As the older adult segment of the population increases, Alzheimer’s disease (AD) has emerged as a significant public health epidemic. Over the past 3 decades, advances in the understanding of the ...biology of AD have led to a somewhat unified hypothesis of disease pathogenesis that emphasizes the precipitating role of beta amyloid protein. However, several lines of evidence suggest that multiple pathologies are necessary for clinical manifestation of the disease. Our focus over the past several years has been on the contribution of small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on magnetic resonance imaging, to AD. White matter hyperintensity volume, particularly in parietal regions, is elevated among individuals with and at risk for AD, predicts future diagnosis of AD, predicts the rate of progression of cognitive symptoms among individuals with AD, and increases over time among individuals destined to develop AD. White matter hyperintensities may represent an independent source of impairment and/or may interact more fundamentally with “primary” AD pathology. Future work should focus on more inclusive models of that better define “normal” vs “pathological” aging.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Alzheimer's disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and neurofibrillary tangles. However, over ...the past several years, neuroimaging studies have implicated micro- and macrostructural abnormalities in white matter in the risk and progression of AD, suggesting that in addition to the neuronal pathology characteristic of the disease, white matter degeneration and demyelination may be also important pathophysiological features. Here we review the evidence for white matter abnormalities in AD with a focus on myelin and oligodendrocytes, the only source of myelination in the central nervous system, and discuss the relationship between white matter changes and the hallmarks of Alzheimer's disease. We review several mechanisms such as ischemia, oxidative stress, excitotoxicity, iron overload, Aβ toxicity and tauopathy, which could affect oligodendrocytes. We conclude that white matter abnormalities, and in particular myelin and oligodendrocytes, could be mechanistically important in AD pathology and could be potential treatment targets.
AbstractObjectiveTo evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.DesignInstrumental variable meta-analysis.Setting14 ...randomized controlled trials of drugs for the prevention or treatment of Alzheimer’s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.PopulationAdults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer’s disease, and amyloid positivity at baseline.Main outcome measuresAnalyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.ResultsPooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval −0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.ConclusionsPooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.
Objective
White matter hyperintensities (WMHs) are areas of increased signal on T2‐weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. ...Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.
Methods
The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first‐degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed‐effects piece‐wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.
Results
Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.
Interpretation
Autosomal‐dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929–939
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To evaluate the safety, efficacy, and performance of the TriGuard™ HDH Embolic Deflection Device (TriGuard) compared with no cerebral protection in patients undergoing transcatheter aortic valve ...implantation (TAVI).
From February 2014 to March 2015, 85 subjects undergoing TAVI at 13 centres in Europe and Israel were randomized to TriGuard protection vs. no protection. Subjects underwent neurologic and cognitive evaluation at baseline, pre-discharge and 30 days; cerebral diffusion-weighted magnetic resonance imaging was performed at 4 ± 2 days post-procedure and at 30 days. Technical success, which included complete 3-vessel cerebral coverage, was achieved in 88.9% (40/45) of cases. The primary in-hospital procedural safety endpoint (death, stroke, life-threatening or disabling bleeding, stage 2 or 3 acute kidney injury, or major vascular complications) occurred in 21.7% of TriGuard and 30.8% of control subjects (P = 0.34). In the Per Treatment population (subjects with complete three-vessel cerebral coverage), TriGuard use was associated with greater freedom from new ischaemic brain lesions (26.9 vs. 11.5%), fewer new neurologic deficits detected by the National Institutes of Health Stroke Scale (3.1 vs. 15.4%), improved Montreal Cognitive Assessment (MoCA) scores, better performance on a delayed memory task (P = 0.028) at discharge, and a >2-fold increase in recovery of normal cognitive function (MoCA score >26) at 30 days.
TriGuard cerebral protection during TAVI is safe and complete cerebral vessel coverage was achieved in 89% of subjects. In this exploratory study, subjects undergoing protected TAVI had more freedom from ischaemic brain lesions, fewer neurologic deficits, and improved cognitive function in some domains at discharge and 30 days compared with controls.
Age-related hearing loss (HL) is a common and treatable condition that has been associated with cognitive impairment. The level of hearing at which this association begins has not been studied to ...date.
