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To investigate how the fatty acid composition of brain phospholipids influences brain-specific processes, we leveraged the AdipoR2 (adiponectin receptor 2) knockout mouse model in which the brain is enlarged, and cellular membranes are excessively rich in saturated fatty acids. Lipidomics analysis of brains at 2, 7, and 18 months of age showed that phosphatidylcholines, which make up about two-thirds of all cerebrum membrane lipids, contain a gross excess of saturated fatty acids in AdipoR2 knockout mice, and that this is mostly attributed to an excess palmitic acid (C16:0) at the expense of oleic acid (C18:1), consistent with a defect in fatty acid desaturation and elongation in the mutant. Specifically, there was a ~12% increase in the overall saturated fatty acid content within phosphatidylcholines and a ~30% increase in phosphatidylcholines containing two palmitic acids. Phosphatidylethanolamines, sphingomyelins, ceramides, lactosylceramides, and dihydroceramides also showed an excess of saturated fatty acids in the AdipoR2 knockout mice while nervonic acid (C24:1) was enriched at the expense of shorter saturated fatty acids in glyceroceramides. Similar defects were found in the cerebellum and myelin sheaths. Histology showed that cell density is lower in the cerebrum of AdipoR2 knockout mice, but electron microscopy did not detect reproducible defects in the ultrastructure of cerebrum neurons, though proteomics analysis showed an enrichment of electron transport chain proteins in the cerebellum. Behavioral tests showed that older (33 weeks old) AdipoR2 knockout mice are hyperactive and anxious compared to control mice of a similar age. Also, in contrast to control mice, the AdipoR2 knockout mice do not gain weight in old age but do have normal lifespans. We conclude that an excess fatty acid saturation in brain phospholipids is accompanied by hyperactivity but seems otherwise well tolerated., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

In early neurodevelopment, the central nervous system is established through the coordination of various neural organizers directing tissue patterning and cell differentiation. Better recapitulation of morphogen gradient production and signaling will be crucial for establishing improved developmental models of the brain in vitro. Here, we developed a method by assembling polydimethylsiloxane devices capable of generating a sustained chemical gradient to produce patterned brain organoids, which we termed morphogen-gradient-induced brain organoids (MIBOs). At 3.5 weeks, MIBOs replicated dorsal-ventral patterning observed in the ganglionic eminences (GE). Analysis of mature MIBOs through single-cell RNA sequencing revealed distinct dorsal GE-derived CALB2 + interneurons, medium spiny neurons, and medial GE-derived cell types. Finally, we demonstrate long-term culturing capabilities with MIBOs maintaining stable neural activity in cultures grown up to 5.5 months. MIBOs demonstrate a versatile approach for generating spatially patterned brain organoids for embryonic development and disease modeling., Competing Interests: Declaration of interests The authors listed (Y.S., C.P., F.Y., and N.P. ) have filed a provisionary patent related to this work (Docket Number: UMA 23-023, Title: “A chemical gradient inducing device and methods for developing patterned organoids.”)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite substantial evidence indicating a close link between action production and perception in early child development, less is known about how action experience shapes the processes of perceiving and anticipating others' actions. Here, we developed a novel approach to capture functional connectivity specific to certain brain areas to investigate how action experience changes the networks involved in action perception and anticipation. Nine- and-12-month-old infants observed familiar (grasping) and novel (tool-use) actions while their brain activity was measured using EEG. Infants' motor competence of both actions was assessed. A link between action experience and connectivity patterns was found, particularly during the anticipation period. During action anticipation, greater motor competence in grasping predicted greater functional connectivity between visual (occipital alpha) and motor (central alpha) regions relative to global levels of whole-brain EEG connectivity. Furthermore, visual and motor regions tended to be more coordinated in response to familiar versus novel actions and for older than younger participants. Critically, these effects were not found in the control networks (frontal-central; frontal-occipital; parietal-central; parietal-occipital), suggesting a unique role of visual-motor networks on the link between motor skills and action encoding. HIGHLIGHTS: Infants' motor development predicted functional connectivity patterns during action anticipation. Faster graspers, and older infants, showed a stronger ratio of visual-motor neural coherence. Overall whole-brain connectivity was modulated by age and familiarity with the actions. Measuring inter-site relative to whole-brain connectivity can capture specific brain-behavior links. Measures of phase-based connectivity over time are sensitive to anticipatory action., (© 2022 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

