Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series.

In the aftermath of multiple high-profile cases of chronic traumatic encephalopathy (CTE) in professional American football players, physicians in clinical practice are likely to face an increasing number of retired football players seeking evaluation for chronic neurobehavioral symptoms. Guidelines for the evaluation and treatment of these patients are sparse. Clinical criteria for a diagnosis of CTE are under development.

A Long Journey from Childhood to Senility: The 23rd HUPO BPP Workshop: 16-17 April 2015, São Paulo, Brazil.

The HUPO Brain Proteome Project (HUPO BPP) held its 23rd workshop in São Paulo, Brazil, April 16-17, 2015. The focus of the spring workshop was on strategies and predictive therapies concerning neurodegenerative diseases.

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein.

Higher Prevalence of TDP-43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample.

Transactive response DNA binding protein 43 (TDP-43) proteinopathy is the major hallmark of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. It is also present in a subset of Alzheimer's disease cases. Recently, few reports showed TDP-43 changes in cognitively normal elderly.

Consensus statement for diagnosis of subcortical small vessel disease.

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes.

Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology.

Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti-tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals.

The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features.

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44).

Alzheimer and vascular brain diseases: Focal and diffuse subforms.

Alois Alzheimer is best known for his description of the pre-senile neurodegenerative disease named after him. However, his previous interest in vascular brain diseases, underlying cognitive and behavioral changes, was very strong. Besides describing the Arteriosclerotic atrophy of the brain and the arteriosclerotic subtype of Senile dementia which he viewed as main forms of vascular brain diseases, he also identified and described a series of conditions he considered subforms.

Enrichment of single neurons and defined brain regions from human brain tissue samples for subsequent proteome analysis.

Brain function in normal aging and neurological diseases has long been a subject of interest. With current technology, it is possible to go beyond descriptive analyses to characterize brain cell populations at the molecular level. However, the brain comprises over 100 billion highly specialized cells, and it is a challenge to discriminate different cell groups for analyses.

Amyloid in dementia associated with familial FTLD: not an innocent bystander.

Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case-control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid-negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions.

Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation.

Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal.

A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.

Introduction: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.

Results: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1).

Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment.

Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits.

Alzheimer and vascular brain disease: Senile dementia.

Alois Alzheimer is best known for his description of a novel disease, subsequently named after him. However, his wide range of interests also included vascular brain diseases. He described Senile dementia, a highly heterogeneous condition, and was able not only to distinguish it from syphilitic brain disease, but also to discriminate two clinicopathological subtypes, that may be labeled a "arteriosclerotic subtype", comparable to the present clinicopathological continuum of "Vascular cognitive impairment", and another as a "neurodegenerative subtype", characterized by primary [cortical] ganglion cell [nerve cells] degeneration, possibly foreshadowing a peculiar presenile disease that he was to describe some years later and would carry his name.

Factors associated with morphometric brain changes in cognitively normal aging.

Objective: Cognitive impairment is associated with reductions in brain weight and volume. The factors related to morphometric brain changes in cognitively normal aging remain unknown. We aimed to identify which clinical factors are associated with morphometric brain changes in cognitively normal aging.

Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography.

Introduction: Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer's disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer's disease neuropathology) in patients presenting with CBS.

Turning on the Light Within: Subcortical Nuclei of the Isodentritic Core and their Role in Alzheimer's Disease Pathogenesis.

Pharmacological interventions in Alzheimer's disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain.

Criminal behavior in frontotemporal dementia and Alzheimer disease.

Importance: Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life.

Objective: To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder.

Alois Alzheimer and vascular brain disease: Arteriosclerotic atrophy of the brain.

Alois Alzheimer is best known for his description of neurofibrillary changes in brain neurons of a demented patient, identifying a novel disease, soon named after him by Kraepelin. However, the range of his studies was broad, including vascular brain diseases, published between 1894 and 1902. Alzheimer described the clinical picture of Arteriosclerotic atrophy of the brain, differentiating it from other similar disorders.

Argyrophilic grain disease: An underestimated tauopathy.

Argyrophilic grain disease (AGD) is an under-recognized, distinct, highly frequent sporadic tauopathy, with a prevalence reaching 31.3% in centenarians. The most common AGD manifestation is slowly progressive amnestic mild cognitive impairment, accompanied by a high prevalence of neuropsychiatric symptoms.

Complex network-driven view of genomic mechanisms underlying Parkinson's disease: analyses in dorsal motor vagal nucleus, locus coeruleus, and substantia nigra.

Parkinson's disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples.

Sexual dimorphism in the human olfactory bulb: females have more neurons and glial cells than males.

Sex differences in the human olfactory function reportedly exist for olfactory sensitivity, odorant identification and memory, and tasks in which odors are rated based on psychological features such as familiarity, intensity, pleasantness, and others. Which might be the neural bases for these behavioral differences? The number of cells in olfactory regions, and especially the number of neurons, may represent a more accurate indicator of the neural machinery than volume or weight, but besides gross volume measures of the human olfactory bulb, no systematic study of sex differences in the absolute number of cells has yet been undertaken. In this work, we investigate a possible sexual dimorphism in the olfactory bulb, by quantifying postmortem material from 7 men and 11 women (ages 55-94 years) with the isotropic fractionator, an unbiased and accurate method to estimate absolute cell numbers in brain regions.

Primary age-related tauopathy (PART): a common pathology associated with human aging.

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex).