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Background The Ginkgo biloba special extract, EGb 761® has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer’s disease (AD). Methods To guide clinical practice in the Asian region, the Asian Clinical Expert Group on Neurocognitive Disorders compiled evidence‐based consensus recommendations regarding the use of EGb 761® in neurocognitive disorders with/without cerebrovascular disease. Results Key randomized trials and robust meta‐analyses have demonstrated significant improvement in cognitive function, neuropsychiatric symptoms, activities of daily living (ADL) and quality of life with EGb 761®versus placebo in patients with mild‐to‐moderate dementia. In those with mild cognitive impairment (MCI), EGb 761® has also demonstrated significant symptomatic improvement versus placebo. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and N‐methyl‐D‐aspartate (NMDA) antagonists e.g. memantine (Grade 3 recommendation; Level B evidence). Only EGb 761® had Level B evidence in improving cognition, behaviour, and ADL in both AD and vascular dementia patients. Safety analyses show EGb 761® to have a positive risk‐benefit profile. While concerns have been raised regarding a possible increased bleeding risk, several randomized trials and two meta‐analyses have not supported this association. Conclusions The Expert Group foresee an important role for EGb 761®, used alone or as an add‐on therapy, in the treatment of MCI and dementias, particularly when patients do not derive benefit from acetylcholinesterase inhibitors or NMDA antagonists. EGb 761® should be used in alignment with local clinical practice guidelines.

The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer’s disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.

Loneliness is a neuropsychiatric symptom that has been associated with cognitive impairment and dementia. We aimed to investigate whether depressive symptomatology and biomarkers of Alzheimer’s disease (AD) and cerebrovascular disease (CVD) are associated with loneliness. Secondly, we aimed to investigate whether loneliness, depressive symptomatology, and biomarkers of AD and CVD are associated with subjective cognitive decline (SCD). We included 215 cognitively unimpaired participants (70 y/o) with cerebrospinal fluid biomarkers, magnetic resonance imaging, and questionnaires for loneliness, depressive symptomatology, and SCD. For aim 1, our findings showed that CVD and depressive symptomatology were the most relevant measures to discriminate people with loneliness. For aim 2, a random forest classification model showed that loneliness contributed to discriminate individuals with SCD, but logistic regression showed that its partial predictive effect was non-significant when depressive symptomatology and AD biomarkers were included in the models. We conclude that loneliness is associated with SCD, CVD, and depressive symptomatology. Given the complex interplay between loneliness, depressive symptomatology, and SCD, more research is needed to fully clarify the unique role of each neuropsychiatric symptom in relation to biomarkers of brain pathology.

Yuesong Pan and colleagues discuss the relation between cerebrovascular diseases and impairment of cognition, with an emphasis on a chance to prevent dementia by preventing cerebrovascular diseases

Background Mixed vascular and neurodegenerative dementia, such as Alzheimer’s disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. Methods We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. Results The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. Conclusions Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

INTRODUCTION Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US‐representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross‐sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. Highlights Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition–neuropathology associations. Transportability methods can provide insight into selection bias.

INTRODUCTION The presence and interaction of multiple comorbid neuropathologies are a major contributor to the worldwide dementia burden. METHODS We analyzed 1183 subjects from the National Alzheimer's Coordinating Center dataset with various combinations of isolated and mixed neurodegenerative pathologies and conducted mixed‐effects multiple linear regression modeling to comprehensively compare the neurocognitive and neuropsychological trajectories between groups over time. RESULTS In combination with Alzheimer's disease neuropathologic change, various combinations of limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy, Lewy body dementia, and cerebrovascular disease further impair global cognition and specific neurocognitive domains; however, they do not appear to extensively affect the rate of decline with time across these domains, suggesting an additive but not synergistic effect. DISCUSSION These findings corroborate the known cumulative effects of mixed pathologies on cognition and add nuance to our understanding of their specific interactions, which is crucial for the development of biomarkers and effective therapeutics. Highlights Mixed neurodegenerative pathologies are common in the elderly population. The most common neurodegenerative pathologies were Alzheimer's disease neuropathologic change (ADNC), cerebrovascular disease (CVD), Lewy body dementia (LBD), and limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy (LATE). The addition of various combinations of comorbid CVD, LBD, and LATE to ADNC worsened overall performance on cognitive and neuropsychological testing across time. In general, the addition of multiple comorbid neurodegenerative pathologies did not influence the rate of decline across the evaluated time period.

Background Beta-amyloid (Aβ) plaques and tau tangles are pathological hallmarks of Alzheimer’s disease (AD); however, autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. It remains unclear how Aβ and tau relate to cognition in the context of concurrent CVD. In initially cognitively unimpaired older adults with CVD, this study aimed to determine ante-mortem cognitive trajectories associated with elevated Aβ and/or tau at autopsy. Methods Participants aged 65–95 classified as cognitively unimpaired at baseline from the National Alzheimer’s Coordinating Center database, with ≥ 1 follow-up between 2005 and 2015, and available autopsy/ APOE data were included in this cohort study ( N  = 863). All participants had at least one of six CVD markers at autopsy. Participants were classified into four groups (A − T−, A + T−, A − T+, A + T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque staging and Braak staging. Linear mixed models assessed rate of change in Preclinical Alzheimer’s Cognitive Composite scores, episodic memory, and executive function. Results A + T + adults demonstrated significantly faster cognitive decline on all outcomes in the ~ 10 years preceding death compared to A − T− adults (d = 0.34–0.46). Similarly, when compared to A + T − adults, A + T + adults showed significantly faster decline on all outcomes (d = 0.19–0.37). At the last visit prior to death, a greater proportion of A + T + adults (36%) received a dementia diagnosis compared to A − T+ (15%; OR = 6.00), A + T− (14%; OR = 8.00) and A − T− adults (12%; OR = 6.86), p  <.001. When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes ( p ’s < 0.001, d = 0.29–0.37) was similarly observed in A + T + adults compared to A − T− adults. Conclusions In older adults with concurrent CVD, A + T + at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A − T− older adults. Faster cognitive decline in A + T + in the context of low final visit dementia diagnoses may suggest that post-mortem A + T + is associated with a steep trajectory of cognitive decline ante-mortem , but that dementia progression is not inevitable.

Background/Aims: To evaluate the psychometric properties of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease (SVD). Methods: 40 SVD patients and 40 matched controls were recruited. Concurrent and criterion validity, inter-rater and test-retest reliability, internal consistency of the HK-MoCA were examined and clinical observations were made. Results: Performance on the HK-MoCA was significantly predicted by both executive (β = 0.23, p = 0.013) and non-executive (β = 0.64, p < 0.001) composite scores. It differentiated SVD patients from controls (area under the curve = 0.81, p < 0.001) with an optimal cutoff at 21/22. Reliability, internal consistency and clinical utility were good. Conclusion: The HK-MoCA is a useful cognitive screening instrument for use in SVD patients.

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) – a network implicated in AD and other brain disorders – in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β=−0.063, 95% CI: −0.106, −0.020), anterior cingulate (β=−0.055, 95% CI: −0.101, −0.010), and medial frontal lobe (β=−0.050, 95% CI: −0.092, −0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β=−0.024, 95% CI: −0.062, 0.014) and the hippocampus (β=−0.006, 95% CI: −0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life. •Cerebrovascular reactivity (CVR) was examined in relation to vascular risk factors (VRF).•CVR was compared in brain regions underlying the default-mode network vs non-DMN.•CVR was lower for DMN regions relative to non-DMN regions in those with VRF.•CVR may represent an important preclinical marker for brain health in later life.