Method for reducing caregiver burden associated with alzheimer's disease

Abstract

Provided is a method of reducing caregiver burden associated with Alzheimer's disease by administering to an Alzheimer's disease patient a therapeutically effective amount of fasudil, or a salt or hydrate thereof. Doses of 90 to 180 mg / day of fasudil are contemplated for reducing caregiver burden.

Description

[0001] 3000079-032977 METHOD FOR REDUCING CAREGIVER BURDEN ASSOCIATED WITH ALZHEIMER’S DISEASE BACKGROUND Alzheimer’s disease is the most common progressive neurodegenerative disease (60 to 80% of dementia patients) that eventually leads to death. There are an estimated 6 million people in the United States (US) with Alzheimer's dementia and this number is expected to reach 14 million by 2050. A significant number of Alzheimer’s disease patients are cared for at home by family members. Caring for a person with dementia is a very demanding task both emotionally and physically. Many Alzheimer’s disease patients exhibit agitation, aggression, hallucinations, delusions, and wandering (elopement) behaviors that pose a serious burden to caregivers. Caregivers often struggle to balance dementia care while working and coping with feelings of anticipatory grief. The suffering and emotional burdens of caregivers from these responsibilities include depression, despair, weariness, sleep deprivation, stress, and social withdrawal, and lead to a decreased quality of life for the caregivers. Caregivers also delay their own medical care and develop poor health habits such as poor nutrition. (Dawood S.2016). Increased caregiver burden is associated with poorer outcomes for patients, including increased institutionalization of Alzheimer’s patients. (Kuzuya M 2011). There is also an unfortunate risk of maltreatment of a dementia patient by a caregiver experiencing a high burden. Caregivers can become angry or frustrated with the Alzheimer’s patient for being unable to perform self-care. Agitation and / or aggression are estimated to affect up to approximately 80% of patients with dementia (Ryu 2005; Tractenberg 2003). Agitation in AD and dementia patients leads to caregiver stress, increased morbidity and mortality for the patients, and earlier placement into care facilities. Agitation and irritability, in particular, pose a threat to the health and quality of life of dementia patients. For example, common paranoid delusions in agitated dementia patients include beliefs that the house has been invaded, that personal objects have been misplaced or stolen, that family members have been replaced by impostors, or that spouses have been unfaithful. A higher level of severity of behavioral and psychological symptoms of dementia in the patient leads to a higher level of depressive symptoms and perception of stress in caregivers. (Deardorff and Grossbert 2010). A meta-analysis of several studies on mental health disorders among Alzheimer’s caregivers found that the prevalence of depression was 34 percent and anxiety was 43.6 percent. (Pinyopornpanish 2021). Another study found that 40% of caregivers experience depression, with about 25% of caregivers reported taking antidepressant medication (although 69% of these continued to experience significant symptoms of depression). (Mausbach 2013). 3000079-032977 Some studies have found that adult children experienced higher caregiver stress than spousal caregivers, while others showed the opposite. In one controlled, randomized study conducted with 206 caregivers in the UK, it was observed that when these caregivers were provided with places / people where they can get support, behavior management, spending quality time on education, psychological support, and the negative effect of patient symptoms on the caregiver decreased and the quality of life of the caregiver improved. (Anderson LA 2009). Non-pharmacological, behavioral approaches to control behavior Alzheimer’s patients are a challenge and take time to implement, which is not conducive for care facilities where poor staff to resident ratios exist. There are currently no FDA-approved pharmacological treatments for agitation in Alzheimer's disease, and clinicians therefore resort to off-label use of antipsychotics, sedatives / hypnotics, anxiolytics, and antidepressants to attempt to control symptoms. Common medications used to treat agitation include beta blockers such as propranolol and pindolol, anxiety medications such as buspirone, anti-convulsants such as valproate and lamotrigine, anti- psychotics such as haloperidol and other high-potency dopamine-blocking agents and atypical antipsychotics. In Alzheimer’s disease, for example, pharmacological treatment frequently includes use of atypical antipsychotics which have modest effects that are outweighed by safety and efficacy concerns leading to “black box” warnings by the U.S. Food and Drug Administration (FDA). There is an increased risk of death and potentially life-threatening side effects when such antipsychotics are used, especially at higher doses. (Maust 2015). Other adverse effects of antipsychotic use include increased cerebrovascular events, gait abnormality, falls, and metabolic syndrome. According to the Alzheimer’s Association, Alzheimer’s patients typically live four to eight years after diagnosis but can live up to 20 years, especially if the patient is younger when diagnosed. Given that Alzheimer’s is a progressive disease, dementia caregivers can expect their responsibilities and stress levels to steadily increase over time. There is accordingly a great need to reduce caregiver burden of Alzheimer’s patients for the benefit of both the caregiver and the patient. The use of fasudil to treat agitation and anxiety in dementia patients was the subject of an earlier patent application (PCT / US2022 / 079861). Surprisingly, it has not been shown that caregiver burden of Alzheimer’s patients is reduced upon administration of fasudil in Alzheimer’s disease patient. 3000079-032977 SUMMARY In one embodiment, provided is a method of reducing caregiver burden associated with Alzheimer's disease by administering to the Alzheimer’s disease patient a therapeutically effective amount of fasudil, or a salt or hydrate thereof. In certain embodiments, the patient is considered to be at least a mild burden to at least one caregiver. In other embodiments, the patient is considered to be a moderate or severe burden. In different embodiments, the patient’s burden before treatment results in a score of > 21, > 41 or > 61 on the Zarit Burden Interview, which represents mild, moderate, and severe burden, respectively. In one embodiment of any of the foregoing embodiments, the patient with Alzheimer’s disease is aged 65 or younger (≤ 65). In an embodiment of any of the preceding embodiments, fasudil is orally administered to the Alzheimer’s disease patient. In another embodiment of any of the preceding embodiments, the patient exhibits agitation. In an embodiment of any of the preceding embodiments, the reduction in caregiver burden is measured using the Zarit Burden Interview (ZBI). In an embodiment of any of the preceding embodiments, the ZBI improves by at least four points, at least five points, or preferably at least six points. In an embodiment of any of the preceding embodiments, the reduction in caregiver burden is measured using the Cohen-Mansfield Agitation Inventory C scale (CMAI-C). In a further embodiment of any of the preceding embodiments, the Alzheimer’s disease patient has a baseline score on the CMAI-C of at least 10, at least 12, at least 15, or at least 20. In an embodiment of any of the preceding embodiments, an improvement with fasudil on the CMAI-C is at least five, at least ten points, at least twelve points, at least twenty points, or at least twenty-five points. In one embodiment, the patient’s NPI-Q score is reduced by at least one point and in particular, improvement is noted on the Distress scale on the magnitude of 2, 3 or even 4 points or more. In a further embodiment, the Alzheimer’s disease patient exhibits a baseline score on the Global Impressions of Wandering scale of at least 4. 