Chronic traumatic encephalopathy — confusion and controversies

The term chronic traumatic encephalopathy (CTE) has recently entered public consciousness via media reports and even a Hollywood movie. However, in contrast to general impressions, the incidence of CTE is unknown, the clinical diagnostic criteria have not been agreed upon and the current neuropathological characterization of CTE is acknowledged as preliminary. Additionally, few studies have compared the pathologies of CTE with those of other neurodegenerative disorders or of age-matched controls. Consequently, disagreement continues about the neuropathological aspects that make CTE unique. Furthermore, CTE is widely considered to be a consequence of exposure to repeated head blows, but evidence suggests that a single moderate or severe traumatic brain injury can also induce progressive neuropathological changes. These unresolved aspects of CTE underlie disparate claims about its clinical and pathological features, leading to confusion among the public and health-care professionals alike

Plasma Neuronal Exosomal Levels of Alzheimer\u27s Disease Biomarkers in Normal Aging

Plasma neuronal exosomal levels of pathogenic Alzheimer\u27s disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal exosomal levels of P-T181-tau, P-S396-tau, Aβ1-42, cathepsin D, repressor element 1-silencing transcription factor, and neurogranin were quantified longitudinally in cognitively intact older adults using two samples collected at 3- to 11-year intervals. Except for P-S396-tau, exosomal protein levels changed significantly with aging, but were largely outside the range observed in AD patients

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players

Chronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugby players with dementia were assessed for neurodegenerative pathologies using established and preliminary consensus protocols. Thereafter, next of kin interviews were conducted to obtain detailed accounts of the patient’s clinical presentation and course of disease to inform a final, integrated clinicopathological diagnosis. Neuropathologic change consistent with CTE (CTE-NC) was confirmed in five of seven former soccer and three of four former rugby players’ brains, invariably in combination with mixed, often multiple neurodegenerative pathologies. However, in just three cases was the integrated dementia diagnosis consistent with CTE, the remainder having alternate diagnoses, with the most frequent integrated diagnosis Alzheimer’s disease (AD) (four cases; one as mixed AD and vascular dementia). This consecutive autopsy series identifies neuropathologic change consistent with preliminary diagnostic criteria for CTE (CTE-NC) in a high proportion of former soccer and rugby players dying with dementia. However, in the majority, CTE-NC appears as a co-morbidity rather than the primary, dementia causing pathology. As such, we suggest that while CTE-NC might be common in former athletes with dementia, in many cases its clinical significance remains uncertain

Clinically Silent Alzheimer\u27s and Vascular Pathologies Influence Brain Networks Supporting Executive Function in Healthy Older Adults

Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer’s disease (AD) pathology and cerebral white matter hyperintensities (WMHs). Twenty-nine younger adults and thirty-four cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Older adults further underwent lumbar cerebrospinal fluid (CSF) draw for assessment of AD pathology and FLAIR imaging for assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked with lower levels of clinically silent AD pathology. In addition, AD pathology and WMHs were each independently related to increased fMRI response in the left dorsolateral prefrontal cortex, a pattern associated with slower task performance. Our results suggest that clinically silent AD pathology is related to lower expression of a fronto-visual fC pattern supporting executive task performance. Further, our findings suggest that AD pathology and WMHs appear to be linked with ineffective increases in frontal response in CN older adults

Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure−activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases

Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity.Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion.Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease.This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits

Sites of synthesis of chromogranins A and B in the human brain

The sites of synthesis of the chromogranins A and B, and their potential processed peptides, were examined by quantitating the levels of chromogranin A and B mRNA in various regions of the human brain by Northern blot analysis. Chromogranin A and B mRNA expression in the brain is region-specific and confined to grey matter. In situ hybridization histochemistry detected chromogranin A and B mRNA in pyramidal neurons of human cerebral cortex. Cell-specific expression in subpopulations of cerebrocortical neurons suggest that chromogranin A and B gene products may play a role in central neuronal function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30124/1/0000500.pd