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.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

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Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. Although risk stratification of patients with MB based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon. In this study, we investigated the potential of rapid tumor characterization with Picosecond infrared laser desorption mass spectrometry (PIRL-MS) for MB subgroup classification based on small molecule signatures. One hundred and thirteen ex vivo MB tumors from a local tissue bank were subjected to 10-to 15-second PIRL-MS data collection and principal component analysis with linear discriminant analysis (PCA-LDA). The MB subgroup model was established from 72 independent tumors; the remaining 41 de-identified unknown tumors were subjected to multiple, 10-second PIRL-MS samplings and real-time PCA-LDA analysis using the above model. The resultant 124 PIRL-MS spectra from each sampling event, after the application of a 95% PCA-LDA prediction probability threshold, yielded a 98.9% correct classification rate. Post-ablation histopathologic analysis suggested that intratumoral heterogeneity or sample damage prior to PIRL-MS sampling at the site of laser ablation was able to explain failed classifications. Therefore, upon translation, 10-seconds of PIRL-MS sampling is sufficient to allow personalized, subgroup-specific treatment of MB during surgery.Significance: This study demonstrates that laser-extracted lipids allow immediate grading of medulloblastoma tumors into prognostically important subgroups in 10 seconds, providing medulloblastoma pathology in an actionable manner during surgery.

Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.RÉSUMÉ: L'initiative de recherche sur les maladies neurodégénératives en Ontario. La démence constituant la manifestation d'un trouble neurodégénératif ou neurovasculaire, il importe de mettre au point des approches fiables permettant son identification. Nous somme ainsi en train de mener une étude observationnelle -Initiative de recherche sur les maladies neurodégénératives en Ontario ou « ONDRI » -qui inclut l'analyse du génome, la neuro-imagerie et diverses techniques d'évaluation en lien avec les aspects suivants : la cognition, le langage, la démarche, l'imagerie rétinienne et le suivi du regard. Parmi les affections à l'étude, on peut mentionner la maladie d'Alzheimer, la sclérose latérale amyotrophique, la démence fronto-temporale, la maladie de Parkinson et la déficience cognitive vasculaire. Les données de l'ONDRI seront recueillies à partir de la base de données du Brain-CODE afin de faciliter les analyses de corrélation. De plus, l'ONDRI entend fournir un répertoire des endophénotypes associés aux sujets de recherche, répertoire unique en son genre qui sera accessible au public.

The in-plane nearest-neighbor Heisenberg magnetic coupling constant, J, of La 2 CuO 4 , Nd 2 CuO 4 , Sr 2 CuO 2 Cl 2 , YBa 2 Cu 3 O 6 , and undoped HgBa 2 Ca n21 Cu n O 2n121d (n 1, 2, 3) is calculated from accurate ab initio configuration interaction calculations. For the first four compounds, the theoretical J values are in quantitative agreement with experiment. For the Hg-based compounds the predicted values are 2135 meV (n 1) and ϳ2160 meV (n 2, 3), the latter being much larger than in previous cases and, for n 3, increasing with pressure. Nevertheless, the physics governing J in all these layered cuprates appears to be the same. Moreover, calculations suggest a possible relationship between J and T c . PACS numbers: 74.25.Jb, 74.25.Ha, 75.30.Et More than ten years have passed since the discovery of the high-T c superconductivity in several cuprate compounds and, up to now, there has been no agreement on a complete theory capable of explaining their anomalous physical properties [1]. The layered crystal structure, the strong antiferromagnetic coupling between neighbor Cu 21 ions in these layers, and the strongly correlated nature of their electronic structure have been pointed out to play a very important role in the fundamental mechanisms of superconductivity [1,2]. The high-T c superconductors are produced by moderate doping of "parent compounds" such as La 2 CuO 4 , Nd 2 CuO 4 , or YBa 2 Cu 3 O 6 . It is widely accepted that proximity to the insulating phase and the interaction of dopant carriers with magnetic degrees of freedom are fundamental aspects for the existence of high-T c superconductivity. Recent theories strongly suggest that magnetic coupling is at the very origin of the superconducting state [2]. Thus, the magnetic coupling constants defining the magnetic structure of these compounds are key magnitudes in establishing trends and theories based on model Hamiltonians.Recently, several families of layered cuprates, containing Bi, Tl, or Hg, have been synthesized. The HgBa 2 Ca n21 Cu n O 2n121d (n 1, 2, 3) family [3][4][5] includes HgBa 2 Ca 2 Cu 3 O 81d , the compound with the highest transition temperature observed to date (133 K at ambient pressure and 164 K under 31 GPa) [4,6,7]. The difficult synthesis and the layered structure of those materials limits the capability of obtaining pure crystals large enough to perform accurate measurements of their magnetic properties. This restricts the theoretical understanding due to the difficulty to obtain reliable estimates of the model Hamiltonian parameters. Modern theoretical approaches to electronic structure could provide accurate values of these parameters, such as the nearest-neighbor Heisenberg magnetic coupling constant J, thus providing a more detailed description of these materials.Unfortunately, because of the strong correlated nature of the electronic structure and the antiferromagnetic insulating character of these cuprates, band structure calculations based on the local density approximation (LDA) or on the generalized gradient app...

ObjectiveThe Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same PD subjects vs healthy controls (HC).MethodsS4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and non-motor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA.ResultsThe final cohort included 59 PD and 21 HC. CSF α-synuclein was lower in PD vs HC; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2% respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100% respectively. There were no significant relationships between different measures of α-synuclein within subjects.ConclusionsS4 confirms lower total α-synuclein levels in CSF in PD compared to HC, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within subjects across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed.Classification of evidenceThis study provides Class III evidence that total CSF α-synuclein does not accurately distinguish PD from HC, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.

Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.