3000079-032977 In an embodiment, the patient exhibits a decrease on the overall GIW score of at least 1 point, at least 2 points, at least 3 points, or 4 points or more. In an embodiment of any of the preceding embodiments the fasudil administered is fasudil hydrochloride hemihydrate. In an embodiment of any of the preceding embodiments, the fasudil or pharmaceutically acceptable salt or hydrate thereof, is administered in a dose of between 90 and 180 mg / day. In a specific embodiment of any of the preceding embodiments, the fasudil is administered to the patient in an immediate-release formulation. In another embodiment of any of the preceding embodiments, the fasudil is administered to the patient in an extended-release formulation, wherein the maximum plasma concentration and area under the curve in plasma over 24 hours do not exceed by more than 15% what is obtained using a dosing regimen of 90 to 240 mg / day as an immediate release formulation. In a specific embodiment of any of the preceding embodiments, the fasudil is administered to the patient two times per day (BID) or three time per day (TID). In another specific embodiment of any of the preceding embodiments, the fasudil is administered to the patient in a daily dose of 90 mg administered in equal portions TID. In another specific embodiment of any of the preceding embodiments, the fasudil is orally administered to the patient. In an embodiment of any of the preceding embodiments, the caregiver is female. In an embodiment of any of the preceding embodiments, the caregiver is aged 50 or younger. In an embodiment of any of the preceding embodiments, the caregiver has been caring for the Alzheimer’s disease patient for at least 2 years, at least 4 years, or 5 years or more. In an embodiment of any of the preceding embodiments, the reduction in caregiver burden is reflected by lower reported depression among the caregiver compared to that prior to fasudil treatment. In another embodiment of any of the preceding embodiments, the ≤ 65 patient is male. In an embodiment of any of the foregoing embodiments, the ≤ 65 patient treated with fasudil exhibits reduced wandering. 3000079-032977 DETAILED DESCRIPTION Provided is a method of reducing caregiver burden associated with caring for an Alzheimer’s disease patient. In one embodiment, the patient may be aged ≤ 65 and the method may comprise administering to the Alzheimer’s patient a therapeutically effective amount of fasudil. In another embodiment, the patient also displays agitation and the reduction in caregiver burden is associated with a reduction in agitation in the Alzheimer’s disease patient. The term “agitation,” as used in this disclosure, is includes the definition of agitation as described by Cummings 2015. Broadly, Cummings et al. define agitation as: 1) occurring in patients with a cognitive impairment or dementia syndrome; 2) exhibiting behavior consistent with emotional distress (e.g. rapid changes in mood, anxiety, irritability, outbursts, etc.) and the behavior has been persistent or frequently recurrent for a minimum of two weeks and is a change from the patient's usual behavior; 3) the behaviors are severe enough to produce excess disability; and 4) and the agitation is not solely attributable to another disorder (psychiatric, suboptimal care conditions, medical, or substance-related). Agitation also includes “sundowning,” which refers to behavioral disturbances that peak in the late afternoon or evening. Sundowning affects up to two-thirds of patients with dementia and is closely related to disturbed circadian rhythms Fasudil The disclosed methods contemplate the administration of the rho kinase (ROCK) inhibitor fasudil in the treatment of a disease or condition. Two mammalian ROCK homologs are known, ROCK1 (aka ROKβ, Rho-kinase β, or p160ROCK) and ROCK2 (aka ROKα) (Nakagawa 1996). In humans, the genes for both ROCK1 and ROCK2 are located on chromosome 18. The two ROCK isoforms share 64% identity in their primary amino acid sequence, whereas the homology in the kinase domain is even higher (92%) (Jacobs 2006; Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have a similar structure. The isoquinoline derivative fasudil was the first small molecule ROCK inhibitor developed by Asahi Chemical Industry (Tokyo, Japan). The characteristic chemical structure of fasudil consists of an isoquinoline ring, connected via a sulphonyl group to a homopiperazine ring. Fasudil is a potent inhibitor of both ROCK isoforms. 3000079-032977 In vivo, fasudil is subjected to hepatic metabolism to its active metabolite hydroxyfasudil (aka, M3). Other examples of isoquinoline derived ROCK inhibitors include dimethylfasudil, ripasudil, Y- 27632, and Y39983. Fasudil has been reported to have a number of potentially beneficial effects in conditions of the CNS, although no there is no Level 1 evidence of treatment effect in any condition, meaning any potential medical application remains speculative. Greathouse 2019, report that depletion of rho kinases or treatment with fasudil induces anxiety- like behavior in mice. Six-month old mice were dosed with 10 mg / kg fasudil or water by oral gavage once a day for 30 days. Behaviors were assessed over the final 3 days of drug treatment by elevated plus maze and open field. Fasudil treatment significantly reduced the amount of time the mice spent in the “open arms” part of the maze, indicating anxiety. Genetic reduction of rho kinase inhibitors (heterozygotes for ROCK1 and ROCK2) exhibited the same behavior. It is commonly understood that anxiety and agitation are strongly associated, and that agitation may be caused by anxiety. The present invention is based on the surprising discovery that, despite the anxiety-producing effects of fasudil in mice, it can be successfully employed in the treatment of agitation. As used herein, the term fasudil includes the various forms of the drug, including the free base, salts, ion pairs, different hydrates and polymorphs of fasudil. It also includes M3 and the corresponding forms of M3. One of skill in the art can readily determine the molar equivalents of each form of the molecule and, thus, translate dosing from fasudil hydrochloride hemihydrate to any other form a fasudil or M3. Dosage and Administration In accordance with the treatment methods, a therapeutically effective amount of fasudil or a pharmaceutically acceptable salt thereof, such as fasudil hydrochloride hemihydrate, for administration one or more times a day may comprise from about 10 mg to about 1000 mg. 3000079-032977 Fasudil hydrochloride hemihydrate, for example, is suitably administered in a daily amount of about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 20 mg to about 10 mg. One dosing regimen involves the treatment with 25, 30 or 40 mg of fasudil hydrochloride hemihydrate three times per day using an immediate-release formulation, for a total daily dose of 70 to 240 mg per day. Most preferred dosing exceeds a daily dose of 70 mg, with most preferred ranges for daily dosing being 90 to 180 mg administered in two or three equal amounts during the day. A particularly preferred daily dose is 90 mg / day administered 30 mg TID immediate release tablets. Fasudil is most preferably administered orally in accordance with the foregoing using an immediate release formulation. In another embodiment, fasudil is administered in a dose of 180 mg / day administered 60 mg TID immediate-release tablets. Another embodiment involves the treatment with 90-180 mg of fasudil hydrochloride hemihydrate once per day in an extended-release dosage form. Treatment with an extended-release total daily dose of 90 mg fasudil hydrochloride hemihydrate once per day is preferred. In one embodiment, the fasudil is administered to the patient in a dose from about 90 to 240 mg / day as an immediate release formulation. In another embodiment, the fasudil is administered to the patient in an extended-release formulation, wherein the maximum plasma concentration and area under the curve in plasma over 24 hours do not exceed by more than 15% what is obtained using a dosing regimen of 70 to 240 mg / day as an immediate release formulation. Methods of administering compositions according to the invention would generally be continued for at least one day. Some preferred methods treat for up to 30 days or up to 60 days or even up to 90 days or even more. Treatment for more than 60 days is preferred and treatment for at least 6 months is particularly preferred. The precise duration of treatment will depend on the patient’s condition and response to treatment. In one embodiment, the Alzheimer’s disease patient treated with fasudil does not have a history of schizophrenia. Pharmaceutical Compositions In a preferred embodiment, fasudil is administered in an oral dosage form. Pharmaceutical compositions of fasudil or its salts or hydrates for oral administration may be in the form of tablets 3000079-032977 or capsules and may be immediate-release formulations or may be controlled- or extended- release formulations, which may contain pharmaceutically acceptable excipients, such as corn starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose and similar substances. The oral pharmaceutical composition comprising fasudil or a salt or hydrate thereof may comprise one or more pharmaceutically acceptable excipients, which are known in the art. Formulations also include oral films, orally disintegrating tablets, effervescent tablets and granules or beads that can be sprinkled on food or mixed with liquid as a slurry or poured directly into the mouth to be washed down. In one embodiment, the fasudil is administered in a taste-masked oral formulation. An example of a bitterness masker that can bind a rho kinase inhibitor is an ion exchange resin, for example, as disclosed in U.S. Application Serial Nos.18 / 171,007; 18 / 171,070; and 18 / 171,077. In another embodiment, the fasudil is orally administered in the form of liposomes. Pharmaceutical compositions containing fasudil, or salts or hydrates thereof can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include the steps of bringing fasudil or a pharmaceutically acceptable salt or hydrate thereof into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit. Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition used in accordance with the methods of the present invention may comprise between 0.001% and 100% (w / w) active ingredient. Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, 3000079-032977 lubricating agents, and / or oils. Excipients such as coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a granulating and / or dispersing agent. Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a binding agent. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM.RTM.), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a preservative. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. 3000079-032977 In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise an antioxidant. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a chelating agent. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. In certain embodiments, the pharmaceutical composition may comprise a buffering agent together fasudil or salt or hydrate thereof. Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof. In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a lubricating agent. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. 3000079-032977 In other embodiments, the pharmaceutical composition of containing fasudil or salt or hydrate thereof will be administered as a liquid dosage form. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. Some compositions of the invention relate to extended- or controlled-release formulations. These may be, for example, diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems or ionic resin systems. Diffusion-controlled products comprise a water-insoluble polymer which controls the flow of water and the subsequent egress of dissolved drug from the dosage from. Dissolution-controlled products control the rate of dissolution of the drug by using a polymer that slowly solubilizes or by microencapsulation of the drug – using varying thicknesses to control release. Erosion products control release of drug by the erosion rate of a carrier matrix. Osmotic pump systems release a drug based on the constant inflow of water across a semi permeable membrane into a reservoir which contains an osmotic agent. Ion exchange resins can be used to bind drugs such that, when ingested, the release of drug is determined by the ionic environment within the gastrointestinal tract. 3000079-032977 Burden Assessment Questionnaires In some embodiments, the improvement by treatment with fasudil in agitation and / or aggression and / or associated symptoms in subjects with dementia, such as AD, may be measured by improvements of one or more of the Zarit Burden Interview (ZBI); the Cohen-Mansfield Agitation Inventory, clinician version (CMAI-C); the Neuropsychiatric Inventory (NPI) including the agitation subscales thereof. In certain embodiments, treated patients have a measurable minimum amount of agitation before commencing treatment. ZBI. In one embodiment, the Alzheimer’s disease patient treated with fasudil to reduce caregiver burden exhibits a reduction in score on the Zarit Burden Interview (ZBI). The Zarit Burden Interview (ZBI) is a caregiver self-report measure commonly used to assess caregiver burden. It originated as a 29-item questionnaire designed to assess burden among caregivers of community dwelling dementia patients. (Zarit, Reever & Bach-Peterson, 1980). A revised version contains 22 items. The ZBI consists of 22 items rated on a 5-point Likert scale that ranges from 0 (never) to 4 (nearly always) with the sum of scores ranging between 0–88. 3000079-032977 Higher scores indicating a greater burden. 