subject comprising:a) analysing one or more ocular microtremor (OMT) measurements obtained from the subject; andb) based on the one or more OMT measurements, diagnosing dementia in the subject.

2. The method of claim 1, wherein analysing the one or more OMT measurements comprises comparing the OMT measurements obtained from the subject with a threshold value.

3. The method of claims 1-2, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean OMT frequency.

4. The method of claim 3, wherein if the frequency, optionally the mean frequency, is below a threshold value of about 65 Hz, dementia is diagnosed.

5. The method of claims 1-4, wherein analysing the one or more OMT measurements further comprises correlating the one or more OMT measurements to a cognitive impairment test score, optionally wherein the cognitive impairment test score is a MoCA (Montreal Cognitive Assessment) score.

6. The method of claims 3-5, wherein:a) the lower the frequency, optionally the mean frequency, is indicative of more progressed dementia; orb) the lower the frequency, optionally the mean frequency, the lower the determined cognitive test score indicating more progressed dementia.

7. The methods of any of the preceding claims, wherein the dementia is Alzheimer’s disease.

8. A method of detecting cognitive impairment in a subject comprising:a) analysing one or more OMT measurements from the subject; and b) based on the one or more OMT measurements, detecting cognitive impairment.

9. The method of claim 8, wherein analysing the one or more OMT measurements comprises comparing the OMT measurements obtained from the subject with a threshold value.

10. The method of claims 8-9, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean OMT frequency.

11. The method of claim 10, wherein if the frequency, optionally the mean frequency, is below a threshold value of 69 Hz, mild cognitive impairment is diagnosed.

12. A method of monitoring cognitive impairment progression in a subject comprising: a) analysing one or more OMT measurements obtained from the subject at a first time point;b) analysing one or more OMT measurements obtained from the subject at a second later time point; andc) comparing the one or more measurements obtained in a) with those obtained in b), wherein a change in the one or more OMT measurements from a) to b) is indicative of a change in cognitive impairment in the subject.

13. The method of claim 12, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean OMT frequency.

14. The method of claim 13, wherein a decrease in the OMT frequency from a) to b), optionally the mean OMT frequency, is indicative of a decline in cognitive impairment.

15. A method of determining the therapeutic effect of a treatment regimen for cognitive impairment in a subject comprising:a) analysing one or more OMT measurements obtained from the subject, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean OMT frequency;b) repeating step a) after treatment; andc) comparing the OMT frequency obtained in a) with the OMT frequency obtained in b), wherein:i) an increase in the OMT frequency indicates that the treatment has a therapeutic effect; orii) a decrease or no change in the OMT frequency indicates that the treatment is not having a therapeutic effect.

16. The methods of any of claims 12-15 wherein the cognitive impairment is dementia, optionally wherein the dementia is Alzheimer’s disease.

17. The method of claims 8-16, wherein analysing the one or more OMT measurements further comprises correlating the OMT measurements to a cognitive impairment test score, optionally wherein the cognitive impairment test score is a MoCA (Montreal Cognitive Assessment) score.

18. The method of any of the preceding claims, further comprising a computer-implemented step of calculating the one or more OMT measurements from OMT data obtained from the subject, optionally wherein the OMT measurement is the OMT frequency, and the OMT data is the OMT waveform.

19. A computer-readable storage media, or a computer program, comprising computerexecutable instructions, which when executed by a computing system, are capable of causing the computing system to perform the method according to any of the preceding claims.

20. A kit comprising:a) An OMT device for obtaining OMT data from a subject; andb) the computer-readable storage media; or computer program, of claim 19.

21. Apparatus comprising processing circuitry configured to perform the method of any one of claims 1 to 18, optionally wherein the apparatus is an OMT device configured to obtain OMT data from the subject.

22. A system comprising:a) an OMT device for obtaining OMT data from a subject; andb) an electronic device operably connected to the OMT device;wherein the OMT device and electronic device are configured to perform the method of any of claims 1 to 18.

23. The kit, apparatus or system of claims 20-22 wherein:a) the OMT data comprises an OMT waveform, optionally wherein the OMT device or apparatus is configured to calculate the OMT frequency, optionally the mean OMT frequency, from the OMT waveform; and / orb) the OMT device comprises:i) a light source for illuminating a target area of the eye with a light beam;ii) a detector arranged to detect scattered light from the interaction of the light beam with the target area of the eye;iii) a focusing lens arranged on the focal plane to resolve the angle of the scattered light for the detector; andiv) a port in a wall of the device through which the light beam can exit the device and / or through which the scattered light can enter the device; andwherein the OMT device is configured to stabilise and / or support the device on or against a patient’s head.

24. Use of one or more OMT measurements obtained from a subject to: a) detect cognitive impairment; or b) diagnose dementia, optionally wherein the dementia is Alzheimer’s disease.

25. The use of claim 24, wherein the one or more OMT measurements comprise the OMT frequency, optionally the mean frequency.

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