Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Association of Dilated Perivascular Spaces With Cognitive Decline and Incident Dementia.

OBJECTIVE: To determine whether severe perivascular space (PVS) dilation is associated with longitudinal cognitive decline and incident dementia over 4 and 8 years, respectively, we analyzed data from a prospective cohort study. METHODS: A total of 414 community-dwelling older adults aged 72-92 years were assessed at baseline and biennially for up to 8 years, with cognitive assessments, consensus dementia diagnoses, and 3T MRI. The numbers of PVS in 2 representative slices in the basal ganglia (BG) and centrum semiovale (CSO) were counted and severe PVS pathology defined as the top quartile. The effects of severe PVS pathology in either region or both regions and those with severe BG PVS and severe CSO PVS were examined. White matter hyperintensity volume, cerebral microbleed number, and lacune number were calculated. RESULTS: Participants with severe PVS pathology in both regions or in the CSO alone had greater decline in global cognition over 4 years, even after adjustment for the presence of other small vessel disease neuroimaging markers. The presence of severe PVS pathology in both regions was an independent predictor of dementia across 8 years (odds ratio 2.91, 95% confidence interval 1.43-5.95, p = 0.003). The presence of severe PVS pathology in all groups examined was associated with greater dementia risk at either year 4 or 6. CONCLUSIONS: Severe PVS pathology is a marker for increased risk of cognitive decline and dementia, independent of other small vessel disease markers. The differential cognitive associations for BG and CSO PVS may represent differences in their underlying pathology.

Plasma lipidomic biomarker analysis reveals distinct lipid changes in vascular dementia.

Vascular dementia (VaD) is a complex neurocognitive disorder secondary to a variety of cerebrovascular lesions. Numerous studies have shown that lipid metabolism is involved in the pathobiology of the disease. We examined the plasma lipid profiles in VaD, with the expectation of identifying reliable lipid biomarkers for VaD. 49 VaD patients and 48 healthy controls were recruited from Bankstown-Lidcombe Hospital in Sydney, Australia. Lipids were extracted by single phase 1-butanol/methanol, and untargeted analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). Univariate analysis of variance was used to examine the differences in lipid classes and individual lipids between VaD and control groups. In an independent sample of 161 subjects from the Older Australian Twins Study (OATS), elastic net penalization for the generalized linear model (Glmnet) and Random Forest were applied to the lipid levels to subcategorise the sample into vascular cognitive impairment and controls. Most lipids belonging to the classes of ceramides (Cer), cholesterol esters (ChE) and phospholipids were significantly lower in VaD plasma, while glycerides were elevated compared to controls. Levels of ChE, Cer and the two lipid classes together achieved the best accuracy in discriminating VaD from controls, with more than 80% accuracy. The probable VaD group in the OATS sample predicted by the lipid levels showed greater impairment in most cognitive domains, especially attention and processing speed and executive function from controls but did not differ in white matter hyperintensities and DTI measures. As a conclusion, plasma lipids levels, in particular Cer and ChE, are abnormal in VaD and may help discriminate them from healthy controls. Understanding the basis of these differences may provide insights into the pathobiology of VaD.

Development and validation of a rating scale for perivascular spaces on 3T MRI.

BACKGROUND AND PURPOSE: To develop and validate a novel perivascular space rating scale, based on single axial slices in the basal ganglia and the centrum semiovale on T1-weighted and FLAIR images obtained on a 3T MRI scanner. METHODS: 414 community dwelling older adults age 70-90 were assessed. The number of perivascular spaces in the slices 2 mm (basal ganglia) and 37 mm (centrum semiovale) above the anterior commissure were counted. The construct validity of the scale was tested by examining associations with age, sex, vascular risk factors and neuroimaging markers of small vessel disease; white matter hyperintensities, lacunes and cerebral microbleeds. Associations with cross sectional global and domain specific cognition were also examined. RESULTS: The rating scale had excellent inter-rater reliability (intraclass correlation coefficient in basal ganglia 0.82 and centrum semiovale 0.96), good intra-rater reliability (ICC in basal ganglia 0.72 and centrum semiovale 0.87) and reasonable concurrent validity with an existing perivascular spaces scale (Spearman rho = 0.49, p < .001). There was a median of four basal ganglia and zero centrum semiovale perivascular spaces. Basal ganglia perivascular spaces were more common in men and associated with the other neuroimaging markers. Perivascular spaces in either location were not independently associated with global or domain specific cognitive impairment. CONCLUSION: The new rating scale is easy to use, quick, has good psychometric properties and performs better than existing scales in a community dwelling older cohort. Further studies are needed to validate the scale in more diverse cohorts with greater cerebrovascular burden.

Neuroimaging and neuropathology indices of cerebrovascular disease burden: A systematic review.