3000079-032977 The ZBI has proven to be reliable (Hérbert, R., Bravo, G., & Préville, M.2000), although some studies using the ZBI found that certain factors were associated with caregiver burden. Specifically, adult children of caregivers experienced a higher burden than spousal caregivers despite less time spent caring. (Reed C, 2014). For spouses, younger females with more years of education reported higher caregiver burdens. Caregiver assessments according to the invention are typically performed by spouses or adult children. Patients treated according to the invention will generally be at least a mild to moderate burden and have a minimum ZBI score of 21 when assessed by at least one caregiver. Other patients will have a minimum ZBI score of 41, being considered a moderate to severe burden. Still others will have a minimum ZBI score of 61. These assessments refer to pre-treatment conditions. Treatment according to the invention results in a decrease in ZBI score. Typical improvements will be 5%, 10%, 15%, 20%, 25% or even greater reductions. Numerical changes may range from 3, 5, 10, 15, or 20 point reductions or more. In some embodiments patients presenting a severe burden may shift to moderate, mild or no burden. Likewise, moderate burden may become mild burden or no burden. Patients presenting a mild burden may present no burden during treatment. Clinical observations and other instruments, such as measures of depression, can also be used to supplement this measure. One study found no correlation between the patient performance on the MMSE and the ZBI so in one embodiment, there is no correlation between improvement on the ZBI and improvement on the MMSE. (Waltrowicz 1996). CMAI-C. In one embodiment, the Alzheimer’s disease patient treated with fasudil to reduce caregiver burden is assessed using the Cohen-Mansfield Agitation Inventory-Community based (CMAI-C). 3000079-032977 The CMAI was conceptualized as measuring agitation in two dimensions, verbal and physical, each of which has two poles, aggressive or non-aggressive. Studies based on this conceptualization found behavioral abnormalities of elderly subjects to be comprised of three main factors; verbally aggressive behavior, verbally non-aggressive behavior, and physically non- aggressive behavior (Cohen-Mansfield et al., 1989; Cohen-Mansfield, 1986; Cohen-Mansfield et al., 1995). A fourth factor, physically aggressive behavior, was added because of its importance in patient care, rather than its frequency of occurrence (Cohen-Mansfield et al., 1995; Cohen- Mansfield, 1995). Samples of the symptoms included in each factor based on community populations are (Cohen-Mansfield, 1991; Cohen-Mansfield et al., 1995) Physically Nonaggressive: restlessness, repetitious mannerisms, and pacing; Physically aggressive: hitting, pushing others, scratching others; Verbally Nonaggressive: negativism / uncooperativeness, unwarranted requests for attention; Verbally Aggressive: screaming / shouting, cursing, and temper outbursts. Frequency ratings describe the symptoms in the previous two weeks. The instrument did not include psychosis, mood disturbance, negative symptoms such as loss of initiative, vegetative symptoms such as sleep / wake disturbances, changes in eating patterns or appetite, or incontinence. The CMAI-C is a 37-item scale for caregivers to systematically to quantify agitated behaviors in elderly patients in a community setting. It assesses 35 specific symptoms, plus the time of day of the behavior, and the frequency of “other” behaviors. Subjects are rated by regarding the frequency with which they manifest physically aggressive, physically non-aggressive and verbally agitated behaviors on a 7-point scale from never (0) to several times and hour (6). The CMAI-C also asks the assessor to rate the subject’s behavior for the previous 2 weeks. (Cummings J 2015). The maximum score on the CMAI-C is 210 points, with a higher score representing a higher caregiver burden. The rating scale for the agitated behavior is as follows: 1 = Never 2 = Less than once a week 3 = Once or twice a week 4 = Several times a week 5 = Once or twice a day 6= Several times a day 7 = Several times an hour 1. During the past two weeks how often did [S] repeat sentences or questions? (was repetitive, whether or not addressed at any particular person) 2. During the past two weeks how often did [S] verbally interrupt or cut short others’ interactions or conversations saying something that is are relevant to the conversation? 3000079-032977 3. During the past two weeks how often did [S] verbally interrupt or cut short others interactions or conversations saying something that is not relevant to the conversation (has nothing to do with ongoing activity)? 4. During the past two weeks how often did [S] make strange noises, including strange laughter, moaning or crying? 5. During the past two weeks how often did [S] scream, shout, or howl? 6. During the past two weeks how often did [S] complain or whine? 7. During the past two weeks how often did [S] make unwarranted requests for attention or help? (includes nagging, pleading, calling out) 8. During the past two weeks how often was [S] negative, uncooperative or unwilling to participate in activities? (bad attitude, doesn’t like anything, nothing is right; includes social activities, eating, bathing) 9. During the past two weeks how often did [S] curse or was [S] verbally threatening or insulting? (verbal aggression; score only if intelligible words are used; otherwise score under item 4) 10. During the past two weeks how often did [S] spit (including during meals)? (do not include involuntary salivation; i.e., drooling) 11. During the past two weeks how often was [S] verbally bossy or pushy? 12. During the past two weeks how often did [S] make verbal sexual advances? (includes direct sexual propositioning or obvious sexual hints) 13. During the past two weeks how often did [S] make physical sexual advances or expose his / her sexual parts? (include inappropriate sexual touching of self or others) 14. During the past two weeks how often was [S] restless or fidgety, or tend to move around when in a seat or repeatedly get up and sit down? (can’t sit still) 15. During the past two weeks how often did [S] pace, walk repeatedly back and forth or wander aimlessly? (include wandering when done in a wheelchair) 16. During the past two weeks how often did [S] try to get out of doors inappropriately, sneak out or inappropriately enter other places? 17. During the past two weeks how often did [S] dress or undress inappropriately? (such as undressing in public, or constantly dressing; it does not refer to ability to get dressed; if only genitals are exposed, rate on item 13) 18. During the past two weeks how often did [S] perform repetitious mannerisms? (includes rocking, rubbing, tapping, picking at skin) 19. During the past two weeks how often did [S] handle things inappropriately? (rummaging through drawers, picking up others’ possessions or things that should not be touched) 3000079-032977 20. During the past two weeks how often did [S] grab or snatch things from others? (including food from others’ plates) 21. During the past two weeks how often did [S] hoard or collect objects? 22. During the past two weeks how often did [S] hide objects? 