The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem ...tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
The capacity to mitigate dementia symptomology despite the prevailing brain pathology has been attributed to cognitive reserve.
This study aimed to investigate how psychometric performance differs ...between individuals with a high school versus college education (surrogate measures for medium and high cognitive reserves) given the same level of brain pathology assessed using quantitative structural MRI.
We used data from the Aging Brain: Vasculature, Ischemia, and Behavior Study (ABVIB). Cognition was assessed using a neuropsychological battery that included those contained in the National Alzheimer's Coordinating Center (NACC) uniform data set. Participants with a medium and high cognitive reserve were matched by level of structural MRI changes, gender, and age.
Matched-pair regression analyses indicated that individuals with a higher education had a significantly better performance in recognition and verbal fluency animals, working memory, and processing speed in complex tasks. Moreover, they had a better performance in interference trails compared to individuals with a high school education (medium cognitive reserve).
Our findings suggest that, given the same level of brain pathology, individuals with a higher education (cognitive reserve) benefit from a superior performance in semantic memory and executive functioning. Differences in these cognitive domains may be key pathways explaining how individuals with a high cognitive reserve are able to diminish dementia symptomatology despite physical changes in the brain.
Vascular contributions to cognitive impairment are increasingly recognized
as shown by neuropathological
, neuroimaging
, and cerebrospinal fluid biomarker
studies. Moreover, small vessel disease of ...the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)
. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)
, and more recently tau
. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown
. Although neurovascular dysfunction
and BBB breakdown develop early in AD
, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia
, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β
, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging
. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.
Objectives
To compare the effects of three antihypertensive medications on cerebral hemodynamic and cognitive function in hypertensive individuals with executive dysfunction.
Design
Double‐blind ...randomized clinical trial.
Setting
Community.
Participants
Fifty‐three individuals aged 60 and older with hypertension and executive dysfunction.
Intervention
Lisinopril, candesartan, or hydrochlorothiazide for 1 year.
Measurements
Cerebral blood flow velocity (BFV; transcranial Doppler ultrasonography during rest, sitting, standing, hypercapnia, and hypocapnia), cognition, and blood pressure were measured at baseline and after 6 and 12 months. Linear mixed models were used to compare the three groups.
Results
Of the 53 participants, 47 had successful insonation (mean age 72; 70% white; 57% women). There was a tendency toward an increase in BFV in the candesartan group and a decrease in the lisinopril and hydrochlorothiazide groups (between‐group P = .57) that was significant in those with low BFV at baseline (<median 27.6 cm/s, between‐group P = .03). The candesartan group also had the greatest improvement in executive function (Trail Making Test Part B improved by 17.1 seconds, vs hydrochlorothiazide improved by 4.2 seconds and lisinopril worsened by 14.4 seconds, P = .008). Carbon dioxide vasoreactivity and vasomotor range declined significantly in the lisinopril (within‐group P = .001 for vasoreactivity and .02 for vasomotor range) and hydrochlorothiazide groups (within‐group P = .10 and .009, respectively) but not in the candesartan group (within‐group P = .25 and .38, respectively; between‐group P = .30 and .46, respectively).
Conclusion
Angiotensin receptor blockers may preferentially preserve cerebral hemodynamics and executive function in individuals with executive dysfunction. These findings warrant further investigation in a larger trial.