OBJECTIVE: To systematically review the literature on the use of both neuroimaging and neuropathologic indices of cerebrovascular disease (CVD) burden, as estimation of this burden could have multiple benefits in the diagnosis and prognosis of cognitive impairment and dementia. METHODS: MEDLINE and EMBASE databases were searched (inception to June 2017) to obtain and then systematically review all pertinent neuroimaging and neuropathology studies, where an index of CVD was developed or tested. RESULTS: Twenty-five neuroimaging articles were obtained, which included 4 unique indices. These utilized a limited range of CVD markers from mainly structural MRI, most commonly white matter hyperintensities (WMH), cerebral microbleeds, and dilated perivascular spaces. Weighting of the constituent markers was often coarse. There were 7 unique neuropathology indices, which were heterogeneous in their regions sampled and lesions examined. CONCLUSION: There is increasing interest in indices of total CVD burden that incorporate multiple lesions, as traditional individual markers of CVD such as WMH only provide limited information. Neuropathologic indices are needed to validate neuroimaging findings. The studies clearly demonstrated proof of concept that information from multiple imaging measures of CVD provide more information, including a stronger association with cognitive impairment and dementia, than that provided by a single measure. There has been limited exploration of the psychometric properties of published indices and no comparison between indices. Further development of indices is recommended, including the use of data from diffusion tensor and perfusion imaging.

The association of regional white matter lesions with cognition in a community-based cohort of older individuals.

Emerging evidence from lesion-symptom mapping (LSM) studies suggested that regional white matter lesions (WML) on strategic white matter (WM) fiber tracts are significantly associated with specific cognitive domains, independent of global WML burden. However, previous LSM investigations were mostly carried out in disease cohorts, with little evidence from community-based older individuals, making findings difficult to generalize. Moreover, most LSM studies applied a threshold to the probabilistic atlas, leading to the loss of information and threshold-dependent findings. Furthermore, it is still unclear whether associations between regional WML and cognition are independent of global grey matter (GM) and WM volumes, which have also been linked to cognition. In the current study, we undertook a region of interest (ROI) LSM study to examine the relationship between regional WML on strategic WM tracts and cognitive performance in a large community-based cohort of older individuals (N = 461; 70-90 years). WML were extracted using a publicly available pipeline, UBO Detector (https://cheba.unsw.edu.au/group/neuroimaging-pipeline). Mapping of WML to the Johns Hopkins University WM atlas was undertaken using an automated TOolbox for Probabilistic MApping of Lesions (TOPMAL), which we introduce here, and is implemented in UBO Detector. The results show that different patterns of brain structural volumes in the ageing brain were associated with different cognitive domains. Regional WML were associated with processing speed, executive function, and global cognition, independent of total GM, WM and WML volumes. Moreover, regional WML explained more variance in executive function, compared to total GM, WM and WML volumes. The current study highlights the importance of studying regional WML in age-related cognitive decline.

Mild Cognitive Impairment Subtypes in Older People With Depressive Symptoms: Relationship With Clinical Variables and Hippocampal Change.

AIMS: To examine the rates and clinical characteristics of mild cognitive impairment (MCI) in older people with depressive symptoms and to determine the relative contribution of hippocampal volume and MCI to memory change. METHOD: One hundred and fifty-two participants with lifetime Major Depression and remitted or mild symptoms and 28 healthy controls underwent psychiatric and neuropsychological assessments. Magnetic resonance imaging was also conducted in a subset of the patients (n = 81) and healthy controls (n = 18). RESULTS: MCI was diagnosed in 75.7% of the patients and was associated with increasing age, medical burden, vascular risk factors, later age of depression onset and smaller hippocampi. Multiple regression showed that both hippocampal volume and MCI diagnosis mediate memory performance in depression. CONCLUSIONS: MCI occurs in older adults with a history of depression and is not simply due to symptom severity. Memory change is linked to underlying hippocampal atrophy in this patient group.

Randomized controlled trial of a healthy brain ageing cognitive training program: effects on memory, mood, and sleep.

BACKGROUND: With the rise in the ageing population and absence of a cure for dementia, cost-effective prevention strategies for those 'at risk' of dementia including those with depression and/or mild cognitive impairment are urgently required. OBJECTIVE: This study evaluated the efficacy of a multifaceted Healthy Brain Ageing Cognitive Training (HBA-CT) program for older adults 'at risk' of dementia. METHODS: Using a single-blinded design, 64 participants (mean age = 66.5 years, SD = 8.6) were randomized to an immediate treatment (HBA-CT) or treatment-as-usual control arm. The HBA-CT intervention was conducted twice-weekly for seven weeks and comprised group-based psychoeducation about cognitive strategies and modifiable lifestyle factors pertaining to healthy brain ageing, and computerized cognitive training. RESULTS: In comparison to the treatment-as-usual control arm, the HBA-CT program was associated with improvements in verbal memory (p = 0.03), self-reported memory (p = 0.03), mood (p = 0.01), and sleep (p = 0.01). While the improvements in memory (p = 0.03) and sleep (p = 0.02) remained after controlling for improvements in mood, only a trend in verbal memory improvement was apparent after controlling for sleep. CONCLUSION: The HBA-CT program improves cognitive, mood, and sleep functions in older adults 'at risk' of dementia, and therefore offers promise as a secondary prevention strategy.

