Cognitive Impairment In Older Individuals Research Articles

Screening and Recognition of Cognitive Impairment in Older People Visiting Hearing Aid Dispensers in the Netherlands

ObjectivesThis study aims to determine how prevalent suspected cognitive impairment is in older people visiting hearing aid dispensers, and to assess whether hearing aid dispensers’ judgment on cognition was in accordance with the outcome of a cognitive screening. DesignThis observational study was conducted between April and May 2022. Setting and ParticipantsFour private hearing aid retail stores in the Netherlands, where cognitive impairment was screened in people aged ≥60 years. MethodsThe Mini-Cog was used for cognitive screening. In addition, hearing aid dispensers were asked to provide their professional judgment if they suspected cognitive impairment. ResultsOf the total 239 older individuals screened, 133 were men [56%, mean age: 79 years (SD 8.6)], and 51 (21.3%) had abnormal outcomes on the Mini-Cog test. The recognition of possible cognitive impairment by the hearing aid dispensers compared to the outcome of the Mini-Cog resulted in correct predictions for 183 of the 239 individuals. Conclusion and ImplicationsCognitive screening in hearing-impaired older adults who visit a hearing aid dispenser suggests that cognitive impairment might be present in approximately 1 in 5 individuals. Hearing aid dispensers' response to the presence of a cognitive impairment was in 2 of 3 in accordance with an abnormal outcome on cognitive screening. To improve hearing care for people with cognitive impairment, it might be important to enhance hearing care professionals’ recognition of cognitive impairment in older individuals.

Post‐mortem MRI white matter hyperintensities are associated with cortical astrocytopathy and water channel expression in the oldest‐old

AbstractBackgroundCerebrovascular small vessel disease, a common cause of cognitive impairment in older individuals, is characterized by the presence of MRI white matter hyperintensities (WMH). Our previous MRI‐targeted histopathological studies have found WMHs and the surrounding NAWM penumbra to be associated with glial markers. This study aims to assess the relationship between cortical markers of glial dysfunction and post‐mortem (PM) MRI WMH.MethodLeft brain hemispheres were obtained from 45 Oregon Alzheimer’s Disease Research Center subjects >/ = 80 years of age without significant AD pathology. Intact and sliced hemispheres were scanned at 7T MRI. MRI scans were used to target histological sampling. Slides were stained for glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), aquaporin‐1 (AQP1), aquaporin‐4 (AQP4), vimentin and amyloid‐beta (ABETA). Slides were co‐registered to MRI. Tissue masks were hand‐drawn to delineate white matter and cortex. Cortical ROIs were quantified for mean pixel value (AQP1, AQP4, GFAP, and Vimentin) or area coverage (IBA1, ABETA). Cassettes with no local WMH were compared with those in the top third of slide WMH coverage (187 cassettes). Global WMH burden was dichotomized at the mean. Linear mixed‐effects models regressed stain quantification on local WMH (in slide) and global WMH burden, with a random effect for staining batch (levels = 4). The final model controlled for age at death and ABETA expression within a slide. Interactions between local and global WMH were included where appropriate.ResultHigh local WMH burden was associated with greater cortical vimentin (p = 0.036), GFAP (p = 0.066), and AQP4 (p = 0.004), while high global WMH burden was associated with greater IBA1 (p = 0.034) and AQP1 (p = 0.071). An interaction was identified between local and global WMH burden for AQP1 (p<0.10), such that in subjects with high global WMH burden, high local WMH burden was associated with higher AQP1. Greater local cortical ABETA was associated with cortical AQP1 (p = 0.004) expression.ConclusionIn oldest‐old individuals without significant AD pathology, high local and global PM‐MRI WMH burden is associated with cortical astrocytopathy, including increased water channel expression and inflammation. Findings implicate WMH as a state marker of widespread cortical pathology that may confer increased vulnerability to cognitive decline with advanced age.

The Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy

AbstractBackgroundCerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage and cognitive impairment in older individuals. Hallmark manifestations of CAA on MRI include cortical hemorrhages, as well as perivascular spaces (PVS) in the white matter centrum semiovale and white matter hyperintensities (WMH) in a subcortical multi‐spot pattern. We performed an ex vivo MRI‐neuropathological study to: 1) determine the relationship between WMH volume and CAA severity, and 2) assess the histopathological substrate of confluent WMH, WMH in a multi‐spot pattern (WM_MS), and normal‐appearing white matter (NAWM).MethodNineteen autopsy cases with pathologically confirmed CAA (age 75±8y; 7F) and five non‐CAA controls (age 88±5y; 3F) were included. Formalin‐fixed hemispheres underwent 3T MRI, including a T2‐weighted (500µm isotropic resolution, to obtain manual WMH segmentations) and a T2*‐weighted sequence (1mm isotropic resolution, to automatically segment hemisphere volume using SynthSeg). After scanning, five pre‐defined standard areas were sampled from each brain, then processed to obtain manually assessed arteriolosclerosis scores and AI‐derived cortical and leptomeningeal CAA area measurements. In the CAA cases, specific areas with ex vivo MRI‐observed WM_MS (n = 7), confluent WMH (n = 9), and NAWM (n = 9) were sampled. Sections were stained with LH&E (to determine WM rarefaction, % PVS area, and degree of arteriolosclerosis), and CD68 (a marker of activated microglia, to assess density of CD68‐positive cells).ResultTotal normalized WMH volume did not differ between CAA cases (0.037±0.024) and non‐CAA controls (0.027±0.026) (Mann‐Whitney U test 36, p = 0.31). Within the CAA cases, a multivariable regression model corrected for age at death revealed that normalized WMH volume was associated with cortical CAA area (p = 0.010) and arteriolosclerosis (p = 0.066), but not leptomeningeal CAA area (p = 0.94). Targeted neuropathological assessment revealed that WM rarefaction, arteriolosclerosis score, and density of CD68‐positive cells were higher in areas with WMH compared to WM_MS and NAWM. In contrast, % PVS area was higher in WM_MS compared to WMH and NAWM.ConclusionThe observed differences in neuropathological correlates between WMH in a multi‐spot pattern and confluent WMH in CAA suggest different pathophysiological mechanisms. Future studies are needed to determine these mechanisms as well as the causal relationship between cortical CAA severity and WMH burden.

Correlation between air pollution and cognitive impairment among older individuals: empirical evidence from China

BackgroundLittle information is available regarding the impact of air pollution on cognitive impairment in older individuals in developing countries. This study empirically tested the impacts of the air quality index (AQI), air pollution intensity (quantified by the number of days of extreme air pollution in a year), and different pollutants on the cognitive abilities of older Chinese individuals.MethodsA panel of 28,395 participants spanning 122 cities in 2015 and 2018 was used, based on 3-year follow-up survey data from the China Health and Retirement Longitudinal Study (CHARLS) database. Data from the two phases of the CHARLS microsurvey were combined with relevant statistical data on air pollution in each region in the current year. These two surveys were used to investigate changes in basic health and macro-environmental indicators in older individuals in China, and a mean difference test was conducted. We then reduced the sample selection error by controlling for environmental migration and used two-way fixed and instrumental variable methods for endogenous treatment to avoid the estimation error caused by missing variables.ResultsAir pollution had a significantly negative effect on the cognitive abilities of older individuals (odds ratio [OR]: 1.4633; 95% confidence interval [95% CI]: 1.20899–1.77116). Different pollution intensities(only AQI value is greater than 200 or more) had apparent effects on cognitive impairment, with an OR of approximately 1.0. Sulfur dioxide had significantly negative effects on cognitive ability, with OR of 1.3802 (95% CI: 1.25779–1.51451). Furthermore, air pollution impact analysis showed heterogeneous results in terms of age, sex, education, and regional economic development level. In addition, social adaptability (calculated using social participation, learning, adaptability, and social support) not only had a significant positive effect on the cognitive abilities of older individuals, but also regulated the cognitive decline caused by air pollution.ConclusionsAir pollution affects cognitive impairment in older individuals, especially in those with lower education levels, and living in economically underdeveloped areas. This effect is synchronous and has a peak at an AQI of > 200.

