Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis
ABSTRACT 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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ABSTRACT: Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern.
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ABSTRACT: The proinflammatory cytokine osteopontin (OPN) is elevated in the cerebrospinal fluid (CSF) in individuals with HIV-associated neurocognitive disorders (HAND) and remains so in those on suppressive antiretroviral therapy. To understand the pathophysiological significance of elevated OPN in the CNS, we sought to determine the cellular source of this cytokine. As HIV-1 replicates productively in macrophages/microglia, we tested whether these cells are the predominant producers of OPN in the brain. Stringent patient selection criteria, which excluded brain tissues from those with evidence of drug abuse and dependence, were used. Uninfected normal controls, amyotrophic lateral sclerosis (ALS), HIV+ asymptomatic neurocognitive impairment (ANI), and HIV+ mild neurocognitive disorder (MND)/HIV-associated dementia (HAD) groups were included. Double-label immunohistochemistry for CNS cells and OPN was used to quantify OPN expression in astrocytes, macrophages/microglia, and neurons. While resident macrophages/microglia expressed OPN, astrocytes and unexpectedly neurons were also a major source of OPN. OPN levels in ionized Ca(2+)-binding adapter 1 (Iba1)/allograft inflammatory factor-1 (AIF-1)+ microglia in HIV+ ANI and MND/HAD exceeded those of HIV-negative controls and were comparable to expression seen in ALS. Moreover, in neurons, OPN was expressed at the highest levels in the HIV+ ANI group. These findings suggest that while infiltrating HIV-infected macrophages are most likely the initial source of OPN, resident CNS cells become activated and also express this inflammatory cytokine at significant levels. Moreover, as OPN levels are elevated compared to uninfected individuals and increases with the severity of impairment, it appears that the expression of OPN is persistent and sustained within the brain parenchyma in those that progress to HAND.Journal of NeuroVirology 01/2015; DOI:10.1007/s13365-015-0317-3 · 3.32 Impact Factor
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ABSTRACT: IntroductionAmyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). Patients with amyotrophic lateral sclerosis also may demonstrate non-motor symptoms and signs of autonomic and energy dysfunction as hypermetabolism and weight loss that suggest the possibility of pathology in the forebrain, including hypothalamus. However, this region has received little investigation in amyotrophic lateral sclerosis. In this study, the frequency, topography, and clinical associations of TDP-43 inclusion pathology in the basal forebrain and hypothalamus were examined in 33 patients with amyotrophic lateral sclerosis: 25 men and 8 women; mean age at death of 62.7 years, median disease duration of 3.1 years (range of 1.3 to 9.8 years).ResultsTDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n=¿10) and hypothalamus (n=¿7). This pathology was associated with non-motor system TDP-43 pathology (¿2=¿17.5, p=¿0.00003) and bulbar symptoms at onset (¿2=¿4.04, p=¿0.044), but not age or disease duration. Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W=¿11, p=¿0.023).Conclusions This is the first systematic demonstration of pathologic involvement of the basal forebrain and hypothalamus in amyotrophic lateral sclerosis. Furthermore, the findings suggest that involvement of the basal forebrain and hypothalamus has significant phenotypic associations in amyotrophic lateral sclerosis, including site of symptom onset, as well as deficits in energy metabolism with loss of body mass index.12/2014; 2(1):1. DOI:10.1186/s40478-014-0171-1