Clinical and Cognitive Correlates of Structural Hippocampal Change in "At-Risk" Older Adults.

With estimates of dementia expected to rise over the coming decades, there is interest in understanding the factors associated with promoting neuroprotection and limiting neurodegeneration. In this study, we examined the change in the volume of the hippocampus over a 2-month period in 34 older people "at risk" of cognitive decline (mean age = 66.8 years, 38% male). Factors that were examined included cognitive reserve, neuropsychological functioning, depression as well as a lifestyle (cognitive training) intervention. The results showed that over a 2-month period, increases in hippocampal size were associated with having higher premorbid intellect, greater occupational attainment, superior memory, and higher levels of functioning. Conversely, depression and disability were associated with decreases in hippocampal volume. Cognitive training was not associated with changes in hippocampal volume. These findings suggest that factors associated with cognitive reserve, cognition and depression may play an integral pathophysiological role in determining hippocampal volumes in "at-risk" older adults.

Reduced temporal mismatch negativity in late-life depression: an event-related potential index of cognitive deficit and functional disability?

BACKGROUND: Depression in older people has been consistently linked with a variety of neurobiological brain changes. One measure of preattentive auditory processing, the mismatch negativity (MMN), has not been previously examined in late-life depression. This study examined MMN elicited by duration deviant stimuli in older people with lifetime depression, and explored its relationship with neuropsychological functioning and disability. METHODS: Twenty-two older health-seeking patients (mean age=65.2 years) with lifetime major depressive disorder and twelve age and sex-matched control participants (mean age=64.6 years) completed detailed clinical and neuropsychological assessments and the WHO-DAS as a measure of disability. MMN amplitudes were elicited using a two-tone passive auditory oddball paradigm and measured at frontal (Fz), central (Cz) and temporal (left and right mastoid: M1 and M2, respectively) sites. RESULTS: Patients with depression demonstrated reduced mean MMN amplitude at temporal (M1, t=3.1, p<0.01; M2, t=3.8, p<0.01), but not fronto-central sites. Reduced temporal MMN amplitudes did not relate to depressive symptom severity, but were associated with reduced semantic fluency and greater self-rated functional disability. LIMITATIONS: The contribution of depressive symptom 'state' and medications on MMN need to be considered. CONCLUSIONS: Reduced mean amplitudes of mastoid MMN in older patients with lifetime depression may reflect underlying brain changes. This preattentive marker relates to neuropsychological probes of frontotemporal circuits, and importantly, is associated with disability. Longitudinal analysis of MMN in this group will determine its predictive utility as a biomarker for ongoing cognitive decline and illness chronicity.

Does ADHD in adults affect the relative accuracy of metamemory judgments?

OBJECTIVE: Prior research suggests that individuals with ADHD overestimate their performance across domains despite performing more poorly in these domains. The authors introduce measures of accuracy from the larger realm of judgment and decision making--namely, relative accuracy and calibration--to the study of self-evaluative judgment accuracy in adults with ADHD. METHOD: Twenty-eight adults with ADHD and 28 matched controls participate in a computer-administered paired-associate learning task and predict their future recall using immediate and delayed judgments of learning (JOLs). Retrospective confidence judgments are also collected. RESULTS: Groups perform equally in terms of judgment magnitude and absolute judgment accuracy as measured by discrepancy scores and calibration curves. Both groups benefit equally from making their JOL at a delay, and the group with ADHD show higher relative accuracy for delayed judgments. CONCLUSION: Results suggest that under certain circumstances, adults with ADHD can make accurate judgments about their future memory.

Substance use and delinquency during adolescence: a prospective look at an at-risk sample.

This paper focuses on the relationship between adolescent substance use and delinquent behavior in a sample of homeless young people. Confirmatory factor analyses indicated that delinquency and substance use are best described as discrete factors, and competing theoretical models of the longitudinal association between these two factors were examined using structural equations modeling techniques. The results suggest that delinquent behavior is associated with changes in alcohol, marijuana, and drug use across time. This effect was statistically significant over relatively brief lags in time of six months or less. Combined with previous results, these findings challenge the utility of single-factor explanations of adolescent deviance for at-risk populations and suggest that the relationship between substance use and externalizing across time may be more dynamic than previously thought. Implications for intervention are also discussed.

Cultural and contextual influences in mental health help seeking: a focus on ethnic minority youth.

In this article, a mental health help-seeking model is offered as a framework for understanding cultural and contextual factors that affect ethnic minority adolescents' pathways into mental health services. The effects of culture and context are profound across the entire help-seeking pathway, from problem identification to choice of treatment providers. The authors argue that an understanding of these help-seeking pathways provides insights into ethnic group differences in mental health care utilization and that further research in this area is needed.