Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis

Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
Acta Neuropathologica (Impact Factor: 10.76). 03/2012; 123(3):395-407. DOI: 10.1007/s00401-011-0932-x
Source: PubMed


While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.

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    • "In addition to protein inclusions, another feature of ALS and FTD neuropathology is reactive gliosis, which is characterized by astrocytic hypertrophy and microglial proliferation (Al-Chalabi et al., 2012; Ng et al., 2015). Reactive gliosis is an indicator of neuroinflammation (Streit et al., 2004) and occurs in areas of neuronal loss and inclusion pathology in ALS and FTD (Brettschneider et al., 2012). Studies over the past 15 years have strongly indicated that ALS and FTD propagate via multiple cell types, with reactive gliosis being heavily implicated (Ilieva et al., 2009). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.
    Frontiers in Cellular Neuroscience 10/2015; 9. DOI:10.3389/fncel.2015.00414 · 4.29 Impact Factor
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    • "ALS is primarily characterized by motor symptoms. Nevertheless , extra-motor manifestations like cognitive deficits are increasingly recognized as common features of the disease (Brettschneider et al., 2012; Phukan et al., 2011; Strong et al., 2009). Predominant impairment of language and memory domains as well as executive dysfunction is the most reported neuropsychological change (Phukan et al., 2011). "
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    ABSTRACT: There is increasing appreciation of non-motor system involvement in amyotrophic lateral sclerosis (ALS), although its full extent and clinical significance remains to be established. This study tested the hypothesis that memory impairment in patients with ALS is related to hippocampal degeneration. Consecutive patients with ALS (58) and 29 matched controls participated in standardized neuropsychological assessment and magnetic resonance imaging. Patients with ALS performed worse in global cognitive functioning and executive and verbal memory tests (p < 0.05). The hippocampus was manually segmented in each hemisphere, and volumes were calculated with correction for intracranial volume. Analysis of covariance, controlled for the effect of age and education years, showed significantly smaller hippocampal volume on the right (p = 0.004) in patients with ALS. Verbal memory test performance correlated with the left hippocampal volume in patients with ALS (p < 0.05), although there was no significant correlation with tests of executive function and clinical variables underscoring the specificity of the present findings. Hippocampal volume loss and its correlation with the severity of verbal memory impairment highlight significant hippocampal involvement which can occur as a non-motor deficit in patients with ALS.
    Neurobiology of Aging 06/2014; 35(11). DOI:10.1016/j.neurobiolaging.2014.05.035 · 5.01 Impact Factor
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    • "Second, cellular heterogeneity may impair our analysis in the ground tissue from total frontal cortex, as we could not test whether aberrant GRN promoter methylation occurs only in a specific cell type or globally. Microglia activation is a common inflammatory response in FTLD brains (and other neurodegenerative diseases) [40]. Inflammation leads to increased microglial GRN expression [41], which may obscure a neuronal loss of GRN expression. "
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    ABSTRACT: Background Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear. Results We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression. Conclusion These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy.
    05/2013; 1(1). DOI:10.1186/2051-5960-1-16
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