Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update.

Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.

Determinants of long-term care service use by persons with dementia: A national dementia registry study conducted in Taiwan.

BACKGROUND: This study investigated the determinants and use of Taiwan's long-term care (LTC) Plan Version 2.0 (LTC 2.0) services by persons with dementia (PWDs) and their caregivers. METHODS: In total, 1268 PWD-caregiver dyads were enrolled for analysis from a national dementia registry. Andersen's Behavioral Model of Health Services Use was used to investigate the association of LTC service use with several factors, namely the demographic data of PWDs and their caregivers, migrant caregiver employment, monthly household income, caregiver burden as determined by the Zarit Burden Interview (ZBI), Mini-Mental State Examination score, Clinical Dementia Rating scores, neuropsychiatric inventory scores for the behavioral and psychological symptoms of dementia, and PWDs' activities of daily living (ADLs). RESULTS: Among the studied family caregivers, 81.4% did not use LTC resources. A multivariable logistic analysis revealed that aberrant motor behaviors (odd ratio [OR] = 1.31, 95% confidence interval [CI] = 1.10-1.56, p = 0.003), dysfunction in ADLs (OR = 1.06, 95% CI = 1.02-1.10, p = 0.002), higher ZBI scores (OR = 1.02, 95% CI = 1.01-1.03, p = 0.004), not residing with family members (OR = 1.88, 95% CI = 1.32-2.66, p < 0.001), and not employing a migrant caregiver (OR = 4.41, 95% CI = 2.59-7.51, p < 0.001) were the factors most significantly associated with LTC service use. CONCLUSION: Factors such as whether PWDs live alone, specific neuropsychiatric symptoms, and impaired function should be considered in future policy amendments to provide required activities and care resources for PWDs and their caregivers.

Effects of caregiver counselling on medication persistence and adherence in patients with dementia at a pharmacist-managed clinic: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Low treatment persistence and adherence in patients with dementia results in a rapid loss of disease control. This pilot study evaluated the impact of pharmacist-provided caregiver counselling on treatment persistence, adherence, quality of life (QoL) in patients with dementia, as well as caregiver's knowledge of dementia, and caregiver burden. METHODS: This prospective, randomized controlled study was performed at a hospital-based pharmacist-managed clinic from December 2017 to December 2019. Patients with mild-to-moderate Alzheimer's disease (AD), initiating cholinesterase inhibitors within 3 months, and coming with their caregivers were included and randomized 1:1 to intervention or control group. The intervention group received pharmacist counselling and education sheets about AD, whereas the control group only received standard of care. Patients' treatment persistence and adherence were assessed at months 3, 6, 9, and 12; QoL, and caregiver burden were assessed at baseline and month 12. Caregiver's knowledge of dementia was assessed at baseline and 2 weeks after counselling in the intervention group. Nonparametric statistics and generalized estimating equation models were used for statistical analysis. RESULTS AND DISCUSSION: A total of 40 patients and 40 caregivers were included, with 20 pairs for each group. One-year medication persistence (16/20 vs. 16/20) and adherence rates (87%-99%) were high in both groups without significant differences. Dementia knowledge scores improved significantly after counselling in the intervention group (77.5 vs. 95.8, p < 0.01). Although the change of caregiver burden was non-significant between groups, the score decreased in the intervention group (-0.89; p = 0.78) but increased in the control group (+6.01; p = 0.07). WHAT IS NEW AND CONCLUSION: In this pilot study, pharmacist's counselling for patients with dementia and their caregivers is feasible and can enhance caregiver knowledge of dementia. Further study with larger scale is needed to confirm the impact on these outcomes.

Clinical Trials of New Drugs for Vascular Cognitive Impairment and Vascular Dementia.

