462 research outputs found

    Can aerobic exercise protect against dementia?

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    There are more than 36 million people in the US over the age of 65, and all of them are impacted by the cognitive decline and brain atrophy associated with normal aging and dementia-causing conditions like Alzheimer's disease, Lewy body disease, and vascular dementia. Recently, moderate exercise and improved fitness have been shown to enhance cognition in cognitively normal older persons as well as in individuals who complain of memory difficulty. Additionally, fitness correlates with brain volume in persons who are cognitively normal and those with Alzheimer's disease. Exercise in mouse models causes neurogenesis in the dentate gyrus. This review will discuss animal experiments, epidemiology, limited prospective studies, and biomarker data that make the case that prospective blinded studies are urgently needed to evaluate the role of aerobic exercise in protecting against dementia

    A nonsense mutation in PRNP associated with clinical Alzheimer's disease

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    AbstractHere, we describe a nonsense haplotype in PRNP associated with clinical Alzheimer's disease. The patient presented an early-onset of cognitive decline with memory loss as the primary cognitive problem. Whole-exome sequencing revealed a nonsense mutation in PRNP (NM_000311, c.C478T; p.Q160*; rs80356711) associated with homozygosity for the V allele at position 129 of the protein, further highlighting how very similar genotypes in PRNP result in strikingly different phenotypes

    Normal pressure hydrocephalus, or Hakim syndrome: review and update

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    This review makes the case that idiopathic normal pressure hydrocephalus (iNPH) is an outdated term because new information indicates that the syndrome is less idiopathic and that the cerebrospinal fluid (CSF) pressure of normal individuals is affected by several factors such as body mass index, age, and sex. Our review updates the epidemiology of iNPH and provides a clinical approach to the management of these patients. All the clinical features of iNPH are common in older individuals, and each has many causes, so the diagnosis is difficult. The first step in reaching an accurate diagnosis is to address the possible contributory factors to the gait abnormality and determine what if any role iNPH may be playing. The two best diagnostic tests are neuroimaging and cerebrospinal fluid (CSF) diversion (large volume lumbar puncture or external lumbar drainage) with pre/post gait evaluation. This review provides an update on the growing evidence that vascular disease, impaired CSF absorption, congenital, and genetic factors all contribute to the pathogenesis of iNPH. We suggest replacing the term iNPH with the term Hakim syndrome (HS) in acknowledgement of the first person to describe this syndrome. Lastly, we discuss the improvements in shunt technology and surgical techniques that have decreased the risks and long-term complications of shunt surgery

    Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers.

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    Background and purposeThe objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression.MethodsWe identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope.ResultsThe decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset.ConclusionsOur findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage

    Comparing biological markers of Alzheimer\u27s disease across blood fraction and platforms: Comparing apples to oranges

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    Introduction: This study investigated the comparability of potential Alzheimer\u27s disease (AD) biomarkers across blood fractions and assay platforms. Methods: Nonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots. Results: On the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared \u3e50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty acid-binding protein (FABP) R2 = 0.94, I309 R2 = 0.94, IL-5 R2 = 0.94, IL-6 R2 = 0.94, eotaxin3 R2 = 0.91, IL-18 R2 = 0.87, soluble tumor necrosis factor receptor 1 R2 = 0.85, and pancreatic polypeptide R2 = 0.81). When examining protein concentrations across platforms, only five markers shared \u3e50% of the variance (beta 2 microglobulin R2 = 0.92, IL-18 R2 = 0.80, factor VII R2 = 0.78, CRP R2 = 0.74, and FABP R2 = 0.70). Discussion: The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers

    Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

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    Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers

    Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

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    The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis
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