Background and Purpose— Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease–related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods— Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network–based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results— The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi ( P <0.001 for global cognitive function, processing speed, executive functions, and memory and P <0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes ( P <0.001) even above the contribution of the individual brain changes. Conclusions— Global burden of small vessel disease–related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.

Background and purpose Impairment of executive functions (EFs) is a common cognitive symptom post‐stroke and affects independence in daily activities. Previous studies have often relied on brief cognitive tests not fully considering the wide spectrum of EF subdomains. A detailed assessment of EFs was used to examine which of the subdomains and tests have the strongest predictive value on post‐stroke functional outcome and institutionalization in long‐term follow‐up. Methods A subsample of 62 patients from the Helsinki Stroke Aging Memory Study was evaluated with a battery of seven neuropsychological EF tests 3 months post‐stroke and compared to 39 healthy control subjects. Functional impairment was evaluated with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living (IADL) scale at 3 months, and with the mRS at 15 months post‐stroke. Institutionalization was reviewed from the national registers of permanent hospital admissions in up to 21‐year follow‐up. Results The stroke group performed more poorly than the control group in multiple EF tests. Tests of inhibition, set shifting, initiation, strategy formation and processing speed were associated with the mRS and IADL scale in stroke patients. EF subdomain scores of inhibition, set shifting and processing speed were associated with functional outcome. In addition, inhibition was associated with the risk for earlier institutionalization. Conclusions Executive function was strongly associated with post‐stroke functional impairment. In follow‐up, poor inhibition was related to earlier permanent institutionalization. The results suggest the prognostic value of EF subdomains after stroke.

Treatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Objectives: Neuropsychiatric symptoms are related to disease progression and cognitive decline over time in cerebral small vessel disease (SVD) but their significance is poorly understood in covert SVD. We investigated neuropsychiatric symptoms and their relationships between cognitive and functional abilities in subjects with varying degrees of white matter hyperintensities (WMH), but without clinical diagnosis of stroke, dementia or significant disability. Methods: The Helsinki Small Vessel Disease Study consisted of 152 subjects, who underwent brain magnetic resonance imaging (MRI) and comprehensive neuropsychological evaluation of global cognition, processing speed, executive functions, and memory. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory Questionnaire (NPI-Q, n = 134) and functional abilities with the Amsterdam Instrumental Activities of Daily Living questionnaire (A-IADL, n = 132), both filled in by a close informant. Results: NPI-Q total score correlated significantly with WMH volume (rs = 0.20, p = 0.019) and inversely with A-IADL score (rs = −0.41, p < 0.001). In total, 38% of the subjects had one or more informant-evaluated neuropsychiatric symptom. Linear regressions adjusted for age, sex, and education revealed no direct associations between neuropsychiatric symptoms and cognitive performance. However, there were significant synergistic interactions between neuropsychiatric symptoms and WMH volume on cognitive outcomes. Neuropsychiatric symptoms were also associated with A-IADL score irrespective of WMH volume. Conclusions: Neuropsychiatric symptoms are associated with an accelerated relationship between WMH and cognitive impairment. Furthermore, the presence of neuropsychiatric symptoms is related to worse functional abilities. Neuropsychiatric symptoms should be routinely assessed in covert SVD as they are related to worse cognitive and functional outcomes.

Objective: Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their interrelations and combined effects on functional outcome have not been elucidated. We investigated the associations between cognitive and motor functions and their interactions and mediating effects on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH). Methods: Participants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, neuropsychological and MRI protocol. Cognitive composite scores for global cognition, processing speed, executive functions and memory were constructed from multiple tests within each domain. Physical examination included measures of gait speed, balance (single-leg-stance) and functional mobility (timed-up-and-go test). IADL was evaluated with a proxy-based Amsterdam IADL questionnaire and quality of life with a self-report EUROHIS-Qol index. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Sets of linear regression analyses were used to model the associations between motor and cognitive performances, WMH and GM volumes, and IADL and quality of life. Results: Domain-specific cognitive and motor functions had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on IADL, but not on quality of life. In particular, low cognitive scores together with decline in the timed-up-and-go test and gait speed were strongly related to impaired IADL. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance. Conclusion: The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than the individual effects of each of the two impairments. WMH and brain atrophy contribute to disability through cognitive and motor impairment.

BackgroundThe usefulness of neurofilament light (NfL) as a biomarker for small vessel disease has not been established. We examined the relationship between NfL, neuroimaging changes, and clinical findings in subjects with varying degrees of white matter hyperintensity (WMH).MethodsA subgroup of participants (n = 35) in the Helsinki Small Vessel Disease Study underwent an analysis of NfL in cerebrospinal fluid (CSF) as well as brain magnetic resonance imaging (MRI) and neuropsychological and motor performance assessments. WMH and structural brain volumes were obtained with automatic segmentation.ResultsCSF NfL did not correlate significantly with total WMH volume (r = 0.278, p = 0.105). However, strong correlations were observed between CSF NfL and volumes of cerebral grey matter (r = −0.569, p &lt; 0.001), cerebral cortex (r = −0.563, p &lt; 0.001), and hippocampi (r = −0.492, p = 0.003). CSF NfL also correlated with composite measures of global cognition (r = −0.403, p = 0.016), executive functions (r = −0.402, p = 0.017), memory (r = −0.463, p = 0.005), and processing speed (r = −0.386, p = 0.022). Regarding motor performance, CSF NfL was correlated with Timed Up and Go (TUG) test (r = 0.531, p = 0.001), and gait speed (r = −0.450, p = 0.007), but not with single-leg stance. After adjusting for age, associations with volumes in MRI, functional mobility (TUG), and gait speed remained significant, whereas associations with cognitive performance attenuated below the significance level despite medium to large effect sizes.ConclusionNfL was strongly related to global gray matter and hippocampal atrophy, but not to WMH severity. NfL was also associated with motor performance. Our results suggest that NfL is independently associated with brain atrophy and functional mobility, but is not a reliable marker for cerebral small vessel disease.