Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.
Humans ; Hypotension/complications* ; Cognitive Dysfunction/etiology* ; Alzheimer Disease/epidemiology* ; Cerebrovascular Circulation/physiology* ; Cognition Disorders/etiology*

Objective: To construct and compare the dynamic prediction models of the risk of mild cognitive impairment (MCI) in the elderly based on six different cognitive function scales. Methods: Based on longitudinal data from the Alzheimer's Disease Neuroimaging Initiative from 2005 to 2020, Mini-mental state examination (MMSE), functional activities questionnaire (FAQ), Alzheimer's disease assessment scale-cognitive (ADAS-Cog) 11, ADAS-Cog13, ADAS delayed word recall (ADASQ4), and Rey auditory verbal learning test (RAVLT)_immediate were used as longitudinal cognitive function evaluation indicators to assess the longitudinal changes in cognitive function. The joint model was used to analyze association between indicators variation trajectory and survival outcome MCI, and construct the risk prediction model of MCI in the elderly, the linear mixed model was constructed the longitudinal sub-model which described the evolution of a repeated measure over time, a proportional hazards model was constructed the survival sub-model, and the two sub-models were connected through the correlation parameter (α). The areas under the receiver operator characteristic curve (AUC) were used to evaluate the predictive efficacy of the model in the follow-up period of (t, t+Δt). The starting point t was selected at the 30^th, 42^nd, and 54^th month, and the Δt was selected as 15 and 21 months. Based on the prediction model, an example of the research object was selected for dynamic individual predictions of the risk of MCI. Results: Finally, 544 older adults (aged 60 years and above) with normal baseline cognitive status were included, of which 119 cases (21.9%) had MCI during the follow-up process were regarded as the case group, and 425 cases remained normal as the control group. The joint model suggests that the longitudinal trajectories of the six evaluation indicators are all related to the risk of MCI (P<0.001). The risk of MCI decreased by 32.3% (HR=0.677, 95%CI: 0.541-0.846) and 10.8% (HR=0.892, 95%CI: 0.865-0.919) for each one-point increase of MMSE and RAVLT_immediate longitudinal scores. The risk of MCI increased by 53.2% (HR=1.532, 95%CI: 1.393-1.686), 36.2% (HR=1.362, 95%CI: 1.268-1.462), 23.2% (HR=1.232, 95%CI: 1.181-1.285), and 85.1% (HR=1.851, 95%CI:1.629-2.104) for each one-point increase of FAQ, ADAS-Cog11, ADAS-Cog13, and ADASQ4 longitudinal scores. AUC results show that RAVLT_immediate (0.760 2) and ADASQ4 (0.755 8) have higher average prediction efficiency, followed by ADAS-Cog13 (0.743 7), ADAS-Cog11 (0.715 3), FAQ (0.700 8) and MMSE (0.629 5). ADASQ4 joint model was used to provide a dynamic individual prediction of the risk of MCI. The average probability of MCI after five years of follow-up and ten years of follow-up in the example individuals were 8% and 40%, respectively. Conclusions: The RAVLT_immediate and ADASQ4 scales, which are only for memory tests, have high accuracy in predicting the risk of MCI. Using the RAVLT_immediate and ADASQ4 scales as longitudinal cognitive function evaluation indicators to construct a joint model, the results can provide a basis for realizing MCI risk prediction for the elderly.
Aged ; Alzheimer Disease/psychology* ; Cognition ; Cognitive Dysfunction/epidemiology* ; Humans ; Middle Aged ; Neuropsychological Tests ; Risk Factors

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.
Aged ; Alzheimer Disease/genetics* ; Dementia/genetics* ; Environment ; Female ; Humans ; Incidence ; Japan/epidemiology* ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Risk Factors

