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.

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.

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.

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.

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.

Rifaximin Modifies Gut Microbiota and Attenuates Inflammation in Parkinson's Disease: Preclinical and Clinical Studies.

Patients with Parkinson's disease (PD) exhibit distinct gut microbiota, which may promote gut-derived inflammation. Rifaximin is a nonabsorbable antibiotic that can modify gut microbiota. The present study investigated the effect of rifaximin on gut microbiota and inflammation status in PD. The study examined the effect of long-term rifaximin treatment on in vivo transgenic PD mice (MitoPark) and short-term rifaximin treatment on patients with PD. Rifaximin treatment caused a significant change in gut microbiota in the transgenic PD mice; in particular, it reduced the relative abundance of Prevotellaceae UCG-001 and increased the relative abundance of Bacteroides, Muribaculum, and Lachnospiraceae UCG-001. Rifaximin treatment attenuated serum interleukin-1ß, interleukin-6 and tumor necrosis factor-α, claudin-5 and occludin, which indicated the reduction of systemic inflammation and the protection of the blood-brain barrier integrity. The rifaximin-treated MitoPark mice exhibited better motor and memory performance than did the control mice, with lower microglial activation and increased neuronal survival in the hippocampus. In the patients with PD, 7-day rifaximin treatment caused an increase in the relative abundance of Flavonifractor 6 months after treatment, and the change in plasma proinflammatory cytokine levels was negatively associated with the baseline plasma interleukin-1α level. In conclusion, the present study demonstrated that rifaximin exerted a neuroprotective effect on the transgenic PD mice by modulating gut microbiota. We observed that patients with higher baseline inflammation possibly benefited from rifaximin treatment. With consideration for the tolerability and safety of rifaximin, randomized controlled trials should investigate the disease-modification effect of long-term treatment on select patients with PD.

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.

Poststroke Cognitive Impairment: A Longitudinal Follow-Up and Pre/Poststroke Mini-Mental State Examination Comparison.

BACKGROUND: Poststroke cognitive impairment (PSCI) is a prevalent cause of disability in people with stroke. PSCI results from either lesion-dependent loss of cognitive function or augmentation of Alzheimer's pathology due to vascular insufficiency. The lack of prestroke cognitive assessments limits the clear understanding of the impact of PSCI on cognition. OBJECTIVE: The present study aims to make a direct comparison of longitudinal cognitive assessment results to clarify the impact of ischemic stroke on PSCI and assess the cognitive decline in PSCI compared to people with Alzheimer's disease (AD). METHODS: All study participants had their Mini-Mental State Examination (MMSE) at the chronic poststroke stage (≥6 months after stroke), which was compared with prestroke or acute poststroke (<6 months after stroke) MMSE to investigate the two aspects of PSCI. A group of patients with AD was used to reference the speed of neurodegenerative cognitive deterioration. Repeated measures analysis of variance was used to compare the longitudinal change of MMSE. RESULTS: MMSE score between acute and chronic poststroke revealed a 1.8 ± 6.49 decline per year (n=76), which was not significantly different from the AD patients who underwent cholinesterase inhibitors treatment (-1.11 ± 2.61, p=0.35, n=232). MMSE score between prestroke and chronic poststroke (n=33) revealed a significant decline (-6.52 ± 6.86, p < 0.001). In addition, their cognitive deterioration was significantly associated with sex, age, and stroke over the white matter or basal ganglia. CONCLUSION: Ischemic stroke substantially affects cognition with an average six-point drop in MMSE. The rate of cognitive decline in PSCI was similar to AD, and those with white matter or basal ganglia infarct were at greater risk of PSCI.

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.

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.

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.

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.

Factors associated with burden among male caregivers for people with dementia.