Population aging has challenged the treatment of cognitive impairment or dementia. Vascular dementia is the second leading cause of dementia after Alzheimer's disease. Cognitive consequences after ischemic brain injury have been recognized as a preferred target for therapeutic strategies, prompting the search for potential agents. The keyword "vascular dementia" was used to search ClinicalTrials.gov to determine agents represented in phases I, II, III, and IV. The agents were classified on the basis of their mechanisms. Of the 17 randomized controlled trials meeting our inclusion criteria, 9 were completed in the past 10 years, and 8 are ongoing or in the planning stages. We also identified one trial in phase I, nine in phase II, six in phase III, and one in phase IV. Fewer trials of new drugs for improving cognition or ameliorating the behavioral and psychological symptoms of dementia target vascular dementia than Alzheimer's dementia. Drug trials on vascular dementia overlap with drug trials targeting functional outcomes in cerebrovascular disease. International pharmaceutical companies' investment in new drugs targeting VCI and vascular dementia remains insufficient.

Predictors of caregiver burden in aged caregivers of demented older patients.

BACKGROUND: Dementia in the oldest-old is projected to increase exponentially as is the burden of their caregivers who may experience unique challenges and suffering. Thus, we aim to investigate which factors are associated with older caregivers' burden in caring demented outpatients in a multicenter cohort. METHODS: Patients and their caregivers, both aged ≧65 years, in the National Dementia Registry Study in Taiwan (T-NDRS) were included in this study. Caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The correlations between the ZBI scores and characteristics of caregivers and patients, including severity of dementia, physical comorbidities, instrumental activities of daily living (IADL), neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory (NPI), and family monthly income, were analyzed. RESULTS: We recruited 328 aged informal caregiver-patient dyads. The mean age of caregivers was 73.7 ± 7.0 years, with female predominance (66.8%), and the mean age of patients was 78.8 ± 6.9 years, with male predominance (61.0%). Multivariable linear regression showed that IADLs (ß = 0.83, p < 0.001) and NPI subscores of apathy (ß = 3.83, p < 0.001)and irritability (ß = 4.25, p < 0.001) were positively associated with ZBI scores. The highest family monthly income (ß = - 10.92, p = 0.001) and caregiver age (ß = - 0.41, p = 0.001) were negatively correlated with ZBI scores. CONCLUSIONS: Older caregivers of older demented patients experience a higher care burden when patients had greater impaired functional autonomy and the presence of NPI symptoms of apathy and irritability. Our findings provide the direction to identify risky older caregivers, and we should pay more attention to and provide support for these exhausted caregivers.

High-intensity functional exercise in older adults with dementia: A systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the efficacy of high-intensity functional exercise among older adults with dementia. METHODS: In this systematic review and meta-analysis of randomized controlled trials, we collected articles published before August 2020 from PubMed, Embase, and the Cochrane Library to evaluate the effect of high-intensity functional exercise on older adults with dementia. Primary outcomes included improvements in balance function and gait performance (speed, cadence, and stride length). The secondary outcomes included lower limb strength, activities of daily living, psychiatric well-being, depression, and cognition. Furthermore, we performed subgroup analysis with two high-intensity functional exercise programs: the Umeå program and Hauer's program. RESULTS: We identified 15 articles describing six trials including older adults with dementia undergoing high-intensity functional exercise or control activity. The meta-analysis indicated that high-intensity functional exercise, both in Hauer's program and in the Umeå program, significantly improved balance function (pooled standardized mean difference 0.57, 95% confidence interval 0.31-0.83). Hauer's program significantly improved gait speed, cadence, stride length, and lower limb strength. Beneficial effects on speed, cadence, and lower limb strength were retained for several months. The Umeå program facilitated activities of daily living and psychiatric well-being, with effects on activities of daily living lasting several months. In the only eligible trial, no effects on cognition were observed. Adverse effects of high-intensity functional exercise were minimal to none. CONCLUSIONS: High-intensity functional exercise is generally safe and is recommended for older individuals with mild or moderate dementia to provide benefits in motor performance and daily functioning.

Clinical trials of new drugs for Alzheimer disease.

Alzheimer disease (AD) accounts for 60-70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies.In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov. We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.