23. During the past two weeks how often did [S] have a temper outburst, including verbal or non- verbal expression of anger? 24. During the past two weeks how often did [S] hit people, self or objects? 25. During the past two weeks how often did [S] kick people or objects? 26. During the past two weeks how often did [S] throw things such as food or knock objects off surfaces? 27. During the past two weeks how often did [S] tear or destroy objects or property? 28. During the past two weeks how often did [S] grab on to or cling to people physically? 29. During the past two weeks how often did [S] push other persons? 30. During the past two weeks how often did [S] bite people or things? 31. During the past two weeks how often did [S] scratch people, self, or things? 32. During the past two weeks how often did [S] hurt him / herself by cutting, burning or other means? (with harmful object) 33. During the past two weeks how often did [S] hurt others by cutting, burning or other means? (with harmful object) 34. During the past two weeks how often did [S] appear to fall intentionally? (include from bed or wheelchair) 35. During the past two weeks how often did [S] attempt to or did [S] actually eat or drink nonfood substances? 36. During the past two weeks, was there any other inappropriate behavior? If so, what? How often? 37. Did agitated behavior occur most often In morning In afternoon In evening No time more than others Different times for different behaviors In an embodiment, the assessment is made using the total 210 point score scale. As assessed by the CMAI-C, patients will have a threshold baseline minimum score of at least 10 or 15, with a preferred minimum of 20. However, minimum 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31 are also contemplated. 3000079-032977 In another embodiment, improvements on the CMAI-C may be driven by one or more domains of the CMAI-C, including the verbally aggressive, verbally non-aggressive, physically aggressive, physically non-non-aggressive domains. In a specific embodiment of the invention, the fasudil-treated patient’s CMAI-C score for agitation / aggression is reduced by at least five points from baseline in dementia patients treated with fasudil. In other embodiments, CMAI-C score for agitation / aggression is reduced by at least eight points, at least ten points, or at least twelve points from baseline following treatment with fasudil. Typical improvements will be 5%, 10%, 15%, 20%, 25% or even greater reductions. In some embodiments patients presenting a severe burden may shift to moderate, mild or no burden. Likewise, moderate burden may become mild burden or no burden. Patients presenting a mild burden may present no burden during treatment. NPI-Q. In one embodiment, the Alzheimer’s disease patient treated with fasudil to reduce caregiver burden is assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). The NPI-Q is designed to be a self-administered questionnaire completed by informants about patients for whom they care. Each of the twelve NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are “Yes”(present) or “No” (absent). Thus, a total score of 36 points would indicate maximum severity in all parameters considered. If the response to the domain question is “No,” the informant goes to the next question. If “Yes,” the informant then rates both the Severity of the symptoms present within the last month on a 3- point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a five-point scale. The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the sum of individual domain scores. The NPI-Q Distress ratings have a maximum score of 60 (a score of 5 on all questions). The NPI-Q instructions and questions follow: Circle “Yes” only if the symptom(s) has been present in the last month. Otherwise, circle “No,” For each item marked “Yes”: a) Rate the SEVERITY of the symptom (how it affects the patient): 1 = Mild (noticeable, but not a significant change) 2 = Moderate (significant, but not a dramatic change) 3000079-032977 3 = Severe (very marked or prominent, a dramatic change) b) Rate the DISTRESS you experience due to that symptom (how it affects you): 0 = Not distressing at all 1 = Minimal (slightly distressing, not a problem to cope with) 2 = Mild (not very distressing, generally easy to cope with) 3 = Moderate (fairly distressing, not always easy to cope with) 4 = Severe (very distressing, difficult to cope with) 5 = Extreme or Very Severe (extremely distressing, unable to cope with) Please answer each question carefully. Ask for assistance if you have any questions. Delusions Does the patient have false beliefs, such as thinking that others are stealing from him / her or planning to harm him / her in some way? Yes No SEVERITY: 123 DISTRESS: 012345 Hallucinations Does the patient have hallucinations such as false visions or voices? Does he or she seem to hear or see things that are not present? Yes No SEVERITY: 123 DISTRESS: 012345 Agitation / Aggression Is the patient resistive to help from others at times, or hard to handle? Yes No SEVERITY: 123 DISTRESS: 012345 Depression / Dysphoria Does the patient seem sad or say that he / she is depressed? Yes No SEVERITY: 123 DISTRESS: 012345 Anxiety Does the patient become upset when separated from you? Does he / she have any other signs of nervousness such as shortness of breath, sighing, being unable to relax, or feeling excessively tense? Yes No SEVERITY: 123 DISTRESS: 012345 Elation / Euphoria Does the patient appear to feel too good or act excessively happy? Yes No SEVERITY: 123 DISTRESS: 012345 Apathy / Indifference Does the patient seem less interested in his / her usual activities or in the activities and plans of others? 3000079-032977 Yes No SEVERITY: 123 DISTRESS: 012345 Disinhibition Does the patient seem to act impulsively, for example, talking to strangers as if he / she knows them, or saying things that may hurt people's feelings? Yes No SEVERITY: 123 DISTRESS: 012345 Irritability / Lability Is the patient impatient and cranky? Does he / she have difficulty coping with delays or waiting for planned activities? Yes No SEVERITY: 123 DISTRESS: 012345 Motor Disturbance Does the patient engage in repetitive activities such as pacing around the house, handling buttons, wrapping string, or doing other things repeatedly? Yes No SEVERITY: 123 DISTRESS: 012345 Nighttime Behaviors Does the patient awaken you during the night, rise too early in the morning, or take excessive naps during the day? Yes No SEVERITY: 123 DISTRESS: 012345 Appetite / Eating Has the patient lost or gained weight, or had a change in the type of food he / she likes? Yes No SEVERITY: 123 DISTRESS: 012345 In certain embodiments, improvements will be 5%, 10%, 15%, 20%, 25% or even greater reductions. In some embodiments patients presenting a severe burden may shift to moderate, mild or no burden. Likewise, moderate burden may become mild burden or no burden. Patients presenting a mild burden may present no burden during treatment. In other embodiments, treatment results in a reduction of distressing symptoms such as hallucinations, delusions, and / or aggression. In particular embodiments, these improvements are observed on the Distress scale. CNS-LS. In another embodiment Alzheimer’s disease patient treated with fasudil to reduce caregiver burden is assessed using the Center for Neurological Study-Lability Scale (CNS-LS). The CNS-LS is a short (seven-item), self-administered questionnaire, designed to be completed by the patient, which provides a quantitative measure of the perceived frequency of pseudobulbar affect (inappropriate emotional responses). A CNS-LS score of 13 or higher may suggest pseudobulbar affect. 3000079-032977 In one embodiment, treatment reduces the symptoms by at least 1 point, by at least 2 points, or by at least 3 or more points. In another embodiment, treatment reduces the frequency or number of occurrences of the symptoms in any given time period (day / week / month). GIW. In another embodiment, the Alzheimer’s disease patient treated with fasudil to reduce caregiver burden is assessed for wandering behavior using the Global Impression of Wandering (GIW) scale. The GIW is a clinician-based seven-point scale and is used specifically to obtain the clinician’s overall assessment of severity of the patient’s wandering behavior over the past month. Wandering is defined in the scale as one or more of the following behaviors: leaving or trying to leave the home when the patient is not supposed to, getting lost, excessive walking, and walking back and forth (pacing). Each question answered affirmatively is one point (0-6). 3000079-032977 In one embodiment, the Alzheimer’s disease patient exhibits a decrease on the overall GIW score of at least 1 point, at least 2 points, at least 3 points, or 4 points or more. Specific Outcomes Associated with Reduction in Caregiver Burden In one embodiment, treatment of treatment of Alzheimer’s disease patients with fasudil reduces the caregiver burden associated with agitation by at least 5%, 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50% as assessed by any of the foregoing burden scales. In a specific embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction in the number of occurrences of agitation such as from multiple occurrences daily to one or none per day, or from occurrences daily to fewer than daily. In one embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction the number of days per week agitation occurs in Alzheimer’s disease patients by at least one day per week, preferably by at least two days per week, and more preferably by at least three days per week. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction the severity of the agitation in patients, such by reducing the number of occurrences of verbal or physical aggression. In another specific embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with reduction in the number of occurrences of 3000079-032977 “sundowning” in patients per week or per month. In a further embodiment, fasudil treatment reduces the length of time or the progression of sundowning evening agitation. In a further embodiment, fasudil reduces the severity of the behavior associated with sundowning. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction in aberrant motor activity by at least 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In a specific embodiment, treatment with fasudil reduces the aberrant motor activity occurs during sundowning, or early evening. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction in sleep disturbances such as insomnia by at least 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In a specific embodiment, the number of incidences per week of insomnia is reduced. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with a reduction in the number of occurrence of delusions or hallucinations behavior by at least 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In yet another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients is associated with reduction in anxiety by at least 5%; 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients aged is associated with reduction in disinhibition by at least 5%; 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In a further embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients aged is associated with reduction hostility and suspiciousness by at least 5%; 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In another embodiment, the reduction in caregiver burden seen with fasudil treatment in Alzheimer’s disease patients aged is associated with reduction in eating or appetite disturbances by at least 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45% or 50%. In one embodiment, the dementia patient with agitation who exhibits a reduction in caregiver burden is male. In another embodiment of any of the foregoing embodiments, the patient is aged ≤ 65. EXAMPLES Example 1 3000079-032977 A clinical trial was conducted to determine the effectiveness of oral fasudil in reducing the agitation in patients with Alzheimer’s Dementia (AD). The study population consisted of Alzheimer’s patients or probable Alzheimer’s patients and wandering behaviors of elopement and / or getting lost. Enrolled patients entered the Open-Label Phase and received treatment with fasudil 90 mg / day of fasudil hydrochloride hemihydrate in tablets (30 mg three times daily [TID]) for 6 weeks in Open-Label Period 1. Responders (i.e., subjects who improve two points or more on the GIW) proceeded to the Double-Blind Phase. Patients in whom fasudil was well-tolerated (i.e. subjects with ≤ 2 drug-related AEs of mild intensity, no drug-related AEs of greater than mild intensity, and creatinine level of < 1.5 mg / dL at all times during the period) and who did not enter Open-Label Period 2, and be dosed with fasudil 180 mg / day (60 mg TID) for 6 weeks. Responders proceeded to the Double-Blind Phase and non-responders moved to the final post- treatment visit. In the Double-Blind Phase, subjects received treatment with either placebo or the dose they responded to in the Open-Label Phase (90 mg / day or 180 mg / day) for 6 weeks (Double- Blind Period 1), following which treatment assignment was crossed over for 6 weeks (Double-Blind Period 2). A final post-treatment occurred 14 days after the last dose of study drug. Visits were performed by qualified healthcare professionals at home or other care setting, or at a doctor's office / clinic. Interviews were performed in person or by telephone and / or telemedicine as appropriate. The primary endpoint was the Global Impressions of Wandering (GIW), with secondary endpoints including Weekly Wandering Report - Community Version (WWR-C); the Revised Algase Wandering Scale - Community Version (RAWS-CV); the Mini Mental State Examination (MMSE); the Neuropsychiatric Inventory-Questionnaire (NPI-Q); the Cohen-Mansfield Agitation Inventory - Community Version (CMAI-C); the Center for Neurological Study-Lability Scale (CNS-LS); and the Zarit Burden Interview (ZBI). Results: Surprisingly, results in a sub-population of Alzheimer’s patients aged ≤ 65 showed that fasudil treatment reduced caregiver burden assessed by the ZBI, CMAI-C, and to a certain extent on the NPI-Q. A change of less than five points on the CMAI is considered clinically meaningful so an improvement of five points or more is also meaningful. Subjects ≤ 65 n= 5 3000079-032977 Baseline Active Placebo pGIW (1-6) 4.00 2.40 3.20 0.099 MMSE (0-30) 15.80 16.20 16.80 0.810 CMAI-C (0-210) 21.20 12.40 21.00 0.155 ZBI (0-88) 32.40 27.20 34.40 0.015 NPIQ (0-36) 6.40 5.40 5.80 0.807 NPIQ-Distress (0-60) 6.20 2.00 7.40 0.225 CNS-LS 10.00 7.60 8.00 0.178

[0002] 3000079-032977 List of References All of the below are incorporated by reference into this application in their entireties. Anderson LA et al. The public’s perceptions about cognitive health and Alzheimer’s disease among the U.S. population: a national review. Gerontologist.2009;49:S3–11. Cohen-Mansfield, Agitated behaviours in the elderly: II. Preliminary results in the cognitively deteriorated. JAGS.1986; 34:722-7 Cohen-Mansfield et al., 1989; A description of agitation in a nursing home J Gerontol.1989 May;44(3):M77-84. Cohen-Mansfield J . (1991). Instruction Manual for the Cohen-Mansfield Agitation Inventory. The Research Institute of the Hebrew Home of Greater Washington. Retrieved from www.dementia- assessment.com.au / symptoms / CMAI_Manual.pdf Cohen-Mansfield et al., Sleep and agitation in agitated nursing home residents: an observational study. Sleep.199518(8):674-80. Cummings J et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr.2015;27(1):7–17 Dawood S., Caregiver Burden, Quality of Life and Vulnerability Towards Psychopathology in Caregivers of Patients with Dementia / Alzheimer’s Disease. J Coll Physicians Surg Pak. 2016;26(11): 892–895. Deardorff and Grossbert. Behavioral and psychological symptoms in Alzheimer’s dementia and vascular dementia. Handb Clin Neurol.2019;165: 5–32. Dennehy EB et al., Derivation of a brief measure of agitation and aggression in Alzheimer’s disease. Int. Geriatr Psychiatry.2013; 28(2): 182-9. Greathouse et al., Fasudil or genetic depletion of ROCK1 or ROCK2 induces anxiety-like behaviors. Behavioural Brain Research.2019; 373:112083. Hébert, R., Bravo, G., & Préville, M. (2000). Reliability, validity and reference values of the Zarit Burden Interview for assessing informal caregivers of community-dwelling older persons with dementia. Canadian Journal on Aging, 19(4), 494–507. Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J, The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J Biol Chem.2006; 281(1): 260-68. Kuzuya M et al. Impact of caregiver burden on adverse health outcomes in community-dwelling dependent older care recipients. Am J Geriatr Psychiatry.2011;19(4):382–91. Mausbach et al., A comparison of psychosocial outcomes in elderly Alzheimer caregivers and non-caregivers. Am J Geriatr Psychiatry.2013; 21(1): 5-13. Mohamed et al., Caregiver Burden in Alzheimer Disease: Cross-Sectional and Longitudinal Patient Correlates. Am J Geriatr psychiatry.2010; 18(10: 917-27). 3000079-032977 Nakagawa O, Fukisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S, ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine / threonine kinase in mice. FEBS Lett. 1996 Aug 26;392(2):189-93 Pinyopornpanish, et al. Perceived stress and depressive symptoms not neuropsychiatric symptoms predict caregiver burden in Alzheimer’s disease: a cross-sectional study. BMC Geriatr 21, 180 (2021)). Reed C et al., Alzheimer's Disease: Differential Associations in Adult-Child and Spousal Caregivers in the GERAS Observational Study, Reliability, validity, and reference values of the Zarit Burden Interview for assessing informal caregivers of community-dwelling older persons with dementia. Dement Geriar Cogn Disord Extra.2014; 4: 51-64. Ryu et al., Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study. Am. J. Geriatr. Psychiatry.2005; 13(11):976-83. Trachtenberg et al., Comorbidity of Psychopathological Domains in Community-Dwelling Persons With Alzheimer’s Disease. J. Geriatr. Psychiatry. Neurol.2003; 16(2):94-99. Waltrowicz et al., Burden and stress on relatives (informal carers) of dementia sufferers in psychogeriatric nursing homes. Aust. J. Ageing.1996; 15: 115-8. Yamaguchi H, Miwa Y, Kasa M, Kitano K, Amano M, Kaibuchi K, Hakoshima T, Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632. J Biochem.2006 Sep;140(3):305-11.

