Most common NOTCH3 mutations causing CADASIL or CADASIL-like cerebral small vessel disease: A systematic review.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a monogenic disorder caused by mutations in the NOTCH3 gene. The main aim of our survey was to determine if there is an association between phenotypes and genotypes across the most common NOTCH3 mutations found in CADASIL patients. We systematically searched clinical studies and genomic databases from 1996 to 2023 to first identify the most common mutations responsible for CADASIL. We found the six most common NOTCH3 missense mutations globally were the p.R75P, p.R133C, p.R141C, p.R169C, p.R182C, and p.R544C, of which p.R133C was described to occur most often. Focusing on studies with comprehensive clinical records, our analysis further suggested that the p.R75P, p.R141C, p.R182C and p.R544C genotypes were highly congruent with the presence of white matter hyperintensities on magnetic resonance imaging (MRI), which was the most common phenotypic characteristic across all four mutations. We found the p.R141C mutation was associated with increased severity of disease. We also found the average age of onset in p.R544C carriers was more than a decade later compared to the p.R141C carriers. However, statistical analysis showed there were no overall differences between the phenotypic characteristics of the two common mutations, p.R141C and p.R544C. Geographically, China and Japan were the only two countries to report all the four common mutations vis a vis p.R75P, p.R141C, p.R182C and p.R544C. There is a possibility that this is due to a combination of a founder effect, but there also could be sampling biases.

Hippocampal capillary pericytes in post-stroke and vascular dementias and Alzheimer's disease and experimental chronic cerebral hypoperfusion.

Neurovascular unit mural cells called 'pericytes' maintain the blood-brain barrier and local cerebral blood flow. Pathological changes in the hippocampus predispose to cognitive impairment and dementia. The role of hippocampal pericytes in dementia is largely unknown. We investigated hippocampal pericytes in 90 post-mortem brains from post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD), and AD-VaD (Mixed) subjects, and post-stroke non-demented survivors as well as similar age controls. We used collagen IV immunohistochemistry to determine pericyte densities and a mouse model of VaD to validate the effects of chronic cerebral hypoperfusion. Despite increased trends in hippocampal microvascular densities across all dementias, mean pericyte densities were reduced by ~25-40% in PSD, VaD and AD subjects compared to those in controls, which calculated to 14.1 ± 0.7 per mm capillary length, specifically in the cornu ammonis (CA) 1 region (P = 0.01). In mice with chronic bilateral carotid artery occlusion, hippocampal pericyte loss was ~60% relative to controls (P < 0.001). Pericyte densities were correlated with CA1 volumes (r = 0.54, P = 0.006) but not in any other sub-region. However, mice subjected to the full-time environmental enrichment (EE) paradigm showed remarkable attenuation of hippocampal CA1 pericyte loss in tandem with CA1 atrophy. Our results suggest loss of hippocampal microvascular pericytes across common dementias is explained by a vascular aetiology, whilst the EE paradigm offers significant protection.

The role of the medial prefrontal cortex in cognition, ageing and dementia.

Humans require a plethora of higher cognitive skills to perform executive functions, such as reasoning, planning, language and social interactions, which are regulated predominantly by the prefrontal cortex. The prefrontal cortex comprises the lateral, medial and orbitofrontal regions. In higher primates, the lateral prefrontal cortex is further separated into the respective dorsal and ventral subregions. However, all these regions have variably been implicated in several fronto-subcortical circuits. Dysfunction of these circuits has been highlighted in vascular and other neurocognitive disorders. Recent advances suggest the medial prefrontal cortex plays an important regulatory role in numerous cognitive functions, including attention, inhibitory control, habit formation and working, spatial or long-term memory. The medial prefrontal cortex appears highly interconnected with subcortical regions (thalamus, amygdala and hippocampus) and exerts top-down executive control over various cognitive domains and stimuli. Much of our knowledge comes from rodent models using precise lesions and electrophysiology readouts from specific medial prefrontal cortex locations. Although, anatomical disparities of the rodent medial prefrontal cortex compared to the primate homologue are apparent, current rodent models have effectively implicated the medial prefrontal cortex as a neural substrate of cognitive decline within ageing and dementia. Human brain connectivity-based neuroimaging has demonstrated that large-scale medial prefrontal cortex networks, such as the default mode network, are equally important for cognition. However, there is little consensus on how medial prefrontal cortex functional connectivity specifically changes during brain pathological states. In context with previous work in rodents and non-human primates, we attempt to convey a consensus on the current understanding of the role of predominantly the medial prefrontal cortex and its functional connectivity measured by resting-state functional MRI in ageing associated disorders, including prodromal dementia states, Alzheimer's disease, post-ischaemic stroke, Parkinsonism and frontotemporal dementia. Previous cross-sectional studies suggest that medial prefrontal cortex functional connectivity abnormalities are consistently found in the default mode network across both ageing and neurocognitive disorders such as Alzheimer's disease and vascular cognitive impairment. Distinct disease-specific patterns of medial prefrontal cortex functional connectivity alterations within specific large-scale networks appear to consistently feature in the default mode network, whilst detrimental connectivity alterations are associated with cognitive impairments independently from structural pathological aberrations, such as grey matter atrophy. These disease-specific patterns of medial prefrontal cortex functional connectivity also precede structural pathological changes and may be driven by ageing-related vascular mechanisms. The default mode network supports utility as a potential biomarker and therapeutic target for dementia-associated conditions. Yet, these associations still require validation in longitudinal studies using larger sample sizes.