I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

http://www.ipg.org.br/Rosa_Rademakers_Neuron%20tese%20integra.pdf

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS

Background and Purpose—This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment ...

Vascular Contributions to Cognitive Impairment and Dementia A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

/pdf/national-institute-on-aging-alzheimer-s-association-5crbry24zc.pdf

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy dots); and axons in the white matter (Lewy axons). This novel pathology was abundantly present around LBs and also involved the limbic subcortical white matter, the cerebral cortical molecular layer, and the spongiform changes of the medial temporal lobe associated with cases of dementia with LBs (DLB). The phosphorylated alpha-synuclein was limited to the temporal lobe in cases of Parkinson disease, spread from the temporal lobe to the frontal lobe in cases of DLB transitional form and further spread to the parietal and occipital lobes in DLB neocortical form. Our findings suggest that LB-related pathology initially involves the neuronal perikarya, dendrites, and axons, causes impairment of axonal transport and synaptic transmission, and later leads to the formation of LBs, a hallmark of functional disturbance long before neuronal cell death.

/pdf/accumulation-of-phosphorylated-a-synuclein-in-aging-human-1rycek8m4k.pdf

Accumulation of Phosphorylated α-Synuclein in Aging Human Brain

Microglia are resident myeloid cells of the central nervous system (CNS), activated in the brains of various neurological diseases. Microglia are ontogenetically and functionally distinct from monocyte-derived macrophages that infiltrate the CNS under pathological conditions. However, a lack of specific markers that distinguish resident microglia from circulating blood-derived macrophages in human brain tissues hampers accurate evaluation of microglial contributions to the human brain pathology. By comparative analysis of five comprehensive microglial transcriptome datasets, we identified an evolutionarily conserved protein TMEM119 as the most promising candidate for human microglial markers. TMEM119 was expressed on immortalized human microglia, in which the expression levels were not elevated by exposure to lipopolysaccharide, IFNγ, IL-4, IL-13 or TGFβ1. Notably, TMEM119 immunoreactivity was expressed exclusively on a subset of Iba1(+) CD68(+) microglia with ramified and amoeboid morphologies in the brains of neurodegenerative diseases, such as Alzheimer's disease (AD), whereas Iba1(+) CD68(+) infiltrating macrophages do not express TMEM119 in demyelinating lesions of multiple sclerosis and necrotic lesions of cerebral infarction. TMEM119 mRNA levels were elevated in AD brains, although the protein levels were not significantly different between AD and non-AD cases by western blot and morphometric analyses. TMEM119-positive microglia did not consistently express polarized markers for M1 (CD80) or M2 (CD163, CD209) in AD brains. These results suggest that TMEM119 serves as a reliable microglial marker that discriminates resident microglia from blood-derived macrophages in the human brain.

TMEM119 marks a subset of microglia in the human brain

We have reported that the ambient gyrus is the site with the greatest accumulation of argyrophilic grains (AGs) and that the degeneration of the ambient gyrus is responsible for dementia with grains Here we analyzed 1,405 serial autopsy cases from 2 hospitals and detected AGs only in cases older than 56 years of age The distribution of AGs followed a stereotypic regional pattern Thus, we propose the following staging paradigm: stage I: AGs restricted to the ambient gyrus and its vicinity; stage II: AGs more apparent in the anterior and posterior medial temporal lobe, including the temporal pole, as well as the subiculum and entorhinal cortex; and stage III: abundant AGs in the septum, insular cortex, and anterior cingulate gyrus, accompanying spongy degeneration of the ambient gyrus Sixty-three of 65 (969%) argyrophilic grain stage III cases without other dementing pathology were classified as 05 or higher in the clinical dementia rating Forty-seven of 50 dementia with grains cases (94%) were stage III and 3 were stage II No association with apoE genotyping was detected Our study further confirms that dementia with grains is an age-associated tauopathy with relatively uniform distribution and may independently contribute to cognitive decline in the elderly

Staging of argyrophilic grains: an age-associated tauopathy.

Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease.

Neurofibrillary tangles (NFTs) are pathological hallmarks of several neurodegenerative disorders, including Alzheimer's disease (AD). NFTs are composed of microtubule-binding protein tau, which assembles to form paired helical filaments (PHFs) and straight filaments. Here we show by atomic force microscopy that AD brain tissue and in vitro tau form granular and fibrillar tau aggregates. CD spectral analysis and immunostaining with conformation-dependent antibodies indicated that tau may undergo conformational changes during fibril formation. Enriched granules generated filaments, suggesting that granular tau aggregates may be an intermediate form of tau fibrils. The amount of granular tau aggregates was elevated in prefrontal cortex of Braak stage I cases compared to that of Braak stage 0 cases, suggesting that granular tau aggregation precedes PHF formation. Thus, granular tau aggregates may be a relevant marker for the early diagnosis of tauopathy. Reducing the level of these aggregates may be a promising therapy for tauopathies and for promoting healthy brain aging.

Yuko Saito

Papers

Accumulation of Phosphorylated α-Synuclein in Aging Human Brain

TMEM119 marks a subset of microglia in the human brain

Staging of argyrophilic grains: an age-associated tauopathy.

Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease.

Granular tau oligomers as intermediates of tau filaments.