White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of APP may be sufficient to overexpression's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b and M2c inflammatory phenotypes we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in post-mortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.

Introduction Microglial cells play an important role in the development of Alzheimer's disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology (DSAD) by 40 years of age. We characterized the distribution of different microglial phenotypes in the brains of people with DS and DSAD. Methods Autopsy tissue from the posterior cingulate cortex (PCC) from people with DS, DSAD, and neurotypical controls was immunostained with the microglial marker Iba1 to assess five microglia morphological types. Results Individuals with DS have more hypertrophic microglial cells in their white matter. In the gray matter, individuals with DSAD had significantly fewer ramified microglia and more dystrophic microglia than controls and the younger individuals with DS. The DSAD group also exhibited more rod‐shaped and amoeboid cells than the AD group. Discussion Individuals with DS and DSAD show a microglial phenotype that distinguishes them from non‐DS controls.

Background Vascular contributions to cognitive impairment and dementia (VCID) is a complex form of dementia, combining aspects of vascular disease and other forms of dementia, such as Alzheimer’s disease. VCID encompasses a wide spectrum of cerebrovascular-driven cognitive impairment, from mild cognitive impairment to fully developed dementia. This disease state is further complicated by metabolic disorders, such as type 2 diabetes and hypertension, and lifestyle factors, like obesity and high fat diets. Scope of Review This manuscript is meant to both define VCID and review the in vitro and in vivo models of the disease state. This includes in vitro models of the neurovascular unit, models of chronic cerebral hypoperfusion, animals with NOTCH3 mutations as a model of small vessel disease, large animals with cerebral amyloid angiopathy (CAA), and animal models of mixed dementia. Major Conclusions Synthetic microvessels are a promising technique to study the neurovascular unit and canines, despite the cost, are an excellent model to study CAA. While there are several good models of individual aspects of VCID, the heterogeneity of the disease states prevents there from being a model of all aspects of the disease. Therefore, VCID needs to be further defined into disease states that exist within this umbrella term. This includes specific guidelines for stroke counts and stroke locations and further categorization of overlapping cerebrovascular and AD pathologies that contribute to dementia. This will allow for better models and a more thorough understanding of how vascular disease contributes to dementia. General Significance VCID is the second most common form of dementia and is expected to increase in coming years. The heterogeneity of VCID makes it difficult to study, but without better definitions and models, VCID presents a major public health problem for our aging population.

Cerebrovascular pathology is a significant mediator in Alzheimer’s disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between CAA and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD and control cases (2–83 years). Sections were immunostained against Aβ1–40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials.