There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects.A consecutive series of healthy subjects, aged > or =40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 +/- 9.1 years, was well-educated (mean, 15.5 +/- 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 +/- 1.2).A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 +/- 3.4 years, and subjects had a mean of 2.9 +/- 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined (P <.0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer's disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9-10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45-0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects (P =.0003).These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored.2010 The Alzheimer's Association. All rights reserved.

To investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral β-amyloid (Aβ) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study.The burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Aβ, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.Increased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Aβ (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Aβ. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Aβ levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.Increased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified.© 2016 American Academy of Neurology.

To assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls.Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. β-amyloid (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aβ levels (Aβ(+)), while 23 had normal CSF Aβ levels (Aβ(-)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.We found an increased WM-LL in Aβ(+) compared with both, healthy controls (p=0.003) and Aβ(-) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor of patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001).WM damage is crucial in AD pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Cerebral white matter lesions (WMLs) have been associated with cognitive dysfunction. Whether periventricular or subcortical WMLs relate differently to cognitive function is still uncertain. In addition, it is unclear whether WMLs are related to specific cognitive domains such as memory or psychomotor speed. We examined the relationship between periventricular and subcortical WMLs and cognitive functioning in 1,077 elderly subjects randomly sampled from the general population. Quantification of WMLs was assessed by means of an extensive rating scale on 1.5-T magnetic resonance imaging scans. Cognitive function was assessed by using multiple neuropsychological tests from which we constructed compound scores for psychomotor speed, memory performance, and global cognitive function. When analyzed separately, both periventricular and subcortical WMLs were related to all neuropsychological measures. When periventricular WMLs were analyzed conditional on subcortical WMLs and vice versa, the relationship between periventricular WMLs and global cognitive function remained unaltered whereas the relationship with subcortical WMLs disappeared. Subjects with most severe periventricular WMLs performed nearly 1 SD below average on tasks involving psychomotor speed, and more than 0.5 SD below average for global cognitive function. Tasks that involve speed of cognitive processes appear to be more affected by WMLs than memory tasks.

CAIDE Dementia Risk Score is a validated tool for estimating 20-year dementia risk in the general population based on a midlife risk profile.To investigate the associations between CAIDE score and dementia-related brain changes up to 30 years later on magnetic resonance imaging (MRI).Participants in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples surveyed in 1972, 1977, 1982, or 1987. A first re-examination was conducted in 1998, and a second re-examination in 2005-2008 (total follow-up time up to 30 years). The MRI study population included 112 individuals with MRIs from the first re-examination, and a different group of 69 individuals with MRIs from the second re-examination. MRIs from 1998 were used to determine gray matter volume, and to visually rate white matter hyperintensities (WMH) of presumed vascular origin and medial temporal lobe atrophy (MTA). MRIs from 2005-2008 were used to assess cortical thickness, gray matter and WMH volume, and to visually rate MTA. CAIDE scores were calculated for participants in both re-examinations based on midlife sociodemographic and vascular factors and additionally apolipoprotein E status.Higher midlife CAIDE score was associated with more severe WMH 20 years later: RR (95% CI) was 1.69 (1.15-2.08); and with higher WMH volume (β 0.27, p = 0.036) and higher MTA score (RR 1.91, 95% CI 1.16-2.34) up to 30 years later.CAIDE Dementia Risk Score in midlife was most consistently associated with WMH later in life. A relation with MTA was observed in individuals with longer follow-up time.