Introduction: Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized., Methods: We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non-AD neuropathologies and tauopathies. Thioflavin-S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases., Results: Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin-S. Hippocampal burden generally increased with each Braak stage., Discussion: These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset., Highlights: Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline-rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi-quantitative frequency to calculate tangle maturity frequency., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The last decade has seen increased availability of mobile electroencephalography (EEG). These mobile systems enable researchers to conduct data collection "in-context," reducing participant burden and potentially increasing diversity and representation of research samples. Our research team completed in-home data collection from more than 400 twelve-month-old infants from low-income backgrounds using a mobile EEG system. In this paper, we provide methodological and analytic guidance for collecting high-quality, mobile EEG in infants. Specifically, we offer insights and recommendations for equipment selection, data collection, and data analysis, highlighting important considerations for selecting a mobile EEG system. Examples include the size of the recording equipment, electrode type, reference types, and available montages. We also highlight important recommendations surrounding preparing a nonstandardized recording environment for EEG collection, obtaining informed consent from parents, instructions for parents during capping and recording, stimuli and task design, training researchers, and monitoring data as it comes in. Additionally, we provide access to the analysis code and demonstrate the robustness of the data from a recent study using this approach, in which 20 artifact-free epochs achieve good internal consistency reliability. Finally, we provide recommendations and publicly available resources for future studies aiming to collect mobile EEG., (© 2021 Wiley Periodicals LLC.)

EEG measures such as power and connectivity have been widely used to investigate the neuronal underpinnings of ADHD. Traditionally, the fixed band analysis, in which a single frequency band is applied to all the subjects, has been used to estimate these EEG measures. However, there are important interindividual differences in the predominant frequency of alpha-band oscillations. In this study, we present an individualized estimate of EEG in the alpha band and compared the results with traditional fixed band analysis. We also examined the EEG profile separately in lower and upper alpha bands. We further examined the association between EEG measures and ADHD symptoms. Eyes closed resting EEG was collected from 21 adolescents with clinically elevated levels of ADHD and 21 age and gender matched control subjects. Spectral power and connectivity were computed in lower and upper alpha bands. Results revealed a dissociation between upper and lower alpha band power and connectivity in ADHD. The ADHD group showed reduced power and connectivity in the lower alpha band and an elevation of upper alpha power compared to the Control group. EEG power in the lower alpha band was negatively associated with ADHD severity. Our results, however, did not provide conclusive evidence for IAF as an overall greater measure of EEG compared to the traditional fixed band method., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established., Objective: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance., Methods: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline., Results: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline., Conclusion: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

Background: α-Synuclein (α-syn) is a pre-synaptic protein which progressively accumulates in neuronal and non-neuronal cells in neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders., Methods: To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of α-syn transgenic (tg) mice (e.g., Thy1 promoter line 61) and DLB patients., Results: Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of α-syn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and expression of pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells in the brains of α-syn tg mice revealed that CD1d-tet+ T cells were also increased in the brains of α-syn tg mice suggestive of natural killer T cells. In post-mortem DLB brains, we similarly detected increased numbers of infiltrating CD3+/CD4+ T cells in close proximity with blood vessels., Conclusion: These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

Exposure to early psychosocial deprivation as a result of institutional care disrupts typical brain development. The Bucharest Early Intervention Project (BEIP) is the first longitudinal study to investigate the neurodevelopment of institutionalized infants randomized to a foster care (FCG) intervention versus care as usual (CAUG). Here, we present findings from a follow-up assessment of brain electrical activity as indexed by resting EEG at age 16 years. In addition, we examined the effects of disruption of foster care placement (e.g. the number of moves among foster care placements) on brain electrical activity. Resting-state EEG was collected from 48 CAUG, 46 FCG and 48 never institutionalized (NIG) control participants. Absolute (µV 2 ) and relative (proportion) power were computed from eyes closed, resting EEG data for theta, alpha and beta frequency bands. The CAUG displayed higher relative theta and lower relative alpha power compared to the FCG at 16 years of age. The FCG showed brain activity comparable to the NIG. The results further showed that disruptions following the original foster care placement had an adverse effect on brain electrical activity. Within the foster care group, there were no effects of age of placement on EEG power. Placement of children who have experienced early institutional rearing into stable foster care settings ensure long-term improvement in brain functioning., (© 2019 John Wiley & Sons Ltd.)

