Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

Understanding delirium trajectory and its importance in care provision for older people.

Delirium significantly increases morbidity and mortality in older people, especially those affected by other organic disorders, notably dementia (Siddiqi et al., 2006; Davis et al., 2012; Martins and Fernandes, 2012). Both delirium and dementia are characterized by cognitive decline through disintegration of brain functions, i.e. a "brain failure." Delirium has been described as an acute brain failure, in contrast to dementia being a chronic brain failure (Berrios, 1981). If we consider any other organ failure, for example that of kidneys, delirium superimposed on dementia resembles acute renal exacerbation superimposed on chronic renal failure. The timely recognition and treatment of acute renal failure can reverse its damaging effects, whereas chronic renal failure necessitates long-term and invasive or costly interventions (i.e. dialysis, kidney transplantation). Similarly, recognizing delirium and providing timely interventions can improve its symptoms to recover brain functions, delay cognitive decline, and alleviate distress and disability.

Suicide attempts among the elderly in East Asia.

Among the one million suicide deaths worldwide each year, as many as 60% occur in Asia. The World Health Organization (WHO) found higher suicide rates among the elderly in rapidly industrialized Asian countries such as China, Hong Kong, Japan, South Korea, Malaysia, and Singapore, compared to the corresponding rates of recently industrializing Asian countries like Vietnam and Sri Lanka (WHO, 2014). As a case in point, suicide rates in South Korea have been the highest in the world since 2003 and are rising especially among older people (Hong and Knapp, 2014). Suicide attempts and older age are strong predictors of completed suicide (Szanto et al., 2002; Simon et al., 2013) and, as such, are important in guiding our efforts for suicide prevention; however, most epidemiological studies focus on completed suicides across all ages rather than understanding the reasons behind suicide attempts in older populations.

Mortality rates and predictors in community-dwelling elderly individuals with cognitive impairment: an eight-year follow-up after initial assessment.

BACKGROUND: We assessed eight-year mortality rates and predictors in a rural cohort of elderly individuals with cognitive impairment. METHODS: A total of 1,035 individuals, including 155 (15.0%) individuals with cognitive impairment, no dementia (CIND), and 69 (6.7%) individuals with clinically diagnosed dementia were followed for eight years from 1997. The initial assessment involved a two-step diagnostic procedure performed during a door-to-door survey, and mortality data were obtained from the Korean National Statistical Office (KNSO). The relationship between clinical diagnosis and risk of death was examined using the Cox proportional hazards model after adjusting for age, sex, and education. RESULTS: During follow-up, 392 individuals died (37.9%). Compared to persons without cognitive impairment, mortality risk was nearly double among those with CIND (hazard ratio [95% confidence interval], 1.92 [1.46-2.54]), and this increased more than three-fold among those with dementia (3.20 [2.30-4.44]). Old age and high scores on the behavioral changes scale at diagnosis were two common predictors of mortality among those with CIND and dementia. Among the items on the behavioral changes scale, low sociability, less spontaneity, and poor hygiene were associated with increased mortality in individuals with CIND. Conversely, low sociability, excessive emotionality, and irritability were associated with increased mortality in patients with dementia. CONCLUSIONS: Both dementia and CIND increased mortality risk compared with normal cognition in this community cohort. It is important to identify and manage early behavioral changes to reduce mortality in individuals with CIND and dementia.

Implications of helplessness in depression: diagnosing mild cognitive impairment and analyzing its effects on cognitive decline in older adults.