Claims

3000079-032977 WHAT IS CLAIMED:

1. A method for reducing caregiver burden associated with Alzheimer’s disease comprising orally administering a therapeutically effective amount of fasudil, or a pharmaceutically acceptable salt or hydrate thereof, to an Alzheimer’s disease patient.

2. The method according to claim 1, wherein the Alzheimer’s disease patient is aged 65 or younger (≤ 65).

3. The method according to claims 1 or 2, comprising measuring the reduction in caregiver burden using the Zarit Burden Interview (ZBI).

4. The method according to claim 3, wherein the patient has a baseline ZBI score prior to treatment of > 21.

5. The method according to claim 3, wherein the patient has a baseline ZBI score prior to treatment of > 41.

6. The method according to claim 3, wherein the patient has a baseline ZBI score prior to treatment of > 61.

7. The method according to any one of the preceding claims, wherein the ZBI score improves by at least six points.

8. The method according to claims 1 or 2, comprising measuring the reduction in caregiver burden using the Cohen-Mansfield Agitation Inventory C scale (CMAI-C).

9. The method according to any one of the preceding claims, wherein the Alzheimer’s disease patient has a baseline CMAI-C score of at least twenty (20).

10. The method according to claim 9, wherein the CMAI-C score improves by at least five points following fasudil treatment.

11. The method according to claims 1 or 2, comprising measuring the reduction in caregiver burden using the Neuropsychiatric Inventory-Q (NPI-Q) assessment.3000079-032977 12. The method according to claim 11, wherein the NPI-Q Distress score is reduced by at least 2 points.

13. The method according to any one of the preceding claims, wherein the fasudil is fasudil hydrochloride hemihydrate.

14. The method according to any one of the preceding claims, wherein the fasudil or pharmaceutically acceptable salt or hydrate thereof, is administered in a dose of between 90 and 180 mg / day TID.

15. The method according to claim 14, wherein the fasudil or pharmaceutically acceptable salt or hydrate thereof, is administered in a dose 90 mg / day TID.

16. The method according to any of the preceding claims, wherein the Alzheimer’s disease patient is male.

17. The method according to any of the preceding claims, wherein the Alzheimer’s disease patient exhibits a reduction in wandering assessed according to the Global Impressions of Wandering (GIW) assessment.

18. The method according to claim 17, wherein the GIW is reduced by at least two points with fasudil treatment.

19. The method according to any one of the preceding claims wherein the reduction in caregiver burden is reflected by lower depression among the caregiver compared to that prior to fasudil treatment.

20. The method according to any of the preceding claims, wherein the caregiver is female.

21. The method according to any of the preceding claims, wherein the caregiver is younger than aged 50.