Purpose: To study the imaging patterns of Posterior cortical atrophy (PCA) and Dementia with Lewy bodies (DLB) on fluoro-deoxyglucose positron emission tomography computed tomography ([F]FDG PET/CT), identify areas of overlap and differences and to develop a prediction model to assist in diagnosis using univariate and multivariate analysis., Methods: A retrospective analysis of 72 patients clinically suspected of having posterior dementia was done. All patients underwent [FF]FDG PET/CT of the brain and dopamine transporter imaging with [[Tc]TRODAT-1 SPECT scan on separate days. The patients were divided into PCA with normal TRODAT uptake (n=34) and DLB with abnormal TRODAT uptake (n=38). The FDG PET/CT uptake patterns were recorded and areas of significant hypometabolism by z score analysis were considered as abnormal. Receiver operator characteristics (ROC) curve analysis was used to determine cutoff z scores and binary logistic regression analysis was used to determine the Odds ratio of being in the predicted groups., Results: Significantly hypometabolism was found in parieto-temporo-occipital association cortices and cingulate cortices in PCA patients. DLB patients showed significantly reduced uptake in the visual cortex. No significant difference was found between z score of occipital association cortex which showed hypometabolism in both groups. The cut-off z-score values derived from the ROC curve analysis were as follows- parietal association (cut-off-3, sensitivity-65.6%, specificity - 68.7%), temporal association (cut-off-2, sensitivity-78%, specificity-75%) and posterior cingulate (cut-off-0.5, sensitivity-93.7%, specificity-40.6%), their respective Odds ratio (with 95% confidence interval) for being in the PCA group as derived from univariate logistic regression were 3.66 (1.30-10.32), 10.71 (3.36-34.13) and 7.85 (1.57-39.17). The cut-off z score of primary visual cortex as derived from ROC curve was zero with sensitivity of 87.5%, specificity of 71.9%, and the Odds ratio for being the in the DLB group was 24.7 with 95% confidence interval of 5.99-101.85., Conclusion: [F]FDG PET may be useful as a non-invasive diagnostic modality in differentiating the two posterior cortical dementias, despite significant overlap. Primary visual cortical hypometabolism can serve as an independent diagnostic marker for DLB, even in the absence of TRODAT imaging.

Functional magnetic resonance imaging is a noninvasive tool for studying cerebral function. Many factors challenge activation detection, especially in low-signal scenarios that arise in the performance of high-level cognitive tasks. We provide a fully automated fast adaptive smoothing and thresholding (FAST) algorithm that uses smoothing and extreme value theory on correlated statistical parametric maps for thresholding. Performance on experiments spanning a range of low-signal settings is very encouraging. The methodology also performs well in a study to identify the cerebral regions that perceive only-auditory-reliable or only-visual-reliable speech stimuli.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia., Methods: In this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods., Results: We found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia., Conclusions: The results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Remyelination requires the generation of new oligodendrocytes (OLs), which are derived from oligodendrocyte progenitor cells (OPCs). Maturation of OPCs into OLs is a multi-step process. Here, we describe a microRNA expressed by OLs, miR-27a, as a regulator of OL development and survival. Increased levels of miR-27a were found in OPCs associated with multiple sclerosis (MS) lesions and in animal models of demyelination. Increased levels of miR-27a led to inhibition of OPC proliferation by cell-cycle arrest, as well as impaired differentiation of human OPCs (hOPCs) and myelination by dysregulating the Wnt-β-catenin signaling pathway. In vivo administration of miR-27a led to suppression of myelinogenic signals, leading to loss of endogenous myelination and remyelination. Our findings provide evidence supporting a critical role for a steady-state level of OL-specific miR-27a in supporting multiple steps in the complex process of OPC maturation and remyelination., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases., Methods: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539)., Results: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups., Discussion: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Functional magnetic resonance imaging (fMRI) is an MRI-based neuroimaging technique that measures brain activity on the basis of blood oxygenation level. This study reviews the main fMRI methods reported in the literature and their related applications in clinical and preclinical studies, focusing on relating functional brain networks in the prodromal stages of Alzheimer's disease (AD), with a focus on the transition phases from cognitively normal (CN) to mild cognitive impairment (MCI) and from MCI to AD., New Method: The purpose of this study is to present and compare different approaches of supervised and unsupervised fMRI analyses and to highlight the different applications of fMRI in the diagnosis of MCI and AD., Results: Survey article asserts that brain network disruptions of a given dysfunction or in relation to disease prone areas of the brain in neurodegenerative dementias could be extremely useful in ascertaining the extent of cognitive deficits at the different stages of the disease. Identifying the earliest changes in these activity patterns is essential for the early planning of treatment and therapeutic protocols., Comparison With Existing Methods: Analysis methods such as independent component analysis (ICA) and graph theory-based approaches are strong analytical techniques most suitable for functional connectivity investigations. However, graph theory-based approaches have received more attention due to the higher performance they achieve in both functional and effective connectivity studies., Conclusion: This article shows that the disruption of brain connectivity patterns of MCI and AD could be associated with cognitive decline, an interesting finding that could augment the prospects for early diagnosis. More importantly, results reveal that changes in functional connectivity as obtained through fMRI precede detection of cortical thinning in structural MRI and amyloid deposition in positron emission tomography (PET). However, a major challenge in using fMRI as a single imaging modality, like all other imaging modalities used in isolation, is in relating a particular disruption in functional connectivity in relation to a specific disease. This is a challenge that requires more thorough investigation, and one that could perhaps be overcome through multimodal neuroimaging by consolidating the strengths of these individual imaging modalities., (Copyright © 2018. Published by Elsevier B.V.)