The mediating effect of psychological distress on functional dependence in stroke patients.

AIMS AND OBJECTIVES: To explore varied forms of psychological distress and to determine the mediating influence of psychological distress on functional outcomes in stroke patients. BACKGROUND: Previous studies attest to the influence of depression on poststroke functional recovery. While there is evidence for neuropathological deficits that occur after stroke to be associated with psychological distress, few studies have explored the effect of various types of psychological distress on functional recovery. DESIGN: A cross-sectional study was used. METHODS: Data were collected from 178 first-time stroke patients. Study variables included demographic and disease characteristics (stroke location and stroke syndrome classification), psychological distress (the Chinese language version of the Emotional and Social Dysfunction Questionnaire) and functional outcome (Barthel index). Regression and mediation models were used to evaluate the effect of psychological distress on functional outcome. RESULTS: Results revealed that stroke patients experience various forms of mild psychological distress, including anger, helplessness, emotional dyscontrol, indifference, inertia and euphoria, after stroke. Regression and mediation analyses further confirmed that various forms of psychological distress significantly mediated the effect of severe stroke syndromes on functional dependence. CONCLUSION: The various forms of psychological distress after stroke might play a mediating role in functional recovery and explain how stroke severity affects functional dependence. RELEVANCE TO CLINICAL PRACTICE: By understanding the nature of various forms of psychological distress, healthcare professionals should adopt appropriate assessment instruments and design effective interventions to help improve mental and physical function of stroke patients.

Atypical Ramsay Hunt syndrome.

Ramsay Hunt syndrome (RHS) is the reactivation of herpes zoster in the geniculate ganglion and typically presents the triad of ipsilateral peripheral type facial paralysis, ear pain, and erythematous vesicles in the external auditory canal and auricle. However, some unusual variants may occur. Here we present a patient of atypical RHS with uncommonly extensive dermatomal involvement of cranial nerve (CN) V2 and V3 and cervical roots, C2, C3 in addition to CN VII and VIII involvement.

A Case Report of Japanese Encephalitis Focusing on MR Findings.

meningitis or encephalitis with or without neurological deficits. JEV typically attacks the thalamus, corpus striatum, brainstem and spinal cord. The laboratory diagnosis of JEV infection involves the detection of anti-JEV antibody IgMs using an enzyme-linked immunosorbent assay (ELISA), which has high sensitivity and specificity. Because of the lack of a specific antiviral therapy, JE is usually managed by symptomatic treatment and supportive care. We report a case of JE in a 34-year-old man. With a clinical presentation similar to herpes simplex virus encephalitis, the patient was finally diagnosed as having JE. The distinction of different viral encephalitides in MR findings is briefly reviewed.

Brain Age Is Associated with Cognitive Outcomes of Cholinesterase Inhibitor Treatment in Patients with Mild Cognitive Impairment.

Background: The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer's disease conversion from MCI. Objective: The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Methods: Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. Results: 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067). Conclusions: Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI.

Systemic lupus erythematosus presented as extensive longitudinal myelitis.

BACKGROUND: longitudinal myelitis (LM) is defined by the continuous lesion of more than four spinal cord segments. LM is a rare variant of acute transverse myelitis and it frequently presented poor responses to immunomodulatory therapy, which resulted in severe and disabling sequelae. We reported a case of acute longitudinal myelitis involving extensive lesions from cervical spinal cord to conus medullaris caused by newly diagnosed SLE. CASE REPORT: A 39 years old man who was previously healthy presented to our hospital due to acute urinary retention with progressive lower limb weakness for a week. Brisk deep tendon reflexes in upper limbs and decreased reflexes in lower limbs were noted on admission. The pin-prick, vibration, and light touch sensations were decreased in the lower limbs. Spinal MRI sagittal view showed an T2WI bright up mass in the spinal cord below C3/4 level with extension to conus medullaris. He was diagnosed SLE based on ARA criteria. After ruling out mimics including NMO and MS, SLE with LM explained what happened to him . CONCLUSION: Given the poor prognosis of SLE with LM, which resulted in severe and disabling sequelae. More comprehensive understand of the disease course, real mechanisms and treatment strategy are needed.