To investigate whether the association between hearing and cognition is present among individuals traditionally classified as having normal hearing.
Cross-sectional study of 2 US epidemiologic studies (Hispanic Community Health Study HCHS, 2008-2011, and National Health and Nutrition Examination Study NHANES, 1999-2000, 2001-2002, and 2011-2012 cycles). The dates of analysis were November 2018 to August 2019. Multivariable generalized additive model (GAM) regression and linear regression were used to assess the association between HL (exposure) and cognition (outcome). Participants included 6451 individuals aged 50 years or older from the general Hispanic population (HCHS n = 5190) and the general civilian, noninstitutionalized US population (NHANES n = 1261).
Audiometric HL (4-frequency pure-tone average).
Neurocognitive performance measured by the Digit Symbol Substitution Test (DSST) (score range, 0-113), Word Frequency Test (range, 0-49), Spanish-English Verbal Learning Test (SEVLT) 3 trials (range, 5-40), SEVLT recall (range, 0-15), and Six-Item Screener (range, 0-6); higher scores indicated better cognitive performance.
Among 6451 individuals, the mean (SD) age was 59.4 (6.1) years, and 3841 (59.5%) were women. The GAM regression showed a significant inverse association between hearing and cognition across the entire spectrum of hearing after adjusting for demographics and cardiovascular disease. In separate multivariable linear regressions stratified by the classic binary definition of HL, decreased hearing was independently associated with decreased cognition in adults with normal hearing (pure-tone average ≤25 dB) across all cognitive tests in the HCHS. For example in this group, a 10-dB decrease in hearing was associated with a clinically meaningful 1.97-point (95% CI, 1.18-2.75) decrease in score on the DSST. When using a stricter HL cut point (15 dB), an association was also present in NHANES. The associations between hearing and cognition were stronger or equivalent in individuals with normal hearing than among those with HL. For example, there was a 2.28-point (95% CI, 1.56-3.00) combined cohort DSST score decrease per 10-dB decrease among individuals with normal hearing vs a 0.97-point (95% CI, 0.20-1.75) decrease among those with HL, with a significant interaction term between continuous and binary hearing.
An independent association was observed between cognition and subclinical HL. The association between hearing and cognition may be present earlier in HL than previously understood. Studies investigating whether treating HL can prevent impaired cognition and dementia should consider a lower threshold for defining HL than the current 25-dB threshold.
Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive ...deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States. A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm3 (interquartile range 71.6 to 799.6 mm3 ). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
'Normal aging' in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer's disease. A major barrier to mapping normal brain aging has been the difficulty ...in excluding the earliest preclinical stages of Alzheimer's disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20-72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60-84 years of age, who were Alzheimer's-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives: Social engagement has been linked to preserved cognitive functioning in later life. While social engagement is often operationalized as social network size, social networks can vary not ...only in size, but also in composition. Previous work has found that having a greater proportion of family in a network is associated with worse socioemotional and cognitive outcomes compared to having a greater proportion of friends. In addition, social resources may differentially affect cognition in minority groups at higher risk of cognitive impairment. Therefore, the current study aimed to examine racial/ethnic differences in the relationship between network characteristics and cognition. Method: Ethnically and racially diverse older adults from the Washington Heights-Inwood Columbia Aging Project (n = 548, 60-93 years) were used. Multiple regressions were conducted to examine the effects of ethnicity/race, size, composition, and their interaction on global cognition. Results: Analyses revealed that networks with a greater proportion of friends were associated with better global cognition than networks with a greater proportion of family. Additionally, larger social network size was only associated with better global cognition among individuals who had a greater proportion of friends in their networks. Race further moderated this effect, as it was limited to African Americans. Discussion: Overall, these findings highlight the importance of looking at both composition and size when examining the relationship between social network characteristics and global cognition. These findings suggest that friendships may be especially important and further suggest that social network characteristics and cognitive aging may be more strongly related among African Americans.
General Scientific Summary
The current study's findings suggest that social network characteristics may be a potentially relevant and modifiable social resource for reducing racial disparities in cognitive aging. These findings specifically emphasize that friendships may be particularly important for maintaining cognitive functioning for African American older adults.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
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