Background: This study focuses on how elements of depression correlate with mild cognitive impairment (MCI) in older adults and the diagnostic efficacy of combining these components with the Mini-Mental State Examination (MMSE). The study also investigated the connection between individual depression components and overall cognitive function, as measured by the total score (TS) of the consortium to establish a registry for Alzheimer's disease (AD) assessment battery. Methods: The study included 196 nondemented adults aged 65 to 90 years at a university hospital and community. Comprehensive clinical assessments including the 30-item Geriatric Depression Scale (GDS) to measure components of depressive symptoms, TS, and blood nutritional biomarkers. Results: Our stepwise logistic regression analysis highlighted the 'helplessness item' (odds ratio = 4.531, 95% CI = 2.218 to 9.258, p < 0.001) as a significant predictor for MCI diagnosis. Further, models incorporating 'helplessness item + MMSE' demonstrated markedly enhanced accuracy in diagnosing MCI, surpassing the performance of the MMSE used independently. Notably, the group characterized by helplessness showed a significant reduction in TS (B = -5.300, SE = 1.899, ß = -0.162, p = 0.006), with this trend being particularly pronounced in individuals exhibiting lower levels of physical activity. Interestingly, this correlation did not manifest in participants with higher physical activity levels. Conclusion: Our findings suggest that helplessness is highly effective in diagnosing MCI and is linked to a decrease in cognitive function. Therefore, when addressing MCI and AD-related cognitive decline, clinicians should consider helplessness.

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age.

Background: An abundance of evidence indicates that physical activity may protect against Alzheimer's disease (AD) and related cognitive decline. However, little is known about the association between physical activity and AD-related cognitive decline according to age and the apolipoprotein E (APOE) ε4 allele (APOE4) as major risk factors. Therefore, we examined whether age and APOE4 status modulate the effects of physical activity on episodic memory as AD-related cognition in non-demented older adults. Methods: We enrolled 196 adults aged between 65 and 90 years, with no dementia. All participants underwent comprehensive clinical assessments including physical activity evaluation and APOE genotyping. The AD-related cognitive domain was assessed by the episodic memory, as the earliest cognitive change in AD, and non-memory cognition for comparative purposes. Overall cognition was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Results: We found significant physical activity × age and physical activity × APOE4 interaction effects on episodic memory. Subgroup analyses indicated that an association between physical activity and increased episodic memory was apparent only in subjects aged > 70 years, and in APOE4-positive subjects. Conclusion: Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.

High-intensity walking in midlife is associated with improved memory in physically capable older adults.

BACKGROUND: Little is known about the associations of midlife- and late life-initiated walking with Alzheimer's disease (AD)-related cognitive decline in humans. We aimed to investigate whether high-intensity, prolonged, midlife-initiated walking is associated with changes in AD-related cognitive decline in physically capable older adults. METHODS: We studied 188 physically capable participants aged 65-90 years without dementia who underwent comprehensive clinical assessment, including of their walking modality (i.e., intensity, duration, midlife- or late life-onset), memory- or non-memory and total cognitive performance, and blood or nutritional biomarkers. RESULTS: The walking group showed better episodic memory (B = 2.852, SE = 1.214, ß = 0.144, p = 0.020), but not non-memory cognition, than the non-walking group. High-intensity walking starting in midlife was significantly associated with better episodic memory (B = 9.360, SE = 3.314, ß = 0.446, p = 0.005) compared to the non-walking group. In contrast, there were no differences in cognition according to walking duration, regardless of the onset time. The walking group also showed a similar association with overall cognition. CONCLUSIONS: Among physically capable older adults without dementia, walking, particularly at high intensity and starting in midlife, is associated with improved episodic memory, an AD-related cognitive domain. Further attention should be paid to the role of walking in terms of AD prevention.

Manganese level and cognitive decline in older adults with the APOE e4 allele: a preliminary study.

This study examined the relationship between serum manganese level and cognition, and the moderating effect of apolipoprotein E ε4 (APOE4) on this relationship. A total of 164 non-demented participants underwent clinical assessments including serum manganese level and cognition [episodic memory score (EMS), non-memory score (NMS) for executive function/attention/language/ visuospatial skill, and total score (TS)]. Serum manganese × APOE4 interaction had a significant effect on EMS and TS. Serum manganese level was inversely associated with EMS and TS in APOE4-positive but not APOE4-negative participants. APOE4 should be considered a key component in Alzheimer's disease studies that included manganese imbalance as a risk factor.

Ginseng intake and Alzheimer disease-specific cognition in older adults according to apolipoprotein ε4 allele status.

Background: The probable association among ginseng intake, Alzheimer's disease (AD)-specific cognition, and apolipoprotein ε4 (APOE4) remains poorly investigated. Hence, we examined the association between ginseng intake and AD-specific cognition in older adults under the moderating effect of APOE4 status. Methods: This study enrolled 160 adults aged 65-90 years without dementia. All participants underwent comprehensive dietary and clinical assessments including ginseng intake, AD-related cognition (i.e., delayed episodic memory, as the earliest cognitive change in AD), and non-memory cognition for comparative purposes. Results: Ginseng intake was associated with higher delayed episodic memory, but not non-memory cognition, compared to no ginseng intake. The interaction between ginseng intake and APOE4 status had a significant effect on delayed episodic memory. Subgroup analyses showed that ginseng intake was associated with higher delayed episodic memory in the APOE4-negative but not the APOE4-positive subgroup. The benefits of ginseng intake on delayed episodic memory were prominent in the high duration (≥5 years) and midlife onset (<65 years) groups. Conclusion: Our study of older adults with no dementia suggests that ginseng intake (with high duration and midlife onset) had a beneficial effect on AD-specific cognitive decline, i.e., the delayed episodic memory. In addition, APOE4 status moderates the association between ginseng intake status and AD-specific cognitive decline.

Spicy food intake predicts Alzheimer-related cognitive decline in older adults with low physical activity.

A plausible association exists among spicy food consumption, physical activity, and Alzheimer's disease (AD) or cognitive decline, but it remains poorly investigated. We aimed to examined the association between spicy food and AD-related memory decline or global cognitive decline in older adults under the moderating effect of physical activity. Total 196 non-demented older adults were included. Participants underwent comprehensive dietary and clinical assessments including spicy food intake, AD-related memory, global cognition, and physical activity. The strength of spicy food was stratified into three categories: 'not spicy' (reference), 'low spiciness', and 'high spiciness'. Multiple linear regression analyses were performed to examine the relationships between spicy level and cognition. The spicy level was the independent variable in each analysis; it was entered as a stratified categorical variable using the three categories. We found a significant association between a high level of spiciness in food and decreased memory ([Formula: see text] - 0.167, p < 0.001) or global cognition ([Formula: see text] - 0.122, p = 0.027), but not non-memory cognition. To explore the moderating effects of age, sex, apolipoprotein E ε4 allele-positivity, vascular risk score, body mass index, and physical activity on the associations between spicy level and memory or global cognition, the same regression analyses were repeated including two-way interaction terms between the spicy level and each of the six variables as an additional independent variable. An interactive effect was detected between a high level of spiciness in food and physical activity on the memory ([Formula: see text] 0.209, p = 0.029) or global cognition ([Formula: see text] 0.336, p = 0.001). Subgroup analyses showed that the association between a high level of spiciness in food and a lower memory ([Formula: see text] - 0.254, p < 0.001) and global score ([Formula: see text] - 0.222, p = 0.002) was present only in older adults with low physical activity, but not in older adults with high physical activity. Our findings suggest that spicy food intake is predictive of AD-related cognitive decline, i.e., episodic memory; this relationship is worsened by physically inactive lifestyle.

Association of a History of Sleep Disorder With Risk of Mild Cognitive Impairment and Alzheimer's Disease Dementia.

OBJECTIVE: We explored whether a history of sleep disorder affected a current diagnosis of cognitive impairment and clinical conversion in a non-demented elderly population. METHODS: Comprehensive clinical data collected as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) was analyzed. A history of sleep disorder was recorded in the recent ADNI medical database. Standard clinical and neuropsychological tests were performed both at baseline and follow-up visit. Multiple logistic regression analysis was performed after adjusting for age, sex, education, apolipoprotein E ε4 status, vascular risk score, body mass index, Geriatric Depression Scale score, and use of sleeping pills. RESULTS: A total of 391 cognitively normal individuals, 303 with early mild cognitive impairment (MCI) and 364 with late MCI were included. Sleep disorder history was significantly associated with an increased risk of MCI but not with clinical conversion. A history of insomnia or obstructive sleep apnea (OSA) significantly increased the risk of MCI, but only an OSA history predicted progression to Alzheimer's disease (AD) dementia. CONCLUSION: Our findings suggest that a sleep disorder history usefully aids early detection of cognitive impairment and emphasize that such sleep disorder, particularly OSA, is important as potential target for AD prevention.