INTRODUCTION: Singapore has a rapidly ageing population and an increasing prevalence of Alzheimer's disease (AD). Compliance to AD medications is associated with treatment effectiveness. We investigated compliance to acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist and treatment persistence among patients seen at the General Memory Clinic of National University Hospital, Singapore. We also identified the reasons for non-compliance. METHODS: Patients seen at the General Memory Clinic between 1 January 2013 and 31 December 2014, who were prescribed AChEIs and NMDA receptor antagonist, were included in this retrospective cohort study. Non-compliance to medications was indirectly measured by failure to renew prescription within 60 days of the last day of medication supplied by the previous prescription. The reasons for non-compliance were identified. RESULTS: A total of 144 patients were included. At one year, 107 patients were compliant to AD medications, while 37 patients were non-compliant. Around 60% of the non-compliant patients discontinued the use of AD medications within the first six months, and the mean persistent treatment period among this group of patients was 10.3 ± 3.5 months. The main reason for non-compliance was patients' and caregivers' perception that memory loss was of lower priority than other coexisting illnesses. Other reasons for non-compliance included side effects of medications (18.9%), perceived ineffectiveness of treatment (16.2%), inability to attend clinic (5.4%) and high cost of medications (2.7%). CONCLUSION Our findings suggest that the reasons for medication non-compliance can be identified early. Better compliance may be achieved through a multidisciplinary approach to patient education.
Aged ; Aged, 80 and over ; Alzheimer Disease ; drug therapy ; epidemiology ; psychology ; Caregivers ; Cholinesterase Inhibitors ; therapeutic use ; Drug Costs ; Female ; Humans ; Interdisciplinary Communication ; Male ; Medication Adherence ; Middle Aged ; Patient Compliance ; Quality of Life ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Retrospective Studies ; Singapore ; epidemiology ; Treatment Outcome

Cognitive impairment is age-related and manageable only with early diagnosis and prevention. Moxibustion is widely accepted in East Asia as useful for preventing cognitive impairment. This systematic review of animal studies was conducted to verify the efficacy of moxibustion in preventing cognitive impairment and to elucidate the underlying mechanism. Randomized controlled animal trials that established the efficacy of moxibustion in preventing cognitive impairment were included in the analysis. Results of behavioral tests and the signaling pathways elucidated were extracted and a meta-analysis was conducted with the behavioral test results. The risk of bias was evaluated using 9 items, and reporting quality was evaluated using the ARRIVE (Animal Research: Reporting In Vivo Experiments) Guidelines Checklist. Ten trials involving 410 animals met the inclusion criteria. All studies reported the benefit of moxibustion in preventing cognitive deficits caused by Alzheimer's disease (AD). Among five studies using the Morris water maze test, a significant effect of moxibustion in decreasing the escape time was reported in three studies, increasing the crossing times in four studies, and prolonging the dwelling time in two studies. The effects of moxibustion were demonstrated to be mediated by an increase in the activity of neurotrophins and heat shock protein, modulation of the cell cycle, and suppression of apoptosis and inflammation. However, considering the small number of included studies, the lack of studies investigating entire signaling pathways, and a high risk of bias and low reporting quality, our results need to be confirmed through more detailed studies.
Alzheimer Disease ; Animal Experimentation ; Animals ; Apoptosis ; Behavior Rating Scale ; Bias (Epidemiology) ; Cell Cycle ; Checklist ; Cognition Disorders ; Early Diagnosis ; Far East ; Heat-Shock Proteins ; Inflammation ; Moxibustion ; Nerve Growth Factors ; United Nations ; Water