Utility of linguistic biomarkers for prediction of cognitive impairment and limbic predominant age related TDP‐43 neuropathologic change in the oldest old

AbstractBackgroundThere is an urgent need for accessible biomarkers that can predict cognitive impairment in older individuals. There is also a complete lack of biomarkers for TAR DNA‐binding protein‐43 (TDP‐43), a frequent and important neurodegenerative pathology in older individuals, currently referred to as Limbic‐predominant Age‐related TDP‐43 Encephalopathy‐Neuropathologic Change (LATE‐NC). Here we explored the utility of linguistic markers for prediction of future cognitive impairments and LATE‐NC.Method134 participants of the Leisure World cohort, an epidemiologic study in a California retirement community, produced written descriptions of the cookie‐theft picture from the Boston Aphasia Diagnostic Examination. All had normal cognition at the time. Samples were quantitatively analyzed for 31 linguistic markers (see table 1 for definitions of select relevant variables). Participants subsequently joined the 90+ study and underwent cognitive assessments every 6 months and autopsy after death. Cognitive impairment and its onset date were determined at postmortem conferences. LATE‐NC was considered present in those with TDP‐43 in hippocampus or neocortex, and Alzheimer’s disease neuropathologic change (ADNC) in those with high likelihood ADNC according to NIA‐ AA guidelines. To examine the relationships between linguistic markers and future cognitive impairment and presence of LATE‐NC and ADNC, we used logistic regression analysis. Models were adjusted for sex, education, age at the time of writing the samples and age at death.ResultTable 2 summarizes demographic and neuropathology findings. Additionally, mean age at cognitive impairment was 93.2 in 72% who developed cognitive impairment. Future cognitive impairment was significantly associated with less information content (OR:0.02) and fewer clauses (OR:0.93) (Table 3). Also, presence of LATE‐NC was significantly associated with higher proportions of content words (OR:7.2), higher proportion of function word errors (OR:10.5), and fewer complete units (OR:0.15). Lower number of words also trended towards a significant association (OR:8, p = 0.07) with LATE‐NC. No language measure was associated with ADNC.ConclusionOur results suggest that linguistic markers derived from writing samples obtained on average 8 years prior to development of cognitive impairment and 12 years before death might serve as biomarkers for future cognitive impairment and presence of LATE‐NC at autopsy.

White matter health in the context of Alzheimer’s disease pathophysiology

AbstractBackgroundMulti‐compartment modelling of white matter (WM) microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on WM health through the neurite (axons and dendrites) density index and free water measures. We hypothesized that cerebrovascular disease (CVD), Alzheimer’s disease (AD), and an FDG pattern suggestive of TDP‐43 proteinopathy would be associated with distinct NODDI readouts of WM damage which would be informative for identifying the substrate for cognitive impairment.MethodWe identified two independent cohorts with multi‐shell diffusion MRI, amyloid and tau PET, and cognitive assessments. One, were participants from the Mayo Clinic Study of Aging, a population‐based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota. The second were 61 amyloid positive AD participants from the Mayo AD Research Center.ResultWe observed an increase in free water and decrease in neurite density in the genu of the corpus callosum associated with vascular risk factors, which we refer to as vascular WM component (Figure 1). Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal WM where we measured parahippocampal cingulum and inferior temporal WM bundles. Worsening temporal neurite density was associated with (antemortem confirmed) FDG TDP‐43 signature. Post‐mortem neuropathologic data on a small subset (n=9) of this sample lend support to our findings. In the population‐based cohort where vascular disease was more prevalent, the vascular WM component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory) (Table 1). In the AD dementia clinic‐based cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non‐trivial contribution of the temporal WM component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition.ConclusionWhite matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether CVD versus neurodegenerative disease caused by tau deposition or TDP‐43 pathology) for cognitive impairment in older individuals.

Relationships between urinary metals concentrations and cognitive performance among U.S. older people in NHANES 2011-2014.