Brain Amyloid Index as a Probable Marker Bridging Between Subjective Memory Complaint and Objective Cognitive Performance.

Background: The association between types of subjective memory complaint (SMC), poor objective cognitive performance, and brain Aß deposition have been poorly understood. We investigated the association between types of SMC and objective global cognitive performance, then assessed whether this association is mediated by the brain amyloid prediction index (API). Methods: In total, 173 non-demented older adults [63 cognitively normal (CN) and 110 mild cognitive impairment (MCI)] underwent comprehensive clinical assessments. Objective global cognitive performance and brain amyloid index were measured using the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery and API, respectively. In total, four items of SMC from the subjective memory complaints questionnaire (SMCQ) (SMCQ1: a feeling of memory problem; SMCQ2: the feeling of worse memory than 10 years ago; SMCQ3: the feeling of worse memory than others of similar age; or SMCQ4: the feeling of difficulty in everyday life) in global memory function were assessed. Results: In non-demented and participants with MCI, SMCQ3-positive and SMCQ4-positive groups were associated with decreased TS. In participants with MCI, the SMCQ3-positive group was associated with increased API, and API was associated with decreased TS, but the SMCQ4-positive group did not. In addition, the association between the SMCQ3-positive group and poor TS disappeared when API was controlled as a covariate, indicating that API has a mediation effect. Conclusion: The present findings suggest that SMC, a feeling of worse memory performance than others in a similar age group, in the older adults without dementia is associated with poor objective cognitive performance via increased brain amyloid index.

Association Between Copper and Global Cognition and the Moderating Effect of Iron.

Background: Despite the known association between abnormal serum copper levels and Alzheimer's disease (AD) or cognitive decline, the association between copper, iron, and cognition remains poorly investigated. We examined the association between serum copper levels and global cognition measured using the Mini-Mental State Examination (MMSE) in older adults with normal copper levels. We also explored the moderating effect of iron on this association. Methods: The study enrolled 99 non-demented adults between 65 and 90 years of age. All the participants underwent comprehensive clinical assessments and serum copper measurements. Global cognitive performance was measured by the MMSE. All copper levels were within the normal range and were stratified into three categories: < 87 (low), 87-98 (medium), and > 98 (high: used as a reference category) µg/dL. Results: Serum copper level (as a continuous variable) was significantly associated with MMSE score (B = 0.065, 95% confidence interval = 0.023-0.108, p = 0.003). Low serum copper group showed significantly decreased MMSE score compared to high copper one (B = -2.643, 95% confidence interval = -4.169 to -1.117, p < 0.001), while middle copper category had no difference (B = -1.211, 95% confidence interval = -2.689 to 0.268, p = 0.107). There was a significant low serum copper ×iron interaction effect on the MMSE score (B = 0.065, 95% confidence interval = 0.016-0.114, p = 0.010). Subgroup analyses showed that low serum copper was significantly associated with a low MMSE score in the low-iron (B = -4.174, 95% confidence interval = -6.607 to -1.741, p = 0.001) but not high-iron subgroup (B = -0.721, 95% confidence interval = -2.852 to 1.409, p = 0.495). Conclusion: Our findings from non-demented older adults suggest that a low serum copper level within the normal range was associated with AD or cognitive decline and this is moderated by iron. To prevent AD or cognitive decline, clinicians need to pay attention to avoiding low serum copper and iron levels, even within the clinical normal range.

A combination of midlife diabetes mellitus and the apolipoprotein E ε4 allele increase risk for cognitive decline.

