Physiological changes in neurodegeneration - mechanistic insights and clinical utility.

The effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system.

Lipidomics Analysis of Behavioral Variant Frontotemporal Dementia: A Scope for Biomarker Development.

Behavioral variant frontotemporal dementia (bvFTD) is the most prevalent form of FTD syndromes. bvFTD is characterized clinically by changes in behavior and cognition and pathologically by focal brain atrophy and concomitant loss of lipids. bvFTD is further characterized by eating abnormalities that result in dyslipidemia.

Region- and Cell-specific Aneuploidy in Brain Aging and Neurodegeneration.

Variations in genomic DNA content, or aneuploidy, are a well-recognized feature of normal human brain development. Whether changes in the levels of aneuploidy are a factor in Alzheimer's disease (AD) is less clear, as the data reported to date vary substantially in the levels of aneuploidy detected (0.7-11.

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.

Background: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.

Enhanced Repair of UV-Induced DNA Damage by 1,25-Dihydroxyvitamin D in Skin Is Linked to Pathways that Control Cellular Energy.

Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1α,25-dihydroxyvitamin D (1,25(OH)D), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models.

Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia.

Background: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA).

Objective: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks.

Methods: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA.

Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition.

Background: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels.

Objective: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival.

Methods: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls.

Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies.

See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article.In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms.

Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease.

Multiple neuronal pathologies are common in young patients with pathologically proven Frontotemporal lobar degeneration.

Aims: The past decade has seen a surge in studies identifying mixed pathologies in elderly populations. Importantly however, few studies have focussed on mixed pathology in Frontotemporal Lobar Degeneration (FTLD), particularly in younger cases.

Methods: The present study examined concomitant pathological neuronal inclusions of TDP-43, hyperphosphorylated tau and α-synuclein protein in the anterior cingulate, hippocampus and entorhinal cortex in young (≤65 years at death) vs.

Distinct TDP-43 inclusion morphologies in frontotemporal lobar degeneration with and without amyotrophic lateral sclerosis.

The identification of the TAR DNA-binding protein 43 (TDP-43) as the ubiquitinated cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) confirmed that these two diseases share similar mechanisms, likely to be linked to the abnormal hyperphosphorylation, ubiquitination and cleavage of pathological TDP-43. Importantly however, a quantitative analysis of TDP-43 inclusions in predilection cortical regions of FTLD, FTLD-ALS and ALS cases has not been undertaken. The present study set out to assess this and demonstrates that distinct TDP-43 inclusion morphologies exist in the anterior cingulate cortex, but not the motor cortex of FTLD and FTLD-ALS.

α-Synuclein Regulates Neuronal Cholesterol Efflux.

α-Synuclein is a neuronal protein that is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies, which includes Parkinson's disease (PD). Despite much research, the exact physiological function of α-synuclein is still unclear. α-Synuclein has similar biophysical properties as apolipoproteins and other lipid-binding proteins and has a high affinity for cholesterol.

Parkinson's Disease Is Not Simply a Prion Disorder.

The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors.

The case for DNA methylation based molecular profiling to improve diagnostic accuracy for central nervous system embryonal tumors (not otherwise specified) in adults.

Central nervous system primitive neuro-ectodermal tumors (CNS-PNETs), have recently been re-classified in the most recent 2016 WHO Classification into a standby catch all category, "CNS Embryonal Tumor, not otherwise specified" (CNS embryonal tumor, NOS) based on epigenetic, biologic and histopathologic criteria. CNS embryonal tumors (NOS) are a rare, histologically and molecularly heterogeneous group of tumors that predominantly affect children, and occasionally adults. Diagnosis of this entity continues to be challenging and the ramifications of misdiagnosis of this aggressive class of brain tumors are significant.

Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain.

Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective.

MSA prions exhibit remarkable stability and resistance to inactivation.

In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrP) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrP transmission.

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease.

Parkinson's disease is characterized by progressively distributed Lewy pathology and neurodegeneration. The motor symptoms of clinical Parkinson's disease (cPD) are unequivocally linked to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several features of these neurons appear to make them selectively vulnerable to factors thought to cause cPD, like aging, genetic mutations and environmental toxins.

Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide?

Ultraviolet radiation (UVR) causes DNA damage in melanocytes by producing photolesions such as cyclobutane pyrimidine dimers and 8-oxo-7-hydrodeoxyguanosine. The production of reactive oxygen species by UVR also induces inflammatory cytokines that, together with the inherent immunosuppressive properties of UVR, propagate carcinogenesis. Nicotinamide (Vitamin B ) enhances DNA repair, modulates the inflammatory environment produced by UVR, and reduces UV-induced immunosuppression.

Clinical Aspects of Alzheimer's Disease.

Alzheimer's disease is the most common form of dementia accounting for 50-60% of all dementia cases. This chapter briefly reviews the history of Alzheimer's disease and provides an overview of the clinical syndromes associated with Alzheimer pathology and their associated neuroimaging findings. This chapter also reviews the neuropathology and genetics of Alzheimer's disease and concludes by discussing current work undertaken to identify suitable in vivo biomarkers for the disease.

Assessment of amyloid β in pathologically confirmed frontotemporal dementia syndromes.

Introduction: The diagnostic utility of in vivo amyloid β (Aβ) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Aβ in pathologically confirmed FTD syndromes.

Methods: Aβ was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of C-Pittsburgh compound B (PiB)-positron emission tomography imaging was assessed in a subset of FTD cases ( = 15).

Results: Aβ was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age.

Exploring the Phenotype in Mild Cognitive Impairment to Aid the Prediction of Those at Risk of Transitioning to Parkinson Disease and Dementia With Lewy Bodies.

To date, only limited research has concurrently investigated the presence of rapid eye movement sleep behavior disorder (RBD) and other features associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB) in people presenting with mild cognitive impairment (MCI). As a first step towards a longitudinal research project, the present study explored the relationships between MCI, RBD, and depression in 108 older adults who presented with subjective memory complaints but were not known to have a neurodegenerative condition. The present study found that RBD was a frequent feature in individuals with MCI (35%).