There is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology. We developed the Pten m3m4 mouse, where Pten is largely restricted from the nucleus, which recapitulates patient-like, autism-related phenotypes: behavioral changes, macrocephaly, and white matter abnormalities. This study aimed to investigate the contribution of oligodendrocyte (OL) lineage differentiation and functional changes in myelination to the white matter phenotype. OL lineage differentiation and myelination in Pten m3m4 mice was studied using immunohistochemical and electron microscopic analyses. We also used primary oligodendrocyte progenitor cells (OPCs) to determine the effect of the Pten m3m4 mutation on OPC proliferation, migration and maturation. Finally, we assessed the myelinating competency of mutant OLs via co-culture with wildtype dorsal root ganglia (DRG) neurons. The in vivo analyses of Pten m3m4/m3m4 murine brains showed deficits in proteolipid protein (Plp) trafficking in myelinating OLs. Despite the increased expression of myelin proteins in the brain, myelin deposition was observed to be abnormal, often occurring adjacent to, rather than around axons. Mutant primary OPCs showed enhanced proliferation and migration. Furthermore, mutant OPCs matured precociously, exhibiting aberrant myelination in vitro. Mutant OPCs, when co-cultured with wildtype DRG neurons, showed an inability to properly ensheath axons. Our findings provide evidence that the Pten m3m4 mutation disrupts the differentiation and myelination programs of developing OLs. OL dysfunction in the Pten m3m4 model explains the leukodystrophy phenotype, a feature commonly associated with autism, and highlights the growing importance of glial dysfunction in autism pathogenesis.

Background: Regional cortical thickness (rCTh) among cognitively normal (CN) adults (rCThCN) varies greatly between brain regions, as does the vulnerability to neurodegeneration., Objective: The goal of this study was to: 1) rank order rCThCN for various brain regions, and 2) explore their vulnerability to neurodegeneration in Alzheimer's disease (AD) within these brain regions., Methods: The relationship between rCTh among the CN group (rCThCN) and the percent difference in CTh (% CThDiff) in each region between the CN group and AD patients was examined. Pearson correlation analysis was performed accounting for amyloid-β (Aβ) protein and APOE genotype using 210 age, gender, and APOE matched CN (n = 105, age range: 56-90) and AD (n = 105, age range: 56-90) ADNI participants., Results: Strong positive correlations were observed between rCThCN and % CThDiff accounting for Aβ deposition and APOE status. Regions, such as the entorhinal cortex, which had the greatest CTh in the CN state, were also the regions which had the greatest % CThDiff., Conclusions: Regions with the greatest CTh at the CN stage are found to aggregate in disease prone regions of AD, namely in the medial temporal lobe, including the temporal pole, ERC, parahippocampal gyrus, fusiform and the middle and inferior temporal gyrus. Although rCTh has been found to vary considerably across the different regions of the brain, our results indicate that regions with the greatest CTh at the CN stage are actually regions which have been found to be most vulnerable to neurodegeneration in AD.

Mu desynchronization is the attenuation of EEG power in the alpha frequency range recorded over central scalp locations thought to reflect motor cortex activation. Mu desynchronization during observation of an action is believed to reflect mirroring system activation in humans. However, this notion has recently been questioned because, among other reasons, the potential contamination of mu rhythm and occipital alpha activity induced by attention processes following presentation of visual stimuli in observation conditions. This study examined the validity of mu desynchronization as a measure of mirroring system activation in infants and further investigated the pattern of functional connectivity between the central and occipital regions during execution and observation of movement. EEG was recorded while 46 9-month-old infants executed grasping actions and observed an experimenter grasping. Current source density (CSD) was applied to EEG data and, time-frequency and connectivity analyses were performed in CSD transformed data. Mu desynchronization was evident over central regions during both execution and observation of movements. Independent alpha desynchronization over occipital region was also present in both conditions. The connectivity analyses revealed that central-occipital areas were functionally more connected compared to other areas of the brain during observation of movements. Collectively, the results demonstrate the validity of mu desynchronization as an index of infant mirroring system activity and support the proposal of a functional connection between distinct mirroring and attention processes during observation of action., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Women reportedly make up two-thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.

