Cerebral amyloid burden is associated with white matter hyperintensity location in specific posterior white matter regions

White matter hyperintensities (WMHs) are a common manifestation of cerebral small vessel disease. WMHs are also frequently observed in patients with familial and sporadic Alzheimer's disease, often with a particular posterior predominance. Whether amyloid and tau pathologies are linked to WMH occurrence is still debated. We examined whether cerebral amyloid and tau burden, reflected in cerebrospinal fluid amyloid-beta 1-42 (Aβ-42) and phosphorylated tau (p-tau), are related to WMH location in a cohort of 517 memory clinic patients. Two lesion mapping techniques were performed: voxel-based analyses and region of interest-based linear regression. Voxelwise associations were found between lower Aβ-42 and parieto-occipital periventricular WMHs. Regression analyses demonstrated that lower Aβ-42 correlated with larger WMH volumes in the splenium of the corpus callosum and posterior thalamic radiation, also after controlling for markers of vascular disease. P-tau was not consistently related to WMH occurrence. Our findings indicate that cerebral amyloid burden is associated with WMHs located in specific posterior white matter regions, possibly reflecting region-specific effects of amyloid pathology on the white matter

IMMUNOTHERAPY IN COMBINATION WITH BEHAVIORAL ENRICHMENT IN A CANINE MODEL OF AGING

Alzheimer’s disease (AD) is characterized by cognitive decline and hallmark neuropathology, including β-amyloid (Aβ). Therapeutic strategies for AD are focusing on reducing Aβ. Canines develop Aβ neuropathology and cognitive decline with age similar to AD patients. In previous studies, immunization with Aβ1-42 (VAC) in aged canines decreased brain Aβ but did not improve cognition. Behavioral enrichment (ENR) improved cognition without reducing brain Aβ. We hypothesized that VAC combined with ENR would provide cognitive benefits and reduce Aβ neuropathology, as compared individual VAC and ENR treatments. Aged beagles were placed into groups: control, VAC with fibrillar Aβ1-42, ENR, and combination treatment (VAC+ENR) for 18 months. Learning and memory was evaluated throughout the study. Serum IgG antibody titers, cerebral spinal fluid (CSF) and brain Aβ were measured. Serum anti-Aβ1-42 IgG increased significantly in VAC animals. ENR but not VAC significantly increased CSF Aβ1-40. No cognitive improvements were observed in any group. VAC significantly reduced brain Aβ1-40 and 1-42, as well as reduced plaque load. An overall slowing of plaque accumulation was seen in the ENR group. VAC and ENR were able to modify pathology when used as separate treatments; however, the combination treatment did not succeed in further reducing Aβ or improving cognition. Previous AD clinical trials using immunotherapy yielded similar outcomes to our study showing reduced Aβ pathology but little to no cognitive improvements. In combination these results suggest that future studies should focus on prevention approaches both in the canine model and in human clinical trials