Background: It has been suggested that diabetes mellitus (DM) and the apolipoprotein E (APOE) ε4 allele (APOE4) increase the risk for Alzheimer's disease (AD) and cognitive decline. However, the evidence is sparse. We explored whether APOE4 status modulated the effects of midlife and late-life DM on global cognition of non-demented older adults. Methods: In all, 176 non-demented adults (age 65-90 years) were enrolled. All the participants underwent comprehensive clinical assessments including midlife and late-life DM evaluation and APOE genotyping. The global cognitive performance index was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Results: We found a significant midlife DM × APOE4 interaction effect on the global cognitive performance. Subgroup analyses indicated that an association between midlife DM and decreased global cognitive performance was apparent only in older adults who were APOE4-positive, and not in those with APOE4-negative. Conclusion: Our findings from non-demented older adults suggest that midlife DM increases the risk for AD and cognitive decline, and this risk is modulated by APOE4 status. To prevent AD and cognitive decline, physicians should check for the possible coexistence of midlife DM and APOE4-positive status.

Cholinesterase inhibitors for Alzheimer disease: do they provide more than symptomatic benefits?

OBJECTIVE: This study aims to examine survival of patients with Alzheimer disease (AD) receiving clinical efficacy of cholinesterase inhibitors (ChEIs) and to compare their survival with those of patients with AD who never received ChEIs and cognitively intact old psychiatric outpatients. DESIGN, SETTING, AND PARTICIPANTS: The retrospective cohort study used national mortality data provided by the Korean National Statistics Office and electronic database of 15 general hospitals on older patients who began outpatient treatment with psychiatric medications including ChEIs (N = 3,813). The authors controlled for confounding by using multivariate models and propensity scoring methods. MEASUREMENTS: Mortality rate of patients with AD receiving ChEIs was compared with those of patients with AD who never received ChEIs and cognitively intact old psychiatric outpatients. RESULTS: Observed additional survival of patients with AD receiving ChEIs (mortality rate: 13.1%), when compared with patients with AD who never received ChEIs (15.4%) was not statistically significant (p = 0.74; hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 0.67-1.59). Patients with AD receiving ChEIs showed higher mortality rate (13.1%) compared with that of cognitively intact old psychiatric outpatients (8.6%) (p <0.001; HR: 1.60, 95% CI: 0.96-2.68). CONCLUSION: This study does not support that ChEIs increase survival of patients with AD, compared with patients with AD who have never treated with ChEIs. Therefore, all ChEIs should be considered for symptomatic use only and not to be capable of modifying mortality of patients with AD.

MMSE Subscale Scores as Useful Predictors of AD Conversion in Mild Cognitive Impairment.

PURPOSE: This study was performed to examine the usefulness of subscores on the Mini-Mental State Examination (MMSE) for predicting the progression of Alzheimer's disease (AD) dementia in individuals with mild cognitive impairment (MCI). PATIENTS AND METHODS: A total of 306 MCI individuals in the Alzheimer's Disease Neuroimaging Initiative database were included in the study. Standardized clinical and neuropsychological tests were performed at baseline and at 2-year follow-up. Logistic regression analysis was conducted to examine the MMSE total and subscale scores to predict progression to AD dementia in MCI individuals. RESULTS: The MMSE total score and the MMSE memory, orientation, and construction subscores were inversely associated with AD progression after controlling for all potential confounders; MMSE attention and language subscores were not correlated with AD progression. The MMSE delayed recall score among the MMSE memory subscores and the MMSE time score among the orientation subscores, especially week and day, were inversely associated with AD progression; the MMSE immediate recall and place scores were not correlated with progression. CONCLUSION: Our findings suggest that the MMSE memory, orientation, and construction subscores, which are simple and readily available clinical measures, could provide useful information to predict AD dementia progression in MCI individuals in practical clinical settings.

Olanzapine-induced Concurrent Tardive Dystonia and Tardive Dyskinesia in Schizophrenia with Intellectual Disability: A Case Report.