Over the past few years, several approaches have been proposed to assist in the early diagnosis of Alzheimer's disease (AD) and its prodromal stage of mild cognitive impairment (MCI). Using multimodal biomarkers for this high-dimensional classification problem, the widely used algorithms include Support Vector Machines (SVM), Sparse Representation-based classification (SRC), Deep Belief Networks (DBN) and Random Forest (RF). These widely used algorithms continue to yield unsatisfactory performance for delineating the MCI participants from the cognitively normal control (CN) group. A novel Gaussian discriminant analysis-based algorithm is thus introduced to achieve a more effective and accurate classification performance than the aforementioned state-of-the-art algorithms. This study makes use of magnetic resonance imaging (MRI) data uniquely as input to two separate high-dimensional decision spaces that reflect the structural measures of the two brain hemispheres. The data used include 190 CN, 305 MCI and 133 AD subjects as part of the AD Big Data DREAM Challenge #1. Using 80% data for a 10-fold cross-validation, the proposed algorithm achieved an average F1 score of 95.89% and an accuracy of 96.54% for discriminating AD from CN; and more importantly, an average F1 score of 92.08% and an accuracy of 90.26% for discriminating MCI from CN. Then, a true test was implemented on the remaining 20% held-out test data. For discriminating MCI from CN, an accuracy of 80.61%, a sensitivity of 81.97% and a specificity of 78.38% were obtained. These results show significant improvement over existing algorithms for discriminating the subtle differences between MCI participants and the CN group.

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were β-amyloid positive vs those who were β-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression., Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD., Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018., Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures., Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD., Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive β-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model., Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

Background: The impact of amyloid positron emission tomography (Aβ-PET) in a "real-world" memory disorders clinic remains poorly studied., Objective: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management., Methods: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans., Results: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001)., Conclusions: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

Background: Available therapies for Alzheimer's disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information., Objective: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors., Methods: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors., Results: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874)., Conclusions: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials.

Background: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer's disease (AD)., Objective: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults., Methods: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups., Results: Relative to traditional neuropsychological measures, MCI patients' failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = -0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = -0.49), the failure to recover from PSI (rs = -0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = -0.48)., Discussion: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation.

Background: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer's disease (AD) prone regions and with risk for cognitive impairment., Objective: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4-), Aβ status (Amy+∖Amy-), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI., Methods: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Aβ and APOE4 status and age were examined., Results: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4-participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status., Conclusion: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression.

Objective: To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders., Methods: Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures., Results: LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain., Conclusion: Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Mirror therapy (MT) is an increasingly employed method aimed at reducing phantom pain and other negative sensations following loss of a limb or damage to sensorimotor systems. However, the brain processes associated with the perception of limb ownership, a key correlate of MT, are unknown., Objective: To examine whether transient perceptions of limb ownership together with associated neural activity can be elucidated using a purpose-developed mirror reflection task combined with electrophysiological (EEG) measures and cutting-edge analyses., Methods: Brain activity was measured online using EEG in 20 healthy controls while they produced opening-closing movements of one hand in control conditions or while viewing the mirror reflection of the movements. The key experimental condition required participants to make a foot pedal response whenever a change in perception of ownership (of a mirror-reflected limb) occurred (Mirror condition). Control conditions and a strict epoching regime were employed using standard subtractive logic to isolate the perception of limb ownership (which was further verified by self-reports)., Results: Data from 15 participants were suitable for complete analysis; the remaining reported no experience of ownership. Significant spectral power increases were found in central-parietal regions in association with perceptions of ownership, with the most prominent effect specific to the alpha frequency band (8-13 Hz) measured at the right parietal area. Source localization analyses further identified brain networks associated with the mirror reflection condition in the alpha frequency (parietal lobe) and the beta frequency (middle temporal areas). These were distinct from localized networks associated with the foot pedal response., Conclusion: Transient perceptions of ownership can be captured experimentally, and are associated with localized sites of neural activation. This is an initial step toward eventual development of therapeutic targets for interventions including brain computer interfaces (BCIs) aimed at ameliorating the negative effects associated with impaired or missing limbs.