To investigate the association between midlife systolic blood pressure (SBP) and late-life cognitive decline and brain morphology in a sample of community-dwelling elderly men 68 to 79 years of age.Subjects are surviving members from the prospective National Heart, Lung, and Blood Institute Twin Study (intake, 1969 to 1972) who, when examined for a fourth time in 1995 through 1997, underwent brain MRI and repeated assessment of neurobehavioral functioning. Quantification of the MR images determined cerebral volume and total volume of white matter hyperintensities (WMHIs) for 392 subjects. Midlife SBP levels measured in 1970, 1980, and 1985 were used to classify subjects into low, medium, and high midlife SBP categories. A 10-year change in performance on the Mini-Mental State Examination, Digit Symbol Substitution Test, Benton Visual Retention Test, and Verbal Fluency Test was also calculated for these subjects. For all reported analyses, patients were treated as genetically unrelated individuals.Subjects with high midlife SBP experienced a greater decline in cognitive performance and had larger WMHI volumes at follow-up in late life than did those with low midlife SBP. Decreased brain parenchyma and increased WMHI volumes were associated with decline in neurobehavioral functioning as measured in late life independent of age, education, and baseline levels of cognition.Midlife SBP is a significant predictor of both decline in cognitive function and MR volumetric measures of brain atrophy in late life. Because decline in neurobehavioral functioning was associated with decreased brain volume and increased WMHI volume, we conclude that the long-term impact of elevated SBP on decline in late-life neurobehavioral functioning is likely to be mediated through its chronic, negative effect on structural characteristics of the brain.

White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH.We examined 45 subjects (age range = 50-91 years; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood oxygen level-dependent magnetic resonance imaging signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and 1-year follow-up, with automated coregistration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the 1-year period.CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (p < 0.001). T2 and MD were higher by 8.7% (7.9%) and 17.0% (8.5%), respectively, compared to the contralateral homologous NAWM (p < 0.001).Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.© 2016 American Neurological Association.

Brain tissue from 11 patients with cerebral amyloid angiopathy, changes of Alzheimer's disease, and variable degrees of subcortical leukoencephalopathy was examined by immunohistochemical methods, using primary antibodies to peptide segments representing portions of the Alzheimer A4 (beta-) peptide or gamma-trace peptide (seen most commonly in Icelandic patients with cerebral hemorrhage (hereditary cerebral hemorrhage with amyloidosis [HCHWA-I]). Variable A4 immunostaining was seen within cortical (and rarely white matter) parenchyma in the form of senile plaques (with or without central cores), and within capillary and arteriolar walls. Within individual patients, A4 deposits were often primarily parenchymal or vascular, and when they were vascular they tended to be more prominent in arteriolar than in capillary wall segments. Perivascular A4 deposits were often detected around strongly immunoreactive microvessels. Gamma-trace immunoreactivity was noted in many A4-positive microvessel walls, but staining was always less intense than with the anti-A4 antibody. We conclude that patients with severe cerebral amyloid angiopathy may show wide variation in the severity and topography of A4 deposits within brain parenchyma. A4 may colocalize with gamma-trace peptide, suggesting that A4 and gamma-trace forms of cerebral amyloid angiopathy may not be as biochemically distinctive as has been suggested. Other proteases or protease inhibitors may contribute to the pathogenesis of cerebral amyloid angiopathy or cerebral amyloid angiopathy-related stroke syndromes.

One possible mechanism of cognitive decline in individuals with subcortical vascular disease is disruption of cholinergic fibers by ischemic lesions, such as strategically located white matter hyperintensities (WMH). The authors applied a new MRI visual rating scale to assess WMH within cholinergic pathways in patients with Alzheimer Disease (AD) and subcortical ischemic microvascular disease.Subjects included 60 AD patients with and without WMH, matched for age, as well as 15 control subjects. A visual rating scale was developed based on published immunohistochemical tracings of the cholinergic pathways in humans. On 4 selected axial images, the severity of WMH in the cholinergic pathways was rated on a 3-point scale for ten regions, identified with major anatomical landmarks. A published, consensus-derived, general WMH scale was also applied. All subjects underwent standardized neuropsychological testing.The Cholinergic Pathways HyperIntensities Scale showed reliability and was validated with volumetry of strategic WMH. After accounting for age and education in a multiple linear regression model, The Cholinergic Pathways HyperIntensities Scale ratings were associated with impaired performance on the Mattis Dementia Rating Scale (r=0.40; P=0.02) and accounted for 12% of the variance (corrected r2). A similar model was not significant for general WMH scores.The new MRI rating scale for WMH in cholinergic pathways is reliable and shows stronger correlations with cognitive performance than a general WMH rating scale in AD with WMH. This new rating scale provides indirect evidence that localization of WMH within neurotransmitter systems may contribute to cognitive decline.

