Background and Purose Disruption of the blood-brain barrier (BBB) has been proposed to be important in vascular cognitive impairment (VCI). Increased cerebrospinal fluid (CSF) albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the BBB permeability in patients with VCI is lacking. Therefore, we acquired dynamic contrast-enhanced MRI (DCEMRI) to quantify BBB permeability in VCI. Method We studied 60 patients with suspected VCI. They had neurological and neuropsychological testing, permeability measurements with DCEMRI and lumbar puncture to measure albumin index (Qalb). Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts (MI/LAC), and leukoaraiosis (LA). Twenty volunteers were controls for the DCEMRI studies, and control CSF was obtained from 20 individuals undergoing spinal anesthesia for non-neurological problems. Results Thirty-six patients were classified as SIVD, 8 as MI/LAC and 9 as LA. The Qalb was significantly increased in the SIVD group compared to 20 controls. Permeabilities for the VCI patients measured by DCEMRI were significantly increased over controls (p<0.05). Patient age correlated with neither the BBB permeability nor Qalb. Highest Qalb values were seen in SIVD group (p<0.05), and were significantly increased over MI/LAC. Ki values were elevated over controls in SIVD, but were similar to MI/LAC. Conclusions There was abnormal permeability in white matter in patients with SIVD as shown by DCEMRI and Qalb. Future studies will be needed to determine the relationship of BBB damage and development of WMHs.

The antioxidant N-acetylcysteine (NAC) or placebo was administered in a double-blind fashion to patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Testing for efficacy occurred after 3 and 6 months of treatment. Comparison of interval change favored NAC treatment on nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.

Subcortical ischemic vascular disease (SIVD) is a major subtype of vascular dementia with features that overlap clinically with Alzheimer's disease (AD), confounding diagnosis.Neuroimaging is a more specific and biologically based approach for detecting brain changes and thus may help to distinguish these diseases. There is still a lack of knowledge regarding the shared and specific functional brain abnormalities, especially functional connectivity changes in relation to AD and SIVD. In this study, we investigated both static functional network connectivity (sFNC) and dynamic FNC (dFNC) between 54 intrinsic connectivity networks in 19 AD patients, 19 SIVD patients, and 38 agematched healthy controls. The results show that both patient groups have increased sFNC between the visual and cerebellar (CB) domains but decreased sFNC between the cognitive-control and CB domains. SIVD has specifically decreased sFNC within the sensorimotor domain while AD has specifically altered sFNC between the default-mode and CB domains. In addition, SIVD has more occurrences and a longer dwell time in the weakly connected dFNC states, but with fewer occurrences and a shorter dwell time in the strongly connected dFNC states. AD has both similar and opposite changes in certain dynamic features. More importantly, the dynamic features are found to be associated with cognitive performance. Our findings highlight similar and distinct functional connectivity alterations in AD and SIVD from both static and dynamic perspectives and indicate dFNC to be a more important biomarker for dementia since its progressively altered patterns can better track cognitive impairment in AD and SIVD. K E Y W O R D S Alzheimer's disease (AD), cognitive impairment, dynamic functional network connectivity (dFNC), resting-state functional network connectivity (rs-FNC), subcortical ischemic vascular disease (SIVD)

Background and Purpose Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier (BBB) and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and CSF of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. Methods We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, while other groups included mixed Alzheimer’s disease AD and VCI (MX), multiple strokes (MI), and leukoaraiosis (LA) when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. Results We found reduced MMP-2 index (p<0.001) in the CSF for the full group of patients (SIVD, MI, MX and LA) compared to controls, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared to controls (p<0.01). In SIVD, MMP-2 index showed a negative correlation with Qalb, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the SIVD patients from the controls with high specificity (p<0.0005). Conclusions Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr’s disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient’s disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.