Intranasal administration can potentially deliver drugs to the brain because of the proximity of the delivery site to the olfactory lobe. We prepared triturates of micronized or crystalline zolmitriptan with a GRAS substance, nicotinamide, to form a eutectic. We characterized the formulation using differential scanning calorimetry, powder X-ray diffraction, and FTIR spectroscopy to confirm its eutectic nature and generated a phase diagram. The eutectic formulation was aerosolized using an in-house insufflator into the nares of rats. Groups of rats received zolmitriptan intravenously or intranasally, or intranasal eutectic formulation. Zolmitriptan was estimated in the olfactory lobe, cerebral cortex, cerebellum, and blood plasma at different time-points by LC-MS. Pharmacokinetics in these tissues indicated the superiority of the intranasal eutectic formulation for brain targeting when compared with results of IV solution and intranasal pure zolmitriptan powder. Enhancement of nose-to-brain transport is likely to have resulted from more rapid dissolution of the eutectic as compared to pure drug.

Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothyronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders., Methods: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging., Results: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed., Conclusions: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNA(exp)). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNA(exp) in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuroimaging research is usually conducted in volunteers who meet a priori selection criteria. Selection/volunteer bias is assumed but cannot be assessed. During an ongoing population-based cohort study of 1982 older adults, we asked 1702 active participants about their interest in undergoing a research brain scan. Compared with those not interested, the 915 potentially interested individuals were significantly younger, more likely to be male, better educated, generally healthier, and more likely to be cognitively intact and dementia-free. In 48 of the interested individuals, we conducted a previously reported pilot structural magnetic resonance imaging (sMRI) study modelling mild cognitive impairment (MCI) vs. normal cognition, and Clinical Dementia Rating (CDR) = 0.5 vs. CDR = 0, as a function of sMRI atrophy ratings. We now compare these 48 individuals (1) with all interested participants, to assess selection bias; (2) with all who had been asked about their interest, to assess volunteer bias; and (3) with the entire study cohort, to assess attrition bias from those who had dropped out before the question was asked. Using these data in propensity score models, we generated weights which we applied to logistic regression models reanalyzing the data from the pilot sMRI study. These weighted models adjusted, in turn, for selection bias, interest/volunteer bias, and attrition bias. They show fewer regions of interest to be associated with MCI/ CDR than were in the original unweighted models. When study participants are drawn from a well-characterized population, they can be compared with non-participants, and the information used to correct study results for potential bias and thus provide more generalizable estimates.

Background: Intracranial volume (ICV) is an important normalization measure used in morphometric analyses to correct for head size in studies of Alzheimer Disease (AD). Inaccurate ICV estimation could introduce bias in the outcome. The current study provides a decision aid in defining protocols for ICV estimation in patients with Alzheimer disease in terms of sampling frequencies that can be optimally used on the volumetric MRI data, and the type of software most suitable for use in estimating the ICV measure., Methods: Two groups of 22 subjects are considered, including adult controls (AC) and patients with Alzheimer Disease (AD). Reference measurements were calculated for each subject by manually tracing intracranial cavity by the means of visual inspection. The reliability of reference measurements were assured through intra- and inter- variation analyses. Three publicly well-known software packages (Freesurfer, FSL, and SPM) were examined in their ability to automatically estimate ICV across the groups., Results: Analysis of the results supported the significant effect of estimation method, gender, cognitive condition of the subject and the interaction among method and cognitive condition factors in the measured ICV. Results on sub-sampling studies with a 95% confidence showed that in order to keep the accuracy of the interleaved slice sampling protocol above 99%, the sampling period cannot exceed 20 millimeters for AC and 15 millimeters for AD. Freesurfer showed promising estimates for both adult groups. However SPM showed more consistency in its ICV estimation over the different phases of the study., Conclusions: This study emphasized the importance in selecting the appropriate protocol, the choice of the sampling period in the manual estimation of ICV and selection of suitable software for the automated estimation of ICV. The current study serves as an initial framework for establishing an appropriate protocol in both manual and automatic ICV estimations with different subject populations.

Brain atrophy in mild cognitive impairment (MCI) and Alzheimer's disease (AD) are difficult to demarcate to assess the progression of AD. This study presents a statistical framework on the basis of MRI volumes and neuropsychological scores. A feature selection technique using backward stepwise linear regression together with linear discriminant analysis is designed to classify cognitive normal (CN) subjects, early MCI (EMCI), late MCI (LMCI), and AD subjects in an exhaustive two-group classification process. Results show a dominance of the neuropsychological parameters like MMSE and RAVLT. Cortical volumetric measures of the temporal, parietal, and cingulate regions are found to be significant classification factors. Moreover, an asymmetrical distribution of the volumetric measures across hemispheres is seen for CN versus EMCI and EMCI versus AD, showing dominance of the right hemisphere; whereas CN versus LMCI and EMCI versus LMCI show dominance of the left hemisphere. A 2-fold cross-validation showed an average accuracy of 93.9%, 90.8%, and 94.5%, for the CN versus AD, CN versus LMCI, and EMCI versus AD, respectively. The accuracy for groups that are difficult to differentiate like EMCI versus LMCI was 73.6%. With the inclusion of the neuropsychological scores, a significant improvement (24.59%) was obtained over using MRI measures alone.