BACKGROUND: There is a dearth of information on male dementia caregivers in Asia and, in particular, on the factors relating to caregiver burden. We aimed to identify factors that may be associated with burden among male caregivers of people with dementia (PWD). METHODS: Data were collected from a national dementia registration survey. The caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). We analyzed the correlation between ZBI scores and variables, such as demographic data of PWD and their male caregivers, caregivers' monthly income, the relationship between PWD and caregivers, the severity of dementia, physical comorbidities and activities of daily living (ADL) of PWD, and neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory (NPI). RESULTS: A total of 509 PWD and their male caregivers were included. The majority of caregivers were sons (72.1%) and husbands (22.0%). Sons had higher ZBI scores than husbands (28.5 ± 15.2 vs 22.0 ± 17.0; p < 0.001). Multivariable linear regression showed that sons as caregivers (ß = 7.44, p = 0.034), ADL (ß = 0.52, p = 0.002), and NPI_severity subscore of apathy (ß = 2.74, p = 0.001) were positively associated with ZBI scores. CONCLUSION: Poor ADL and apathy in PWD and being a patient's son were associated with higher levels of burden among male dementia caregivers. Effective interventions are needed to assist male caregivers in accomplishing their caregiving role and at the same time to alleviate their caregiver burden.

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.

Assessment of High Risk for Alzheimer's Disease Using Plasma Biomarkers in Subjects with Normal Cognition in Taiwan: A Preliminary Study.

BACKGROUND: In Alzheimer's disease (AD), cognitive impairment begins 10-15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration of plasma amyloid-ß 1-42×total tau protein higher than 455 pg2/ml2 are assessed as having a high risk of amnesic mild impairment or AD, denoted as high risk of AD (HRAD). OBJECTIVE: The prevalence of high-risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers. METHODS: 422 subjects with normal cognition were enrolled around Taiwan. Plasma Aß1-40, Aß1-42, and T-Tau levels were assayed using immunomagnetic reduction to assess the risk of dementia. RESULTS: The results showed that 4.6% of young adults (age: 20-44 years), 8.5% of middle-aged adults (age: 45-64 years), and 7.3% of elderly adults (age: 65-90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle-aged and elderly adults compared to young adults. CONCLUSION: The percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public-health problem of AD in normal population. Although the subject having abnormal levels of Aß or tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high-risk cognitively normal population. Worth noting, attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle-aged adults.

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.

Balance and gait performance in older adults with early-stage cognitive impairment.

BACKGROUND: People with cognitive impairment are susceptible to fall. Previous studies regarding balance and gait enrolled patients with various severity of dementia. Quantification of the balance and gait performance of people with cognitive impairment may help identify their postural instability and fall risks. AIM: We investigated the differences in balance and gait among older adults with preserved cognition, amnestic mild cognitive impairment, and mild dementia due to Alzheimer's disease. DESIGN: Prospective observational study. SETTING: Outpatient department of neurology or psychology. POPULATION: Older adults (aged ≥65 years) with independent gait were evaluated using the Mini-Mental State Examination and Clinical Dementia Rating scale. People with other neurological or musculoskeletal disorders were excluded. METHODS: Participants were classified into three groups: 30 healthy controls, 30 mild cognitive impairment and 30 mild dementia. Balance were evaluated through functional test (Berg Balance Scale [BBS]) and laboratory test (posturography). Gait was assessed by wearable device. Muscle strength and mass were measured through grip force, calf circumstance, and body composition. RESULTS: The BBS (P=0.04), posturography of fall risk index (FR, P=0.01) and sensory integration indices in eyes open and firm surface (EOFIS, P=0.009), eyes open and foam surface (EOFOS, P=0.003) were substantially different among three groups. EOFIS and EOFOS indices of balance in mild dementia were significantly worse than in MCI. The gait speed (P=0.04) and stride length (P=0.04) were significantly different among three groups. The post-hoc analyses revealed that all above balance and gait indices in subjects with cognitive impairments were significantly worse than in healthy controls. The grip force, calf circumstance and body composition-muscle mass did not significantly differ among three groups. CONCLUSIONS: It is a piece of evidence that cognitive dysfunction, even in early stage of memory decline, may have some bad impact on balance and gait regardless of the effect of musculoskeletal problems. CLINICAL REHABILITATION IMPACT: Understanding the difference of specific indices of balance and gait among different severity of cognitive impairments and healthy controls could help to develop better balance-oriented rehabilitation programs in older adults at early-stage cognitive impairment.

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.