Heterogeneity of Alzheimer's disease identified by neuropsychological test profiling.

Alzheimer's disease (AD) is a highly heterogeneous disorder. Untangling this variability could lead to personalized treatments and improve participant recruitment for clinical trials. We investigated the cognitive subgroups by using a data-driven clustering technique in an AD cohort. People with mild-moderate probable AD from Taiwan was included. Neuropsychological test results from the Cognitive Abilities Screening Instrument were clustered using nonnegative matrix factorization. We identified two clusters in 112 patients with predominant deficits in memory (62.5%) and non-memory (37.5%) cognitive domains, respectively. The memory group performed worse in short-term memory and orientation and better in attention than the non-memory group. At baseline, patients in the memory group had worse global cognitive status and dementia severity. Linear mixed effect model did not reveal difference in disease trajectory within 3 years of follow-up between the two clusters. Our results provide insights into the cognitive heterogeneity in probable AD in an Asian population.

Digital phenotyping: An equal opportunity approach to reducing disparities in Alzheimer's disease and related dementia research.

A rapidly aging world population is fueling a concomitant increase in Alzheimer's disease (AD) and related dementias (ADRD). Scientific inquiry, however, has largely focused on White populations in Australia, the European Union, and North America. As such, there is an incomplete understanding of AD in other populations. In this perspective, we describe research efforts and challenges of cohort studies from three regions of the world: Central America, East Africa, and East Asia. These cohorts are engaging with the Davos Alzheimer's Collaborative (DAC), a global partnership that brings together cohorts from around the world to advance understanding of AD. Each cohort is poised to leverage the widespread use of mobile devices to integrate digital phenotyping into current methodologies and mitigate the lack of representativeness in AD research of racial and ethnic minorities across the globe. In addition to methods that these three cohorts are already using, DAC has developed a digital phenotyping protocol that can collect ADRD-related data remotely via smartphone and/or in clinic via a tablet to generate a common data elements digital dataset that can be harmonized with additional clinical and molecular data being collected at each cohort site and when combined across cohorts and made accessible can provide a global data resource that is more racially/ethnically represented of the world population.

Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways.

BACKGROUND: Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. OBJECTIVE: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. METHODS: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. RESULTS: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores. CONCLUSION: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.

Plasma Phosphorylated-tau181 Is a Predictor of Post-stroke Cognitive Impairment: A Longitudinal Study.

Introduction: Post-stroke cognitive impairment (PSCI) cannot be neglected because it drastically influences the daily life of patients and their families. However, there are no studies exploring the association between preclinical blood biomarkers of neurodegeneration including plasma amyloid-ß (Aß), tau, and brain-derived neurotrophic factor (BDNF) together with the risk of PSCI. This longitudinal study was to investigate whether these blood biomarkers with imaging markers of cerebral small vessel disease can improve the prediction for PSCI. In addition, we also explored the association between blood biomarkers with the trajectories of PSCI. Methods: Adult patients with first-ever acute ischemic stroke were recruited, and the cognitive and functional abilities of these patients were evaluated. Furthermore, blood biomarkers of neurodegeneration including plasma Aß-40, Aß-42, total tau, phosphorylated tau 181 (p-tau181), and BDNF levels and image markers of cerebral small vessel disease were measured. Each patient was followed up at 3 and 12 months at the outpatient department. Results: Of 136 patients, 40 and 50 patients developed PSCI at 3 and 12 months after stroke, respectively. In functional trajectories, 27 patients did not have PSCI at 3 months but did at 12 months. By contrast, the PSCI status of 17 patients at 3 months was reversed at 12 months. Patients with high-acute plasma p-tau181 had a significantly lower PSCI risk at 3 months (odds ratio [OR] = 0.62, 95% CI = 0.40-0.94, p = 0.0243) and 12 months (OR = 0.69, 95% CI = 0.47-0.99, p = 0.0443) after adjustment for covariates and image biomarkers. Discrimination and reclassification statistics indicated that the p-tau181 level can improve discrimination ability for PSCI at 3 and 12 months, respectively. In addition, the plasma p-tau181 level was the highest in subjects without PSCI followed by those with delayed-onset PSCI and early-onset PSCI with reversal, whereas the lowest plasma p-tau181 level was found among those with persistent PSCI, showing a significant trend test (p = 0.0081). Conclusion: Plasma p-tau181 is a potential biomarker for predicting early- and delayed-onset PSCI. Future studies should incorporate plasma p-tau181 as an indicator for timely cognitive intervention in the follow-up of patients with stroke.