Reliable quantification of white matter hyperintensities of presumed vascular origin (WMHs) is increasingly needed, given the presence of these MRI findings in patients with several neurological and vascular disorders, as well as in elderly healthy subjects. We present BIANCA (Brain Intensity AbNormality Classification Algorithm), a fully automated, supervised method for WMH detection, based on the k-nearest neighbour (k-NN) algorithm. Relative to previous k-NN based segmentation methods, BIANCA offers different options for weighting the spatial information, local spatial intensity averaging, and different options for the choice of the number and location of the training points. BIANCA is multimodal and highly flexible so that the user can adapt the tool to their protocol and specific needs. We optimised and validated BIANCA on two datasets with different MRI protocols and patient populations (a "predominantly neurodegenerative" and a "predominantly vascular" cohort). BIANCA was first optimised on a subset of images for each dataset in terms of overlap and volumetric agreement with a manually segmented WMH mask. The correlation between the volumes extracted with BIANCA (using the optimised set of options), the volumes extracted from the manual masks and visual ratings showed that BIANCA is a valid alternative to manual segmentation. The optimised set of options was then applied to the whole cohorts and the resulting WMH volume estimates showed good correlations with visual ratings and with age. Finally, we performed a reproducibility test, to evaluate the robustness of BIANCA, and compared BIANCA performance against existing methods. Our findings suggest that BIANCA, which will be freely available as part of the FSL package, is a reliable method for automated WMH segmentation in large cross-sectional cohort studies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the present study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy and cortical thickness). Three hundred three nondemented older adults (mean age = 79.24 ± 5.29) received high-resolution magnetic resonance imaging at baseline and then again 4.6 years (standard deviation = 1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling, we calculated latent difference scores of parietal and nonparietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the structural equation modeling framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD.Copyright © 2015 Elsevier Inc. All rights reserved.

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia.To determine associations between small-vessel disease and AD pathology.Cross-sectional study from January 2002 to December 2012 using the memory clinic-based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group.We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF β-amyloid 42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) as well as for a subset of apolipoprotein E (APOE) ε4 carriers and noncarriers.Microbleed presence was associated with lower CSF Aβ42 in AD and vascular dementia (standardized beta = -0.09, P = .003; standardized beta = -0.30, P = .01), and higher CSF tau in controls (standardized beta = 0.10, P = .03). There were no effects for P-tau181. The presence of WMH was associated with lower Aβ42 in control participants and patients with vascular dementia (standardized beta = -0.18, P = .002; standardized beta = -0.32, P = .02) but not in patients with AD. There were no effects for tau or P-tau181. The presence of lacunes was associated with higher Aβ42 in vascular dementia (standardized beta = 0.17, P = .07) and lower tau in AD (standardized beta = -0.07, P = .05) but there were no effects for Aβ42 or P-tau181. Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to ε4 carriers.Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E ε4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.

To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD).Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables.Adjusted multiple linear regression models showed that FreeSurfer (B - .245; 95% CI - .1.676, - .393, p = .016) and β burden (SUVR) (B - .180; 95% CI - 2.140, - .292; p = .070) were associated with face-name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face-name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face-name associative memory CCs domain score.Our results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.© 2021. The Author(s).

White matter hyperintensities (WMH), frequently seen in older adults, are usually considered vascular lesions, and participate in the vascular contribution to cognitive impairment and dementia. However, emerging evidence highlights the heterogeneity of WMH pathophysiology, suggesting that non-vascular mechanisms could also be involved, notably in Alzheimer's disease (AD). This led to the alternative hypothesis that in AD, part of WMH may be secondary to AD-related processes. The current perspective brings together the arguments from different fields of research, including neuropathology, neuroimaging and fluid biomarkers, and genetics, in favor of this alternative hypothesis. Possible underlying mechanisms leading to AD-related WMH, such as AD-related neurodegeneration or neuroinflammation, are discussed, as well as implications for diagnostic criteria and management of AD. We finally discuss ways to test this hypothesis and remaining challenges. Acknowledging the heterogeneity of WMH and the existence of AD-related WMH may improve personalized diagnosis and care of patients.© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition.We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5).Subjects with hypertension or Aβ positivity presented the largest WMH volumes (p< 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aβ: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aβ: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aβ: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aβ: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aβ: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aβ: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (p< 0.05). Aβ positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 ± 0.08, p< 0.001; executive: - 0.21 ± 0.08, p< 0.001; PACC5: - 0.29 ± 0.09, p = 0.006; ΔPACC5: - 0.34 ± 0.04, p< 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 ± 0.02, p = 0.029; executive: - 0.04 ± 0.02, p = 0.067; PACC5: - 0.05 ± 0.02, p = 0.030; ΔPACC5: - 0.09 ± 0.03, p = 0.043) and WMH in the optic radiation partially mediated that between Aβ positivity and memory (indirect effect-memory: - 0.05 ± 0.02, p = 0.029).Posterior white matter is susceptible to hypertension and Aβ accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies.German Clinical Trials Register (DRKS00007966, 04/05/2015).© 2023. The Author(s).