BackgroundEpidemiological evidence on Urine metals and cognitive impairment in older individuals is sparse and limited. The goal of this study was to analyze if there was a link between urinary metal levels and cognitive performance in U.S. people aged 60 and up.MethodsThe National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014 were utilized in this cross-sectional analysis. Memory function was quantified using the following methods: Established Consortium for Word Learning in Alzheimer's Disease (CERAD-WL) (immediate learning and recall and delayed recall), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). An inductively coupled plasma mass spectrometry (ICP-MS) was used to estimate urine metal concentrations. The connection of Urine metals level with cognitive function was investigated employing binary logistic regression and restricted cubic spline models.ResultsA total of 840 participants aged 60 years and over were enrolled in this study. After controlling for confounders, the association between cadmium, barium, cobalt, cesium, manganese, and thallium and poor cognitive performance showed significance in multiple logistic regression compared to the lowest quartile of metals. In the DSST test, the weighted multivariate adjusted ORs (95% CI) for cadmium in the highest quartile, barium and cesium in the third quartile were 2.444 (1.310–4.560), 0.412 (0.180–0.942) and 0.440 (0.198–0.979), respectively. There were L-shaped associations between urine cesium, barium, or manganese and low cognitive performance in DSST. Urine lead, molybdenum and uranium did not show any significant relationships with cognitive impairment, respectively, compared to the respective lowest quartile concentrations.ConclusionThe levels of barium (Ba), cobalt (Co), cesium (Cs), manganese (Mn), and thallium (Tl) in urine were found to be negatively related to the prevalence of impaired cognitive performance in our cross-sectional investigation. Higher cadmium (Cd) levels were associated with cognitive impairment.

Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals.

We investigated the effects of aging, white matter hyperintensities (WMH), and cognitive impairment on brain iron levels and cerebral oxygen metabolism, known to be altered in Alzheimer's disease (AD), using quantitative susceptibility mapping and MR-based cerebral oxygen extraction fraction (OEF). In 100 individuals over the age of 50 (68/32 cognitively impaired/intact), OEF and neural tissue susceptibility (χn ) were computed retrospectively from MRI multi-echo gradient echo data, obtained on a 3 Tesla MRI scanner. The effects of age and WMH on OEF and χn were assessed within groups, and OEF and χn were assessed between groups, using multivariate regression analyses. Cognitively impaired subjects were found to have 19% higher OEF and 34% higher χn than cognitively intact subjects in the cortical gray matter and several frontal, temporal, and parietal regions (p<.05). Increased WMH burden was significantly associated with decreased OEF in the cognitively impaired, but not in the cognitively intact. Older age had a stronger association with decreased OEF in the cognitively intact group. Both older age and increased WMH burden were significantly associated with increased χn in temporoparietal regions in the cognitively impaired. Higher brain OEF and χn in cognitively impaired older individuals may reflect altered oxygen metabolism and iron in areas with underlying AD pathology. Both age and WMH have associations with OEF and χn but are modified by the presence of cognitive impairment.

Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice.

Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p.) challenge in SAMP8 mice. Hippocampal IL-1β, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.

Excessive sleep increased the risk of incidence of cognitive impairment among older Chinese adults: a cohort study based on the Chinese Longitudinal Healthy Longevity Survey (CLHLS).

Based on a cohort from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), we aimed to evaluate the relationship between sleep duration and the incidence of cognitive impairment among older Chinese adults. We conducted a prospective analysis based on 3692 participants from the CLHLS at baseline (in 2011), and as a 3-year follow-up (till 2014), 531 participants (14.4%) had cognitive impairment, which was defined as a Mini-Mental State Examination score <24. Sleep duration was classified into three groups: short (≤5 hours/day), normal (>5 but <10 hours), and long (≥10 hours/day). A logistic regression model was used to examine the association between baseline sleep duration and cognitive impairment after adjusting for sociodemographic data, living habits, and health conditions. Five hundred sixty-two participants (15.2%) were in the short-duration group, and 608 participants (16.5%) were in the long-duration group. After adjusting for multiple potential confounders, compared with normal sleep duration, long sleep duration was associated with the incidence of cognitive impairment (OR = 1.309, 95% CI: 1.019-1.683), especially among men (OR = 1.527, 95% CI: 1.041-2.240) and those having a primary and above education level (OR = 1.559, 95% CI: 1.029-2.361). No significant association was observed between short sleep duration and cognitive impairment (OR = 0.860, 95% CI: 0.646-1.145). Excessive sleep may increase the risk of cognitive impairment in older individuals. It may be a suggestive sign of early neurodegeneration and may be a useful clinical tool to identify those at a higher risk of progressing to cognitive impairment.

Vision, vision-specific functioning and mobility, and their relationship with clinically assessed cognitive impairment.