Periodontitis is a potential risk factor for transient ischemic attack and minor ischemic stroke in young adults: A nationwide population-based cohort study.

BACKGROUND: This study aims to determine whether periodontitis is a risk factor for transient ischemic attack (TIA) in young adults. METHODS: The National Health Insurance (NHI) Research Database in Taiwan was the source of the data used in this retrospective cohort study. Individuals aged 20 to 53 years with periodontitis in 2001 and 2002 (n = 792,426) and an age- and sex-matched control group (n = 792,426) were selected. All participants were followed up until TIA diagnosis, 55 years of age, removal from the NHI program, death, or December 31, 2016. The incidence density and hazard ratio (HR) of new-onset TIA were compared between individuals with periodontitis and controls. Periodontitis was defined by dentists according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 523.3-5 with concurrent antibiotic prescription or periodontal treatment excluding scaling performed by certified dentists. TIA was defined according to the ICD-9-CM code 435.x at hospital discharge. RESULTS: After adjustment for confounding factors, the risk of developing TIA/minor ischemic stroke was calculated to be higher in participants with periodontitis (HR, 1.24; 95% confidence interval, 1.15-1.32; P <0.001) than in those without. The HR was slightly higher among people aged 20 to 40 years than among those aged 40 to 53 years. CONCLUSION: Periodontitis is associated with an increased risk of developing TIA/minor ischemic stroke. Periodontitis might be a modifiable risk factor for stroke in young adults. Clinicians must devote greater attention to this potential association to develop new preventive and therapeutic strategies for stroke in young adults.

Validation of the Taiwanese Version of ACE-III (T-ACE-III) to Detect Dementia in a Memory Clinic.

OBJECTIVE: The Addenbrooke's Cognitive Examination III (ACE-III) is a 100-points cognitive test used in detecting dementia in many countries. There has been no validation study of the ACE-III in patients with suspected dementia in a Taiwanese population, where the language is traditional Chinese. We aimed to culturally adapt and validate the ACE-III as a cognitive assessment tool for differentiating between people with and without dementia presenting to healthcare professionals in Taiwan with possible dementia. METHODS: We culturally adapted the ACE-III for Taiwan (T-ACE-III) and tested it with consenting patients with suspected dementia in northern Taiwan who had been through the diagnostic process. We calculated receiver operating characteristic (ROC) curves to test the ability of the T-ACE-III to differentiate between dementia and non-dementia cases using clinician diagnosis as the gold standard. We generated the Youden Index to determine the best cut-off score. RESULTS: We recruited 90 Taiwanese individuals aged 49-93 years: 24 males and 33 females had dementia and 12 males and 21 females did not. The area under the ROC curve was 0.99 for distinguishing dementia from non-dementia. The T-ACE-III had a sensitivity of 100% and specificity of 78.8% when the cut-off score was 86/87. With a cut-off value of 73/74, the specificity was 100.0%, and sensitivity 89.5%. The highest Youden Index was 0.895, indicating the best overall cut-off point to be 73/74. CONCLUSIONS: The T-ACE-III is an acceptable cognitive test with excellent psychometric properties for discriminating dementia from non-dementia in Taiwanese populations in memory clinic settings.