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A White Matter Connection of Schizophrenia and Alzheimer's Disease.

ABSTRACT: Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.

SUBMITTER: Kochunov P

PROVIDER: S-EPMC7825012 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A White Matter Connection of Schizophrenia and Alzheimer's Disease.

Kochunov Peter P Zavaliangos-Petropulu Artemis A Jahanshad Neda N Thompson Paul M PM Ryan Meghann C MC Chiappelli Joshua J Chen Shuo S Du Xiaoming X Hatch Kathryn K Adhikari Bhim B Sampath Hemalatha H Hare Stephanie S Kvarta Mark M Goldwaser Eric E Yang Fude F Olvera Rene L RL Fox Peter T PT Curran Joanne E JE Blangero John J Glahn David C DC Tan Yunlong Y Hong L Elliot LE

Schizophrenia bulletin 20210101 1

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients wi ...[more]

PMID: 32681179

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Project description:Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

Project description:IntroductionObservational studies have indicated widespread comorbidity of white matter (WM) lesions and Alzheimer's disease (AD) in the elderly, but the causality and direction of their relationship remained unclear. Our study aims to examine the bidirectional causal relationship between WM change and AD using a genetically informed method.MethodsWe performed a bidirectional two-sample mendelian randomization (MR) study to investigate the correlation of three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with AD (N = 63,926) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted method (IVW) was used to evaluate the causal estimate and alternative methods to test the heterogeneity, horizontal pleiotropy, and outliers.ResultsThere was no significant causal evidence of WM MRI markers on AD across all MR methods. We identified significant evidence of causal effects of AD on the risk of WMH (OR 1.06, 95% CI 1.03-1.10, p < 0.01). The same direction of effects was observed in MR-Egger, weighted median, and weighted mode analysis. Besides, we also observed a risk causal relationship between AD with MD in MR-Egger, weighted median, and weighted mode-based methods (MR-Egger OR 1.38, 95% CI 1.07-1.79, p = 0.02; weighted median OR 1.21, 95% CI 1.02-1.45, p = 0.03; weighted mode-based OR 1.32, 95% CI 1.14-1.53, p < 0.01). However, the general significance of the causal effect of AD on WMH and MD disappeared when we removed the single nucleotide polymorphisms (SNPs) near the APOE regions, revealing that the ability of AD to increase the risk of white matter damage might be mediated by APOE to some extent. Unfortunately, we did not observe significant causal evidence of AD on FA across all MR analyses.ConclusionsIn this bidirectional MR study, we did not observe that WM injuries were associated with a higher risk of AD. Likewise, genetically predicted AD did not result in a causal effect on white matter damage. However, our research revealed that underlying mechanisms linking AD and white matter lesions might be related to the SNPs near APOE regions.

Project description:ObjectiveFailure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance.MethodsThe study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia.ResultsPatients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms.ConclusionsSchizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target.

Dataset Information

A White Matter Connection of Schizophrenia and Alzheimer's Disease.

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A White Matter Connection of Schizophrenia and Alzheimer's Disease.

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