This paper proposes to combine MRI data with a neuropsychological test, mini-mental state examination (MMSE), as input to a multi-dimensional space for the classification of Alzheimer's disease (AD) and it's prodromal stages-mild cognitive impairment (MCI) including amnestic MCI (aMCI) and nonamnestic MCI (naMCI). The decisional space is constructed using those features deemed statistically significant through an elaborate feature selection and ranking mechanism. FreeSurfer was used to calculate 55 volumetric variables, which were then adjusted for intracranial volume, age and education. The classification results obtained using support vector machines are based on twofold cross validation of 50 independent and randomized runs. The study included 59 AD, 67 aMCI, 56 naMCI, and 127 cognitively normal (CN) subjects. The study shows that MMSE scores contain the most discriminative power of AD, aMCI, and naMCI. For AD versus CN, the two most discriminative volumetric variables (right hippocampus and left inferior lateral ventricle), when combined with MMSE scores, provided an average accuracy of 92.4% (sensitivity: 84.0%; specificity: 96.1%). MMSE scores are found to improve all classifications with accuracy increments of 8.2% and 12% for aMCI versus CN and naMCI versus CN, respectively. Results also show that brain atrophy is almost evenly seen on both sides of the brain for AD subjects, which is different from right-side dominance for aMCI and left-side dominance for naMCI. Furthermore, hippocampal atrophy is seen to be the most significant for aMCI, while Accumbens area and ventricle are most significant for naMCI.

Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

Purpose of Review: The predominant clinical disease course of multiple sclerosis starts with reversible episodes of neurological disability, which transforms into progressive neurological decline. This review provides insight into the pathological differences during relapsing and progressive phases of multiple sclerosis., Recent Findings: The clinical course of multiple sclerosis is variable, and the disease can be classified into relapsing and progressive phases. Pathological studies have been successful in distinguishing between these two forms of the disease and correlate with the clinical findings in terms of cellular responses, the inflammatory environment, and the location of lesions., Summary: Available therapies for multiple sclerosis patients, while effective during the relapsing phase, have little benefit for progressive multiple sclerosis patients. Development of therapies to benefit progressive multiple sclerosis patients will require a better understanding of the pathogenesis of progressive multiple sclerosis. This review discusses and compares the pathological findings in relapsing and progressive multiple sclerosis patients.

Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from human multiple sclerosis-affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis-affected brains than in controls, while genes related to proteolytic processing (for example, LGMN, CTSZ) were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis-affected brains.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with an unknown etiology. The clinical disease course is variable, with the majority of patients experiencing reversible episodes of neurological disability in the third or fourth decade of life, eventually followed by a state of irreversible progression. Continuous axonal and neuronal loss is thought to be the major cause of this progression. Over the last decade, extensive research has targeted the gray matter and its role in MS pathogenesis. While pathological and imaging studies have begun to reveal important clues about the role of cortical pathology, gene expression studies in MS cortex are still emerging. Microarray-based comparative gene expression profiling provides a snapshot of genes underlying a particular condition and has been performed using brain tissues from patients with progressive MS. In this review, we summarize existing data from gene expression changes in cortical tissues from MS brains and how they may provide clues to the pathogenesis.

Diffusion Tensor Imaging (DTI) technique is widely used to probe the white matter (WM) tracts, which is affected most by neurological disorders. The fractional anisotropy (FA) metric has been used predominantly to study changes in the WM tracts. Here an attempt is made to delineate specific regions of interest in the WM that may be probable indicators for the diagnosis of Alzheimer disease (AD). Genetic algorithm has been used as feature reduction method along with Adaptive Boosting (AdaBoost) machine learning technique to determine the most prominent regions in the WM that are indicators of AD. It is found in this study that Fornix region of WM is most affected by Alzheimer. Further, classification was done to differentiate between Alzheimer and Normal controls with accuracy of 84.5%. The results obtained were validated by comparing with the existing literature on Alzheimer.

Objectives: Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location., Methods: This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH., Results: From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤ 2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH., Conclusions: APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.

