Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Ting SK
PROVIDER: S-EPMC4751434 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:Psychotic symptoms, delusions and hallucinations, occur in approximately 50% of individuals with Alzheimer's disease (AD) (AD with psychosis [AD + P]). Pharmacotherapies for AD + P have limited efficacy and can increase short-term mortality. These observations have motivated efforts to identify the underlying biology of AD + P. Psychosis in AD indicates a more severe phenotype, with more rapid cognitive decline beginning even before psychosis onset. Neuroimaging studies suggest that AD + P subjects demonstrate greater cortical synaptic impairments than AD subjects without psychosis, reflected in reduced gray matter volume, reduced regional blood flow, and reduced regional glucose metabolism. Neuroimaging and available postmortem evidence further indicate that the impairments in AD + P, relative to AD subjects without psychosis, are localized to neocortex rather than medial temporal lobe. Neuropathologic studies provide consistent evidence of accelerated accumulation of hyperphosphorylated microtubule associated protein tau in AD + P. Finally, studies of familial aggregation of AD + P have established that the risk for psychosis in AD is, in part, genetically mediated. Although no genes are established as associated with AD + P, the first genome-wide association study of AD + P has generated some promising leads. The study of the neurobiology of AD + P is rapidly accelerating and may be poised for translational discovery. This process can be enhanced by identifying points of convergence and divergence with the neurobiology of AD proper and of schizophrenia, by innovative extension of current approaches, and by development of relevant animal models.
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Project description:This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF A?1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and A?1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and A?1-42 (p = 0.001) were independently associated with BSI in controls; in MCI A?1-42 (p < 0.001) and tau (p = 0.04) were associated with BSI. There was no evidence of independent effects of WMH or CSF measures on BSI in AD. These data support findings that vascular damage is associated with increased brain atrophy in the context of AD pathology in pre-dementia stages.
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Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Here, we used vessel size imaging to investigate the specific microvascular changes and most susceptible brain regions during AD progression in an amyloid precursor protein 23 (APP23) transgenic AD mouse model. Using 9.4 Tesla magnetic resonance imaging (MRI), the values of microvascular density (Density), mean vessel diameter (mVD), and vessel size index (VSI) were compared between APP23 and wild-type (WT) mice at 3, 6, 9, 14, and 20 months of age. Our results demonstrate that in 20-month old APP23 and WT mice, the Density values were significantly decreased, while the vascular dilatation and diameter had increased. However, a transient increase in the cortex Density at 14-months was observed in APP23 mice. Additionally, our results suggest that the hippocampus is the susceptible brain region affected by the abnormal microvascular angiogenesis during the early stages of AD. Together, our findings indicate that vessel size imaging using MRI can provide novel biomarkers for the early detection of AD, and for monitoring the effects of vascular-targeted therapeutics in AD.
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Project description:BackgroundUltra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood.MethodsRate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35).ResultsUHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto-occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use.ConclusionThe development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis.
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