Longitudinal clinical–pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) ...as important factors in the development of Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical–pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.
Cerebrovascular disease (CVD) manifests through a broad spectrum of mechanisms that negatively impact brain and cognitive health. Oftentimes, CVD changes (excluding acute stroke) are insufficiently ...considered in aging and dementia studies which can lead to an incomplete picture of the etiologies contributing to the burden of cognitive impairment. Our goal with this focused review is 3-fold. First, we provide a research update on the current magnetic resonance imaging methods that can measure CVD lesions as well as early CVD-related brain injury specifically related to small vessel disease. Second, we discuss the clinical implications and relevance of these CVD imaging markers for cognitive decline, incident dementia, and disease progression in Alzheimer disease, and Alzheimer-related dementias. Finally, we present our perspective on the outlook and challenges that remain in the field. With the increased research interest in this area, we believe that reliable CVD imaging biomarkers for aging and dementia studies are on the horizon.
Background. As the US population becomes increasingly older and more diverse, the number of Americans with dementia is expected to rise substantially, particularly the number of those with ...concomitant vascular disease. Moreover, the impact of vascular disease on dementia risk may be exacerbated in African Americans and Hispanics, who are at greater risk for vascular disease and for whom vascular disease may play a larger role in clinical dementia. As public health awareness of dementia increases, it is becoming common to see individuals presenting for clinical assessment with minor cognitive complaints. Neuroimaging studies of these individuals frequently identify “incidental” white matter hyperintensities (WMH), usually ascribed to “microvascular disease” by radiologists, raising concerns in patients about their brain health and future risk for dementia.
Methods. To date, however, we are not aware of any studies designed to examine the baseline and future impact of white matter (WM) injury in the clinical setting, particularly among diverse populations where age-related WMH volumes are known to be higher1 or comprehensively examined the impact of individual and combined magnetic resonance imaging (MRI) measures of white matter injury on cognitive performance among a diverse, non-demented, stroke-free population with cognitive complaints over an extended period of observation. For this presentation, I summarized the available evidence of the impact of WMH and cognition and reviewed the design of a new study to prospectively assess this outcome in a diverse population and develop a risk factor profile to assist in the diagnosis of those at risk for dementia.
Results. There is substantial evidence that WMH are common, increase in amount and prevalence with age,2 impact cognition and dementia,3 and are a measure of vascular brain injury. The significance of studying WM injury is buoyed by the fact that dementia risk scales emphasize the role of vascular risk in dementia prediction4 and that institution of effective treatment could lessen the burden of dementia on population.5 Yet, a complete understanding of WMH as markers of vascular brain injury contributing to cognitive complaints and possibly vascular cognitive impairment (VCI) requires a comprehensive determination of the full spectrum of WM injury associated with vascular risk, potential mechanisms of WMH formation and progression, ethnoracial, other genetic influences and how WMH interact with neurodegenerative pathologies, in particular Alzheimer’s disease (AD). Evidence of the importance of “asymptomatic” vascular brain injury on present cognition and future cognitive decline led to the design of a new multi-site study of diverse individuals with cognitive complaints and WMH, that aims to develop a predictive risk factor score that can be widely used in future treatment trials called diverse VCID. Diverse VCID is a multi-site study of 2250 individuals of non-Hispanic Whites, Hispanic/Latinos, and Black African Americans who will be followed for approximately 3 years to deliver a clinical risk score that predicts dementia based on neuroimaging, plasma biomarkers, genetic and clinical data.
Conclusions. Vascular diseases are now recognized to be a major contributor to cognitive impairment and dementia disproportionately affecting individuals from diverse backgrounds. Diverse VCID is designed to address this critical issue and to facilitate future treatment studies of vascular cognitive impairment.
Summary Background Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure ...in the brain are evident as early as the fifth decade of life. Methods In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders. Findings 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann's area 48 on the medial surface of the temporal lobe and Brodmann's area 21 of the middle temporal gyrus. Interpretation Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure. Funding National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
Level of education is often regarded as a proxy for cognitive reserve in older adults. This implies that brain degeneration has a smaller effect on cognitive decline in those with more education, but ...this has not been directly tested in previous research. We examined how education, quantitative magnetic resonance imaging–based measurement of brain degeneration, and their interaction affect cognitive decline in diverse older adults spanning the spectrum from normal cognition to dementia. Gray matter atrophy was strongly related to cognitive decline. While education was not related to cognitive decline, brain atrophy had a stronger effect on cognitive decline in those with more education. Importantly, high education was associated with slower decline in individuals with lesser atrophy but with faster decline in those with greater atrophy. This moderation effect was observed in Hispanics (who had high heterogeneity of education) but not in African-Americans or Caucasians. These results suggest that education is an indicator of cognitive reserve in individuals with low levels of brain degeneration, but the protective effect of higher education is rapidly depleted as brain degeneration progresses.
Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise ...neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies-amyloid plaques and cerebral amyloid angiopathy-in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotate > 70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieve strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived amyloid beta (Aβ)-burden scores correlate well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrates that networks learn patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist's ability suggests a route to neuropathologic deep phenotyping.
Objective
Hyperamylinemia, a common pancreatic disorder in obese and insulin‐resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to β‐cell mass ...depletion and development of type 2 diabetes. Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. We therefore hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients.
Methods
Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer disease (AD), nondiabetic patients with AD, and age‐matched healthy controls was assessed by quantitative real time polymerase chain reaction, immunohistochemistry, Western blot, and enzyme‐linked immunosorbent assay.
Results
Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes. Mixed amylin and amyloid β (Aβ) deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Aβ deposition. Tissues infiltrated by amylin showed increased interstitial space, vacuolation, spongiform change, and capillaries bent at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain.
Interpretation
Metabolic disorders and aging promote accumulation of amylin amyloid in the cerebrovascular system and gray matter, altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Aβ from the brain, thus contributing to the etiology of AD. Ann Neurol 2013;74:517–526
To determine the association between blood pressure during midlife (40-64 years) to late life (≥65 years) and risk of incident dementia.
This study included 1,440 (758 women, mean age 69 ± 6 years) ...Framingham Offspring participants who were free of dementia and attended 5 consecutive examinations at 4-year intervals starting at midlife (1983-1987, mean age 55 years) until late life (1998-2001, mean 69 years) and subsequently were followed up for incident dementia (mean 8 years). We determined the effect of midlife hypertension (≥140/90 mm Hg), late life hypertension, lower late life blood pressure (<100/70 mm Hg), persistence of hypertension during mid- to late life, and steep decline in blood pressure from mid- to late life over an 18-year exposure period.
During the follow-up period, 107 participants (71 women) developed dementia. Using multivariable Cox proportional hazards models, we found that midlife systolic hypertension (hazard ratio HR 1.57, 95% confidence interval CI 1.05-2.35) and persistence of systolic hypertension into late life (HR 1.96, 95% CI 1.25-3.09) were associated with an elevated risk of incident dementia. However, in individuals with low to normal blood pressure (≤140/90 mm Hg) at midlife, a steep decline in systolic blood pressure during mid- to late life was also associated with a >2-fold increase in dementia risk (HR 2.40, 95% CI 1.39-4.15).
Elevated blood pressure during midlife, persistence of elevated blood pressure into late life, and, among nonhypertensives, a steep decline in blood pressure during mid- to late life were associated with an increased dementia risk in a community-based cohort. Our data highlight the potential sustained cognitive benefits of lower blood pressures in midlife but also suggest that declining blood pressure in older adults with prehypertension or normotension, but not in those with hypertension, may be a risk marker for dementia.
Loneliness is common, and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains ...unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability.
This was a retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (September 9, 1948-December 31, 2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded with the Center for Epidemiologic Studies Depression Scale, defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white matter injury.
Of 2,308 participants (mean age 73 SD 9 years, 56% women) who met eligibility in the dementia sample, 14% (329 of 2,308) developed dementia and 6% (144 of 2,308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio 1.54, 95% CI 1.06-2.24). Lonely participants <80 years of age without
ε4 alleles had a 3-fold greater risk (adjusted hazard ratio 3.03, 95% CI, 1.63-5.62). Among 1,875 persons without dementia who met eligibility in the cognition sample (mean age 62 SD 9 years, 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white matter injury.
Over 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low on the basis of age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends.
This study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.
With the long-term goal of improving community health by screening for dementia, we tested the utility of integrating the Six-Item Screener (SIS) into our emergency department neurology ...consultations.
In this cross-sectional observational study, we measured SIS performance within 24 hours of hospital arrival in 100 consecutive English-speaking patients aged ≥45 years. Performance was compared to patient age, previously charted cognitive impairment, and proxies for in-hospital complexity: whether or not a patient was admitted to the hospital and the number of medical studies ordered.
Those with poor SIS performance were older (
= 0.02) and more likely to have previously charted cognitive impairment (
< 0.01; sensitivity 86%, specificity 77%). Poor performers were more likely to be admitted to the hospital (
= 0.04; odds ratio 3.6) and were subjected to more tests once admitted (
< 0.01), relationships that persisted after accounting for age and history of cognitive impairment.
Poor performance on the SIS was associated with previously charted cognitive impairment, justifying future study of its ability to detect unrecognized dementia cases. Until then, its ability to inexpensively anticipate medically complex hospital admissions motivates broader emergency department use of the SIS.
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