The relationship between self-reported visual disability and cognitive impairment in older individuals is unclear. To determine the relationship of vision-specific functioning (VSF), vision-specific mobility (VSM) and visual acuity (VA) with clinically assessed cognitive impairment in the Epidemiology of Dementia in Singapore study. Cross-sectional. Population-based. Eight hundred and seventy-four adults aged ≥60years at higher risk of possible cognitive impairment by the Abbreviated Mental Test and progressive forgetfulness question. VSF and VSM were measured using Rasch-transformed continuous scores of two Impact of Vision Impairment questionnaire domains. Cognitive impairment was objectively determined using detailed neuropsychological testing and defined as no cognitive impairment (NCI), mild cognitive impairment-no dementia (CIND), moderate CIND only and moderate CIND or dementia. Associations were assessed using multinomial logistic regression models. Of the 874 participants (49.0% males, mean age (SD) 65.5 (7.0) years), 277, 281 and 316 had NCI, mild CIND and moderate CIND or dementia, respectively. Compared to NCI, the odds of moderate CIND, and moderate CIND or dementia increased for every SD worsening in VSF (OR: 1.44, 95% CI 1.14-1.82, and OR: 1.52, 95%CI 1.19-1.94, respectively) and VSM (OR: 1.42, 95%CI 1.11-1.81, and OR: 1.50, 95%CI 1.15-1.95). Similarly, the odds of mild CIND (OR: 1.62, 95%CI 1.19-2.22), moderate CIND (OR: 1.93, 95%CI 1.45-2.58), and moderate CIND or dementia (OR: 2.25, 95%CI 1.62-3.11) increased significantly with every SD worsening of VA. Our results emphasise the importance of interventions to prevent vision loss and improve quality of life to reduce likelihood of age-related cognitive decline.

Evaluating pre‐screening tools for older Latino recruitment into preclinical Alzheimer’s disease studies

AbstractBackgroundRecruitment for preclinical Alzheimer’s disease clinical trials and observational studies in the Latino population continues to increase as researchers aim to diversify their samples. The Telephone Interview for Cognitive Status modified version (TICS‐m) is a pre‐screening tool that has shown to have high diagnostic validity for identification of dementia in mostly Caucasian samples. The TICS‐m cut‐off currently used for screening out cognitive impairment in older individuals is ≥26. We aimed to 1) determine whether currently used TICS‐m cut‐offs are appropriate for pre‐screening clinically normal older Latinos, and 2) assess the relationships among the TICS‐m score and outcome measures typically used in clinical trials, such as Mini Mental State Exam (MMSE), Logical Memory Delayed Recall, and Clinical Dementia Rating (CDR).MethodsTwenty‐nine older Latino adults (mean age= 68.7, mean education=15.6, and mean TICS‐m= 33.4/40) from the Harvard Aging Brain Study (HABS) were included in this study. Participants completed the pre‐screening TICS‐m over the phone, followed by an in‐clinic screening neuropsychological battery, which included the MMSE, Logical Memory Delayed Recall, and CDR, administered in Spanish. Linear regression models controlling for age, sex, and education were used to assess the relationships between TICS‐m score and performance on the neuropsychological measures.ResultsTICS‐m scores were positively correlated with years of education (r=0.54, p=0.002). No significant associations were observed among TICS‐m scores and other cognitive measures, after adjusting by age, sex, and education (MMSE: r=0.04, p=0.82; Logical Memory Delayed: r=0.10, p=0.62; and CDR sum of boxes: r=‐0.03, p=0.86).ConclusionPreliminary results suggest that in this sample of largely cognitively normal Latino adults, TICS‐m score is not associated with performance in other cognitive outcome measures typically used in clinical and observational trials for preclinical Alzheimer’s disease. These findings also suggest that the TICS‐m may not accurately reflect actual cognitive function in older Latino participants. However, we do not know if we are inadvertently screen‐failing participants using TICS‐m as a pre‐screening tool. Further research is needed to assess whether this pre‐screening tool is adequate in the pre‐screening process for preclinical Alzheimer’s disease in older Latino adults.

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology

The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

Severe Fear of Falling Is Associated With Cognitive Decline in Older Adults: A 3-Year Prospective Study

ObjectivesFear of falling (FOF) is common in older adults. We investigated whether FOF affects development of cognitive decline over a 3-year period in community-dwelling older adults with intact cognition. DesignRetrospective, cohort, observational. Setting and participantsData for 4280 older adults with normal cognition at baseline from the Survey of Living Conditions and Welfare Needs of Korean Older Persons (2008 and 2011). MethodsHistory of falls and severity of FOF (no fear, somewhat fearful, or very fearful) were assessed at baseline (2008). We evaluated cognitive function using the Korean version of the Mini-Mental State Examination in 2008 and 2011, and defined cognitive decline as a decrease of ≥3 points over the 3-year study period. Multivariable logistic regression analysis was performed to examine the association between FOF and cognitive decline. ResultsThe prevalence of being somewhat fearful of falling was 54.6% and that of being very fearful was 9.7%. The participants who were somewhat fearful of falling had a 1.2-fold higher risk of cognitive decline; this finding lost significance in adjusted models. The participants who were very fearful of falling had a 1.45-fold higher risk of cognitive decline than those with no FOF after adjusting for confounders [odds ratio (OR) 1.45, 95% confidence interval (CI) 1.08–1.95]. When we divided the participants according to age, sex, and baseline cognitive function, the association was significant in men (OR 2.29, 95% CI 1.24–4.25), participants age >70 years (OR 1.57, 95% CI 1.06–2.33), and those with a Mini-Mental State Examination score <30 (OR 1.45, 95% CI 1.07–1.98). Conclusions and implicationsBeing very fearful of falling increased the risk of cognitive decline in older Korean adults. Physicians should be aware of the risk of development of cognitive impairment in older individuals with FOF.

Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia

With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown. To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia. The prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017. The presence, number, and location of L-PVSs. Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines. Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers. Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.

Sleep-Disordered Breathing, Postoperative Delirium, and Cognitive Impairment

Sleep-disordered breathing (SDB) is highly prevalent in the general population and has been associated with cognitive impairment in older individuals. Delirium is an acute decline in cognitive function and attention that often occurs after surgery, especially in older individuals. Several recent studies suggest an association between SDB and postoperative delirium. The aim of this systematic review is to examine the current literature on SDB, postoperative delirium, and cognitive impairment and to discuss the pathophysiology and perioperative considerations. A literature search was performed of Medline (1946-2016), Medline In-Process (June 2016), Embase (1947-2016), Cochrane Central Register of Controlled Trials (May 2016), and Cochrane Database of Systematic Reviews (2005 to June 2016). Inclusion criteria for studies were (1) polysomnography confirmed SDB; (2) postoperative delirium or cognitive impairment confirmed by a validated diagnostic tool; and (3) publications in the English language. All study designs including randomized controlled trials and observational studies were included. The literature search identified 2 studies on SDB and postoperative delirium, 15 studies on SDB and cognitive impairment, and 5 studies on the effect of continuous positive airway pressure on cognitive impairment and delirium in older individuals. SDB was associated with cognitive impairment, and this systematic review revealed that SDB may be a risk factor for postoperative delirium, especially in older individuals. Although the pathophysiology of SDB and postoperative delirium is unclear and effective treatments for SDB to reduce the incidence of delirium have not been studied extensively, preliminary evidence suggests that continuous positive airway pressure therapy may lower the risk of delirium. Health care professionals need to be aware that undiagnosed SDB may contribute to postoperative delirium. Preoperative screening for SDB and strategies to reduce the risk for postoperative delirium may be helpful in older individuals. Further studies are needed to clarify the relationship between SDB and postoperative delirium and elucidate the pathophysiology of postoperative delirium through SDB.

Dementia incidence and predictors in cerebral amyloid angiopathy patients without intracerebral hemorrhage