BACKGROUND AND PURPOSE: Previous studies have suggested a decreased cancer risk among patients with Alzheimer's disease (AD). There remains a lack of data on the specific types of cancer and risk factors for developing cancer in AD. We evaluated the association between AD and cancer risk, and we examined specific types of cancer. METHODS: A population-based longitudinal study was conducted using the National Health Insurance Service-Senior cohort for 2002–2013. A total of 4,408 AD patients were included in the study, as were 19,150 matched controls. Potential associations between the risk of cancer and AD were analyzed using Cox proportional hazard regressions. RESULTS: Cancer developed in 12.3% of the AD group patients and in 18.5% of control group subjects. AD was associated with a reduced risk of cancer (hazard ratio [HR], 0.70; 95% confidence intervals, 0.64–0.78). The risk of head and neck cancers was significantly reduced (HR, 0.49), as were risks for cancers of the digestive tract, including stomach cancer (HR, 0.42), colorectal cancer (HR, 0.61), liver and biliary tract cancers (HR, 0.68), and pancreatic cancer (HR, 0.55). Lung and prostate cancer risks were also significantly lower for the AD group (HR, 0.52 and HR, 0.72, respectively). CONCLUSIONS: Our results showed an inverse association between AD and cancer. Further research involving a large number of patients in a hospital based-study is needed to address the biological associations between cancer development and dementia, including AD.
Alzheimer Disease* ; Biliary Tract Neoplasms ; Cohort Studies ; Colorectal Neoplasms ; Dementia ; Epidemiology ; Gastrointestinal Tract ; Head ; Humans ; Korea* ; Liver ; Longitudinal Studies ; Lung ; National Health Programs ; Neck ; Pancreatic Neoplasms ; Prostatic Neoplasms ; Risk Factors ; Stomach Neoplasms

OBJECTIVE: The aims of this study was to present an association between the presence of psychotic symptoms and cortical thicknesses/subcortical volumes in patients with Alzheimer's disease (AD). METHODS: Fourteen AD patients with psychotic symptoms and 41 without psychotic symptoms underwent 3T MRI scanning. After adjusting the effects of confounding variables, the cortical thicknesses were compared between the AD patients with and without psychotic symptoms in multiple regions, across the continuous cortical surface. In addition, the subcortical volumes were compared with a structure-by-structure manner. RESULTS: AD patients with psychotic symptoms were characterized by significant smaller cortical thickness of left pars opercularis (F=4.67, p=0.02) and left lateral occipital gyrus (F=6.05, p=0.04) rather than those without psychotic symptoms, after adjusting the effects of age and scores on the Stroop test, non-psychotic items of Neuropsychiatry Inventory and Clinical Dementia Rating, triglyceride level and total intracranial volume. However, there were no significant differences in the subcortical volume between the two groups. CONCLUSION: These results suggest that AD psychosis may reflect more severe deterioration of neuropathologic change in specific brain region.
Alzheimer Disease* ; Brain ; Broca Area* ; Confounding Factors (Epidemiology) ; Dementia ; Humans ; Magnetic Resonance Imaging ; Neuropsychiatry ; Occipital Lobe* ; Psychotic Disorders ; Stroop Test ; Triglycerides

OBJECTIVES: Season of birth, an exogenous indicator of early life environment, has been related to higher risk of adverse psychiatric outcomes but the findings for Alzheimer's disease (AD) have been inconsistent. We investigated whether the month or season of birth are associated with AD. METHODS: A nationwide nested case-control study including all community-dwellers with clinically verified AD diagnosed in 2005 to 2012 (n=70 719) and up to four age- sex- and region of residence-matched controls (n=282 862) residing in Finland. Associations between month and season of birth and AD were studied with conditional logistic regression. RESULTS: Month of birth was not associated with AD (p=0.09). No strong associations were observed with season (p=0.13), although in comparison to winter births (December-February) summer births (June-August) were associated with higher odds of AD (odds ratio, 1.03; 95% confidence interval, 1.00 to 1.05). However, the absolute difference in prevalence in winter births was only 0.5% (prevalence of those born in winter were 31.7% and 32.2% for cases and controls, respectively). CONCLUSIONS: Although our findings do not support the hypothesis that season of birth is related to AD/dementia risk, they do not invalidate the developmental origins of health and disease hypothesis in late-life cognition. It is possible that season does not adequately capture the early life circumstances, or that other (postnatal) risk factors such as lifestyle or socioeconomic factors overrule the impact of prenatal and perinatal factors.
Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnosis/epidemiology ; Case-Control Studies ; Finland ; Humans ; Logistic Models ; Middle Aged ; Odds Ratio ; Risk Factors ; Seasons