IMPORTANCE Because deposition of cerebral β-amyloid (Aβ) seems to be a key initiating event in Alzheimer disease (AD), factors associated with increased deposition are of great interest. Whether ...elevated serum cholesterol levels act as such a factor is unknown. OBJECTIVE To investigate the association between serum cholesterol levels and cerebral Aβ during life early in the AD process. DESIGN, SETTING, AND PARTICIPANTS A multisite, university medical center–based, cross-sectional analysis of potential associations between contemporaneously assayed total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cerebral Aβ, measured with carbon C11–labeled Pittsburgh Compound B (PIB) positron emission tomography. Seventy-four persons (mean age, 78 years) were recruited via direct outreach in stroke clinics and community senior facilities following a protocol designed to obtain a cohort enriched for cerebrovascular disease and elevated vascular risk. Three patients had mild dementia. All others were clinically normal (n = 33) or had mild cognitive impairment (n = 38). RESULTS Cerebral Aβ was quantified using a Global PIB Index, which averages PIB retention in cortical areas prone to amyloidosis. Statistical models that controlled for age and the apolipoprotein E ε4 allele revealed independent associations among the levels of LDL-C, HDL-C, and PIB index. Higher LDL-C and lower HDL-C levels were both associated with a higher PIB index. No association was found between the total cholesterol level and PIB index. No association was found between statin use and PIB index, and controlling for cholesterol treatment in the statistical models did not alter the basic findings. CONCLUSIONS AND RELEVANCE Elevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease. This finding, in living humans, is consistent with prior autopsy reports, epidemiologic findings, and animal and in vitro work, suggesting an important role for cholesterol in Aβ processing. Because cholesterol levels are modifiable, understanding their link to Aβ deposition could potentially and eventually have an effect on retarding the pathologic cascade of AD. These findings suggest that understanding the mechanisms through which serum lipids modulate Aβ could offer new approaches to slowing Aβ deposition and thus to reducing the incidence of AD.
The
ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid ...(Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation
are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from
ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from
ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aβ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.
ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation
can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.
Objective
The aim of this study was to examine the putative adverse effects of ambient fine particulate matter (PM2.5: PM with aerodynamic diameters <2.5μm) on brain volumes in older women.
Methods
...We conducted a prospective study of 1,403 community‐dwelling older women without dementia enrolled in the Women's Health Initiative Memory Study, 1996–1998. Structural brain magnetic resonance imaging scans were performed at the age of 71–89 years in 2005–2006 to obtain volumetric measures of gray matter (GM) and normal‐appearing white matter (WM). Given residential histories and air monitoring data, we used a spatiotemporal model to estimate cumulative PM2.5 exposure in 1999–2006. Multiple linear regression was employed to evaluate the associations between PM2.5 and brain volumes, adjusting for intracranial volumes and potential confounders.
Results
Older women with greater PM2.5 exposures had significantly smaller WM, but not GM, volumes, independent of geographical region, demographics, socioeconomic status, lifestyles, and clinical characteristics, including cardiovascular risk factors. For each interquartile increment (3.49μg/m3) of cumulative PM2.5 exposure, the average WM volume (WMV; 95% confidence interval) was 6.23cm3 (3.72–8.74) smaller in the total brain and 4.47cm3 (2.27–6.67) lower in the association areas, equivalent to 1 to 2 years of brain aging. The adverse PM2.5 effects on smaller WMVs were present in frontal and temporal lobes and corpus callosum (all p values <0.01). Hippocampal volumes did not differ by PM2.5 exposure.
Interpretation
PM2.5 exposure may contribute to WM loss in older women. Future studies are needed to determine whether exposures result in myelination disturbance, disruption of axonal integrity, damages to oligodendrocytes, or other WM neuropathologies. Ann Neurol 2015;78:466–476
There is insufficient understanding of diagnosis of etiologic dementia subtypes and contact with specialized dementia care among older Americans.
We quantified dementia diagnoses and subsequent ...health care over five years by etiologic subtype and physician specialty among Medicare beneficiaries with incident dementia diagnosis in 2008/09 (226,604 persons/714,015 person-years).
Eighty-five percent of people were diagnosed by a nondementia specialist physician. Use of dementia specialists within one year (22%) and five years (36%) of diagnosis was low. “Unspecified” dementia diagnosis was common, higher among those diagnosed by nondementia specialists (33.2%) than dementia specialists (21.6%). Half of diagnoses were Alzheimer's disease.
Ascertainment of etiologic dementia subtype may inform hereditary risk and facilitate financial and care planning. Use of dementia specialty care was low, particularly for Hispanics and Asians, and associated with more detection of etiological subtype. Dementia-related professional development for nonspecialists is urgent given their central role in dementia diagnosis and care.
Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement ...has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years.
We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index BMI). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range IQR = 5.0) years of follow-up, declines in both general cognitive status (β = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (β = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion ppb reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability.
In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.
The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, ...and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia.
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