Tardive dystonia and tardive dyskinesia (TDs) are rare extrapyramidal side effects that develop after long-term use of antipsychotics, but they are different syndromes and rarely occur at the same time. Olanzapine is an atypical antipsychotic drug associated with a low risk of extrapyramidal side effects in schizophrenia, but its associations with tardive movements are not clear. We present a case of a 19-year-old Asian female patient with schizophrenia and intellectual disabilities who developed concurrent TDs after long-term use of olanzapine. At her 10-month follow-up examination, her concurrent TDs had been treated successfully with clozapine. This case demonstrates that although the use of olanzapine to treat psychosis and behavioral disturbances is increasing due to its high efficacy and low rate of extrapyramidal side effects, concurrent TDs should be carefully assessed after long-term use of this antipsychotic, especially in patients with schizophrenia and intellectual disabilities. Clozapine, by preventing or reversing the debilitating consequences of concurrent TDs, may be an effective treatment for these patients.

Modeling the cost-effectiveness of galantamine for mild to moderately severe Alzheimer's disease in Korea.

OBJECTIVE: The aim of the study was to determine the cost-effectiveness, from the third-party payer viewpoint, of galantamine compared with usual care in the treatment of mild to moderately severe Alzheimer's disease (AD). METHODS: An existing Markov model was adapted to Korea to predict long-term outcomes over a 5-year time horizon and to estimate the cost-effectiveness of galantamine for the treatment of AD. The model structure is informed by a review of national and international literature on the clinical and cost-effectiveness of galantamine and on the costs and outcomes associated with treatment for AD. The main outcome measure used was the cost per quality-adjusted life year (QALY) gained. All costs were indexed to US$ (2007 value). Multivariate probabilistic sensitivity analysis and scenario analysis were undertaken to assess uncertainty in the results. RESULTS: The study findings indicate that the clinical benefits on AD progression from galantamine treatment resulted in an incremental cost per QALY gained of US$4939 over 5 years (vs. usual care). Probabilistic sensitivity analysis and cost-effectiveness acceptability curve suggest that the probability of galantamine treatment having an incremental cost per QALY over US$6740 is zero. Incremental cost per QALY gained according to scenario analyses ranged from US$2271 to US$8335. CONCLUSION: These findings suggest that the use of galantamine may be a cost-effective use of Korean national health-care resources, considering the gross domestic product per capita of US$21,695 in 2007.

Combination of the CAGE and serum gamma-glutamyl transferase: an effective screening tool for alcohol use disorder and alcohol dependence.

Purpose: The CAGE is a convenient test for alcohol-related disorder due to its brevity, but it is not as effective as the alcohol use disorders identification test (AUDIT). Gamma-glutamyl transferase (GGT) is an objective blood biochemical marker of excessive alcohol intake; however, it has low sensitivity. This study tested the performance of the combined use of CAGE and GGT to screen problem drinking (PD), alcohol use disorder (AUD), and alcohol dependence (AD). Methods: A total of 394 subjects composed of 91 normal controls and 303 subjects with PD were enrolled in this study. Of the PD subjects, 147 were diagnosed with AUD (77 alcohol abuse and 70 AD). A series of multiple logistic regression models for PD, AUD, and AD discrimination were used to obtain new combined CAGE and GGT scores after adjusting for age and gender (CAGE+GGT). A receiver operating characteristic curve analysis was conducted to determine how well the CAGE+GGT score discriminated between individuals with PD, AUD, and AD. Results: The discrimination accuracy of the AUDIT for PD was significantly better than that of the CAGE or the CAGE+GGT (z=6.927, p<0.0001; z=5.301, p<0.0001, respectively). The CAGE and the CAGE+GGT were better than the AUDIT at discriminating AUD (z=2.535, p=0.0112; z=2.894, p=0.0038, respectively). The discrimination accuracy of the AUDIT for AD was significantly better than that of the CAGE and GGT (z=3.233, p=0.0012; z=6.529, p<0.0001, respectively), but the CAGE+GGT was comparable with the AUDIT (z=1.652, p=0.0985). Conclusion: Our findings support the combined use of the CAGE questionnaire and serum GGT level as a sensitive and useful tool for AD screening.