White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia.© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

There is evidence for a vascular cause of late-life depression. Cerebral white matter lesions are thought to represent vascular abnormalities. White matter lesions have been related to affective disorders and a history of late-onset depression in psychiatric patients. Their relation with mood disturbances in the general population is not known. We investigated the relation between white matter lesions and the presence of depressive symptoms or a history of depression in a population-based study.In a sample of 1077 nondemented elderly adults, we assessed the presence and severity of subcortical and periventricular white matter lesions using magnetic resonance imaging, presence of depressive symptoms, and history of depression. Using multiple regression analysis, we examined the relation among white matter lesions, depressive symptoms, and history of depression.Most of the subjects had white matter lesions. Persons with severe white matter lesions (upper quintile) were 3 to 5 times more likely to have depressive symptoms as compared with persons with only mild or no white matter lesions (lowest quintile) (periventricular odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.2-9.5; subcortical OR = 5.4; 95% CI, 1.8-16.5). In addition, persons with severe subcortical but not periventricular white matter lesions were more likely to have had a history of depression with an onset after age 60 years (OR = 3.4; 95% CI, 1.1-10.7) compared with persons with only mild or no white matter lesions.The severity of subcortical white matter lesions is related to the presence of depressive symptoms and to a history of late-onset depression.

Behavioral neurology has primarily focused on brain-behavior relations as revealed by disorders of the cerebral cortex and subcortical gray matter. Disorders of cerebral white matter have received less attention. This article considers the contribution of cerebral white matter to normal behavioral function and the effects of white matter disorders on behavior. Diffuse dysfunction is more common than focal impairment, and the term white matter dementia has been proposed as a clinical entity. Conventional neuroimaging has enabled more accurate identification of white matter regions participating in neurobehavioral operations, and newer imaging techniques may define white matter connectivity within and between the hemispheres. As an essential component of neural networks, cerebral white matter contributes to cognitive and emotional functions, and lesions of white matter disconnect these networks to produce neurobehavioral syndromes.

It has been suggested that subcortical lesions may influence cognitive performances at early stages of cognitive impairment but not in late stages of dementia. We aimed to test whether cognitive decline is associated with subcortical hyperintensities in patients with mild cognitive impairment (MCI).We included 170 consecutive MCI patients (mean follow-up, 3.8+/-1.6 years). We assessed subcortical hyperintensities on a baseline magnetic resonance imaging scan with a semiquantitative rating scale. The mean annual cognitive decline was calculated with the Mini-Mental State Examination and the Dementia Rating Scale at baseline and the end of follow-up.Compared with patients whose cognitive performances remained stable or improved during follow-up, patients whose cognitive performances declined often had a larger amount (greater than the median of the distribution) of periventricular (PVH) (P=0.0005) and white-matter (P=0.02) hyperintensities. The rate of cognitive decline was higher with increasing PVH: mean change in the Mini-Mental State Examination score=0.16 vs -0.66 points/year in patients with PVH in the first versus third tertile (P=0.0002). The rate of decline in executive functioning was also higher with increasing PVH: mean change in the Dementia Rating Scale initiation subscore=-0.05 vs -1.42 points/year in patients with PVH in the first versus third tertile (P=0.04). These associations were independent of vascular risk factors, temporal lobe atrophy, and MCI subtype and were stronger in patients with baseline executive dysfunction.White-matter hyperintensities and especially PVH were significantly associated with cognitive decline in MCI patients. This result was independent of the MCI subtype but stronger in cases of executive dysfunction at baseline.

Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community-dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p < 0.001), but not with episodic memory, semantic memory, working memory, or visuospatial abilities (all p > 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging.

White matter hyperintensities (WMH) are frequently divided into periventricular (PWMH) and deep (DWMH), and the two classes have been associated with different cognitive, microstructural, and clinical correlates. However, although this distinction is widely used in visual ratings scales, how to best anatomically define the two classes is still disputed. In fact, the methods used to define PWMH and DWMH vary significantly between studies, making results difficult to compare. The purpose of this study was twofold: first, to compare four current criteria used to define PWMH and DWMH in a cohort of healthy older adults (mean age: 69.58 ± 5.33 years) by quantifying possible differences in terms of estimated volumes; second, to explore associations between the two WMH sub-classes with cognition, tissue microstructure and cardiovascular risk factors, analysing the impact of different criteria on the specific associations. Our results suggest that the classification criterion used for the definition of PWMH and DWMH should not be considered a major obstacle for the comparison of different studies. We observed that higher PWMH load is associated with reduced cognitive function, higher mean arterial pressure and age. Higher DWMH load is associated with higher body mass index. PWMH have lower fractional anisotropy than DWMH, which also have more heterogeneous microstructure. These findings support the hypothesis that PWMH and DWMH are different entities and that their distinction can provide useful information about healthy and pathological aging processes.Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults.One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old).WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition.WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Studies on synaptic plasticity in the context of learning have been dominated by the view that a single, particular type of plasticity forms the underlying mechanism for a particular type of learning. However, emerging evidence shows that many forms of synaptic and intrinsic plasticity at different sites are induced conjunctively during procedural memory formation in the cerebellum. Here, we review the main forms of long-term plasticity in the cerebellar cortex that underlie motor learning. We propose that the different forms of plasticity in the granular layer and the molecular layer operate synergistically in a temporally and spatially distributed manner, so as to ultimately create optimal output for behaviour.

Function of cerebellum in control and coordination of motor function has been well established for several years. Recent functional magnetic resonance imaging (MRI) studies reveal activation of cerebellum with memory, speech and language tasks. We hypothesize that during every function in the brain signals are relayed to cerebellum. We seek to analyze cognitive, emotional and social functions of cerebellum in patients with brain tumors and epilepsy utilizing functional Magnetic Resonance Imaging. Fifty-one consecutive adult patients who underwent functional MRI examination were retrospectively analyzed for various activation patterns involving cerebellum. The neuropsychological battery of tasks assessed motor, language, memory, visual and auditory functions. Cognitive ability of all participants was assessed by Montreal cognitive assessment (MOCA). Patterns were analyzed for specific lobes and locations in the cerebellum. We found that simultaneous cerebellar activation is a consistent finding with brain activation during every functional MRI task that we tested except visual task. The patterns of functional MRI cerebellar activation were similar in both patient subgroups and control subjects compared to previously described patterns in normal subjects. Clin. Anat. 32:1053-1060, 2019. © 2019 Wiley Periodicals, Inc.© 2019 Wiley Periodicals, Inc.

A growing body of evidence suggests that healthy elderly individuals and patients with Alzheimer's disease retain an important potential for neuroplasticity. This review summarizes studies investigating the modulation of neural activity and structural brain integrity in response to interventions involving cognitive training, physical exercise and non-invasive brain stimulation in healthy elderly and cognitively impaired subjects (including patients with mild cognitive impairment (MCI) and Alzheimer's disease). Moreover, given the clinical relevance of neuroplasticity, we discuss how evidence for neuroplasticity can be inferred from the functional and structural brain changes observed after implementing these interventions. We emphasize that multimodal programmes, which combine several types of interventions, improve cognitive function to a greater extent than programmes that use a single interventional approach. We suggest specific methods for weighting the relative importance of cognitive training, physical exercise and non-invasive brain stimulation according to the functional and structural state of the brain of the targeted subject to maximize the cognitive improvements induced by multimodal programmes.Copyright © 2018 Elsevier B.V. All rights reserved.

Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer's disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention.In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD.Sixty community-dwelling older adults with SCD were randomized to a KK or ML program and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments.Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p's≤0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p's≤0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies.Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group.

Aging is associated with progressive cerebral volume and glucose metabolism decreases. Conditions such as stress and sleep difficulties exacerbate these changes and are risk factors for Alzheimer's disease. Meditation practice, aiming towards stress reduction and emotion regulation, can downregulate these adverse factors. In this pilot study, we explored the possibility that lifelong meditation practice might reduce age-related brain changes by comparing structural MRI and FDG-PET data in 6 elderly expert meditators versus 67 elderly controls. We found increased gray matter volume and/or FDG metabolism in elderly expert meditators compared to controls in the bilateral ventromedial prefrontal and anterior cingulate cortex, insula, temporo-parietal junction, and posterior cingulate cortex /precuneus. Most of these regions were also those exhibiting the strongest effects of age when assessed in a cohort of 186 controls aged 20 to 87 years. Moreover, complementary analyses showed that these changes were still observed when adjusting for lifestyle factors or using a smaller group of controls matched for education. Pending replication in a larger cohort of elderly expert meditators and longitudinal studies, these findings suggest that meditation practice could reduce age-associated structural and functional brain changes.

While effective therapies for preventing or slowing cognitive decline in at-risk populations remain elusive, evidence suggests mind-body interventions may hold promise.In this study, we assessed the effects of Kirtan Kriya meditation (KK) and music listening (ML) on cognitive outcomes in adults experiencing subjective cognitive decline (SCD), a strong predictor of Alzheimer's disease.Sixty participants with SCD were randomized to a KK or ML program and asked to practice 12 minutes/day for 3 months, then at their discretion for the ensuing 3 months. At baseline, 3 months, and 6 months we measured memory and cognitive functioning [Memory Functioning Questionnaire (MFQ), Trail-making Test (TMT-A/B), and Digit-Symbol Substitution Test (DSST)].The 6-month study was completed by 53 participants (88%). Participants performed an average of 93% (91% KK, 94% ML) of sessions in the first 3 months, and 71% (68% KK, 74% ML) during the 3-month, practice-optional, follow-up period. Both groups showed marked and significant improvements at 3 months in memory and cognitive performance (MFQ, DSST, TMT-A/B; p's≤0.04). At 6 months, overall gains were maintained or improved (p's≤0.006), with effect sizes ranging from medium (DSST, ML group) to large (DSST, KK group; TMT-A/B, MFQ). Changes were unrelated to treatment expectancies and did not differ by age, gender, baseline cognition scores, or other factors.Findings of this preliminary randomized controlled trial suggest practice of meditation or ML can significantly enhance both subjective memory function and objective cognitive performance in adults with SCD, and may offer promise for improving outcomes in this population.

Benefits of a Mediterranean diet for cognition have been suggested, but epidemiologic studies have been relatively small and of limited duration. To prospectively assess the association between long-term adherence to a Mediterranean dietary pattern and self-reported subjective cognitive function (SCF). Prospective observational study. The Health Professionals' Follow-up Study, a prospective cohort of 51,529 men, 40-75 years of age when enrolled in 1986, of whom 27,842 were included in the primary analysis. Mediterranean diet (MD) score, computed from the mean of five food frequency questionnaires, assessed every 4 years from 1986 to 2002. Self-reported SCF assessed by a 6-item questionnaire in 2008 and 2012, and validated by association with genetic variants in apolipoprotein-4. Using the average of 2008 and 2012 SCF scores, 38.0% of men were considered to have moderate memory scores and 7.3% were considered to have poor scores. In a multivariate model, compared with men having a MD score in the lowest quintile, those in the highest quintile had a 36% lower odds of a poor SCF score (odds ratio 0.64, 95% CI 0.55-0.75; P, trend < 0.001) and a 24% lower odds of a moderate SCF score (OR 0.76, 95% CI 0.70-0.83; P, trend < 0.001). Both remote and more recent diet contributed to this relation. Associations were only slightly weaker using baseline dietary data and a lag of 22 years. Long-term adherence to the Mediterranean diet pattern was strongly related to lower subjective cognitive function. These findings provide further evidence that a healthy dietary pattern may prevent or delay cognitive decline.