Cerebral amyloid angiopathy (CAA) is a common cause of cognitive impairment in older individuals. This study aimed to investigate predictors of dementia in CAA patients without intracerebral hemorrhage (ICH). A total of 158 non-demented patients from the Stroke Service or the Memory Clinic who met the modified Boston Criteria for probable CAA were included. At baseline, neuroimaging markers, including lobar microbleeds (cerebral microbleeds (CMBs)), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), magnetic resonance imaging (MRI)-visible centrum semiovale perivascular spaces (CSO-PVS), lacunes, and medial temporal atrophy (MTA) were assessed. The overall burden of small vessel disease (SVD) for CAA was calculated by a cumulative score based on CMB number, WMH severity, cSS presence and extent and CSO-PVS severity. The estimated cumulative dementia incidence at 1 year was 14% (95% confidence interval (CI): 5%–23%), and 5 years 73% (95% CI: 55%, 84%). Age (hazard ratio (HR) 1.05 per year, 95% CI: 1.01–1.08, p = 0.007), presence of MCI status (HR 3.40, 95% CI: 1.97–6.92, p < 0.001), MTA (HR 1.71 per point, 95% CI: 1.26–2.32, p = 0.001), and SVD score (HR 1.23 per point, 95% CI: 1.20–1.48, p = 0.030) at baseline were independent predictors for dementia conversion in these patients. Cognitive deterioration of CAA patients appears attributable to cumulative changes, from both vasculopathic and neurodegenerative lesions.

Human Striatal Dopaminergic and Regional Serotonergic Synaptic Degeneration with Lewy Body Disease and Inheritance of APOE ε4

Cognitive impairment in older individuals is a complex trait that in population-based studies most commonly derives from an individually varying mixture of Alzheimer disease, Lewy body disease, and vascular brain injury. We investigated the molecular composition of synaptic particles from three sources: consecutive rapid autopsy brains from the Adult Changes in Thought Study, a population-based cohort; four aged nonhuman primate brains optimally processed for molecular investigation; and targeted replacement transgenic mice homozygous for APOE ε4. Our major goal was to characterize the molecular composition of human synaptic particles in regions of striatum and prefrontal cortex. We performed flow cytometry to measure six markers of synaptic subtypes, as well as amyloid β 42 and paired helical filament tau. Our results showed selective degeneration of dopaminergic terminals throughout the striatum in individuals with Lewy body disease, and serotonergic degeneration in human ventromedial caudate nucleus from individuals with an APOE ε4 allele. Similar results were seen in mouse caudate nucleus homozygous for APOE ε4 via targeted replacement. Together, extension of these clinical, pathologic, and genetic associations from tissue to the synaptic compartment of cerebral cortex and striatum strongly supports our approach for accurately observing the molecular composition of human synapses by flow cytometry.

Association of Visual Acuity and Cognitive Impairment in Older Individuals: Fujiwara-kyo Eye Study.

Both visual impairment and cognitive impairment are essential factors that determine the quality of life in the aged population. The aim of this study was to determine if a correlation existed between visual acuity and cognitive impairment in an elderly Japanese population. The Fujiwara-kyo Eye Study was a cross-sectional study of individuals aged ≥68 years who lived in Nara Prefecture of Japan. Participants underwent ophthalmological examinations and cognitive function test. A mild visual impairment was defined as having a best corrected visual acuity (BCVA) >0.2 logarithm of the minimum angle of resolution (logMAR) units in the better eye. Cognitive impairment was defined as having a Mini-Mental State Examination (MMSE) score of ≤23 points. A total to 2818 individuals completed the examinations. The mean age of the participants was 76.3 ± 4.8 years (mean ± standard deviation). The mean BCVA of the better eye was −0.02 ± 0.13 logMAR units and 6.6% subjects were classified as being mildly visually impaired. The mean MMSE score was 27.3 ± 2.3 and 5.7% subjects were classified as being cognitively impaired. The proportion of subjects with cognitive or moderate visual impairment increased with age, and there was a significant correlation between the visual acuity and MMSE score (r = −0.10, p < 0.0001). Subjects with mild visual impairments had 2.4 times higher odds of having cognitive impairment than those without visual impairment (odds ratio 2.4, 95% confidence interval, 1.5–3.8, p < 0.001) after adjusting for age, sex, and length of education. We conclude that it may be important to maintain good visual acuity to reduce the risk of having cognitive impairment.

Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey.

Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population. We determined whether cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) seropositivity were associated with cognitive impairment among children (aged 6-16 years) and adults aged 20-59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment. Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β, -0.69; 95% confidence interval [CI], -1.18 to -.21 and β, -0.82; 95% CI, -1.29 to -.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13-2.11, and OR, 1.41; 95% CI, 1.09-1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14-1.80). Among older adults, HSV-1 seropositivity was associated with immediate memory impairment (OR, 3.26; 95% CI, 1.68-6.32). Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.