Cognitive impairment, including Alzheimer's disease and other kinds of dementia, is a major health problem in older adults worldwide. Although numerous investigators have attempted to develop effective treatment modalities or drugs, there is no reasonably efficacious strategy for preventing or recovering from cognitive impairment. Therefore, modifiable risk factors for cognitive impairment have received attention, and the growing literature of metabolic risk factors for cognitive impairment has expanded from epidemiology to molecular pathogenesis and therapeutic management. This review focuses on the epidemiological evidence for the association between cognitive impairment and several endocrine risk factors, including insulin resistance, dyslipidemia, thyroid dysfunction, vitamin D deficiency, and subclinical atherosclerosis. Researches suggesting possible mechanisms for this association are reviewed. The research investigating modifiable endocrine risk factors for cognitive impairment provides clues for understanding the pathogenesis of cognitive impairment and developing novel treatment modalities. However, so far, interventional studies investigating the beneficial effect of the "modification" of these "modifiable risk factors" on cognitive impairment have reported variable results. Therefore, well-designed, randomized prospective interventional studies are needed.
Adult ; Alzheimer Disease ; Atherosclerosis ; Cognition ; Cognition Disorders* ; Dementia ; Dyslipidemias ; Epidemiology ; Humans ; Insulin Resistance ; Prospective Studies ; Research Personnel ; Risk Factors* ; Thyroid Gland ; Vitamin D Deficiency

BACKGROUND AND PURPOSE: Dilated Virchow-Robin spaces (dVRS) are not uncommon findings in the normal brain, particularly in the old people, and have been largely regarded as benign lesions. However, there is accumulating evidence that dVRS may serve as an neuroimaging marker of small vessel disease and are associated with cognitive decline. We investigated whether the severity of dVRS would be associated with cognitive dysfunction by comparing the subjects with subjective memory impairment (SMI), mild cognitive impairment (MCI), and Alzheimer's disease (AD). We also examined whether there were differences in the degree of correlation between dVRS and magnetic resonance imaging (MRI) markers of small vessel disease among the three groups. METHODS: In this retrospective study, a total of 225 subjects were included: those with SMI (n=65), MCI (n=100), and AD (n=60). We rated the severity of dVRS using the axial MRI slice containing the greatest number of dVRS in the basal ganglia (dVRS-BG) and in the deep white matter (dVRS-WM), separately. We also assessed baseline characteristics including vascular risk factors and MRI markers of small vessel disease such as white matter hyperintensities (WMH), lacunar infarcts and microbleeds. RESULTS: A cumulative logit model revealed that the severity of cognitive dysfunction was associated with age (p<0.001), hypertension (p=0.006), diabetes mellitus (p=0.042), the severity of dVRS-BG (p=0.001), the severity of WMH (p=0.074) and the presence of lacunar infarcts (p<0.001) and microbleeds (p=0.003) in univariate analysis. However, after adjusting for other confounding variables, the severity of dVRS-BG was not a significant discriminating factor among subjects with SMI, MCI, and AD. Spearman's correlation analysis showed a trend that the correlation between the severity of dVRS-BG and the severity of WMH became more prominent in subjects with AD than in those with MCI or SMI (r=0.191 in SMI; r=0.284 in MCI; r=0.312 in AD), and the same is true of the severity of dVRS-BG and the number of lacunar infarcts. CONCLUSIONS: The severity of dVRS was associated with cognitive dysfunction, which appeared to be confounded by other well-known risk factors. The correlation between dVRS-BG and small vessel disease markers tended to be more significant with the advancement of cognitive impairment. These results suggest that severe dVRS may reflect cerebral small vessel disease and contribute to cognitive impairment.
Alzheimer Disease ; Basal Ganglia ; Brain ; Cerebral Small Vessel Diseases ; Cognition ; Confounding Factors (Epidemiology) ; Diabetes Mellitus ; Hypertension ; Logistic Models ; Magnetic Resonance Imaging ; Memory ; Mild Cognitive Impairment ; Neuroimaging ; Retrospective Studies ; Risk Factors ; Stroke, Lacunar