Alzheimer's disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.

Background: The segmentation of brain structures on magnetic resonance imaging scans for calculating regional brain volumes, using automated anatomic labeling, requires the use of both brain atlases and templates (template sets). This study aims to improve the accuracy of volumetric analysis of hippocampus (HP) and amygdala (AMG) in the assessment of early Alzheimer's disease (AD) by developing template sets that correspond more closely to the brains of elderly individuals., Methods: Total intracranial volume and HP and AMG volumes were calculated for elderly subjects with no cognitive impairment (n = 103), with amnestic mild cognitive impairment (n = 68), or with probable AD (n = 46) using the following: (1) a template set consisting of a standard atlas (atlas S), drawn on a young adult male brain, and the widely used Montreal Neurological Institute template (MNI template set); (2) a template set (template S set) in which the template is based on smoothing the image from which atlas S is derived; and (3) a new template set (template E set) in which the template is based on an atlas (atlas E) created from the brain of an elderly individual., Results: Correspondence to HP and AMG volumes derived from manual segmentation was highest with automated segmentation by template E set, intermediate with template S set, and lowest with the MNI template set. The areas under the receiver operating curve for distinguishing elderly subjects with no cognitive impairment from elderly subjects with amnestic mild cognitive impairment or probable AD and the correlations between HP and AMG volumes and cognitive and functional scores were highest for template E set, intermediate for template S set, and lowest for the MNI template set., Conclusions: The accuracy of automated anatomic labeling and the diagnostic value of the derived volumes are improved with template sets based on brain atlases closely resembling the anatomy of the to-be-segmented brain magnetic resonance imaging scans., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Population-based studies face challenges in measuring brain structure relative to cognitive aging. We examined the feasibility of acquiring state-of-the-art brain MRI images at a community hospital, and attempted to cross-validate two independent approaches to image analysis., Methods: Participants were 49 older adults (29 cognitively normal and 20 with mild cognitive impairment (MCI)) drawn from an ongoing cohort study, with annual clinical assessments within one month of scan, without overt cerebrovascular disease, and without dementia (Clinical Dementia Rating (CDR) < 1). Brain MRI images, acquired at the local hospital using the Alzheimer's Disease Neuroimaging Initiative protocol, were analyzed using (1) a visual atrophy rating scale and (2) a semi-automated voxel-level morphometric method. Atrophy and volume measures were examined in relation to cognitive classification (any MCI and amnestic MCI vs. normal cognition), CDR (0.5 vs. 0), and presumed etiology., Results: Measures indicating greater atrophy or lesser volume of the hippocampal formation, the medial temporal lobe, and the dilation of the ventricular space were significantly associated with cognitive classification, CDR = 0.5, and presumed neurodegenerative etiology, independent of the image analytic method. Statistically significant correlations were also found between the visual ratings of medial temporal lobe atrophy and the semi-automated ratings of brain structural integrity., Conclusions: High quality MRI data can be acquired and analyzed from older adults in population studies, enhancing their capacity to examine imaging biomarkers in relation to cognitive aging and dementia.

Objective: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer's disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures., Methods: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson's Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed., Results: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson's Disease Rating Scale scores and Peri-IIIVent atrophy measures., Conclusions: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. Microarray-based comparative gene profiling provides a snapshot of genes underlying a particular condition. Several large scale microarray studies have been conducted using brain tissue from MS patients. In this review, we summarize existing data from different gene expression profiling studies and how they relate to understand the pathogenesis of MS., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: In the diagnosis of Alzheimer's disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non-Alzheimer's causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage., Methods: Elderly subjects (n = 224) were diagnosed with either no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or AD. Hippocampal and hemispheric gray matter volumes were measured on structural MRI scans, and a new visual rating system was used to score the severity of medial temporal atrophy (VRS-MTA) of the hippocampus (HPC), entorhinal cortex, and perirhinal cortex on a coronal image intersecting the mammillary bodies., Results: Although both VRS-MTA scores and HPC volumes distinguished between subjects with NCI, aMCI, and AD, subjects with aMCI and NCI could be better distinguished using right VRS-MTA scores, in comparison with right HPC volumes. VRS-MTA scores were more highly correlated with episodic memory and Clinical Dementia Rating scores. A combination of left sided VRS-MTA scores and left sided hippocampal volume was the most predictive measure of diagnostic classification., Conclusion: VRS-MTA is a clinically convenient method or distinguishing aMCI or AD from NCI. As compared with volumetric measures, it provides better discriminatory power and correlates more strongly with memory and functional scores., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Functional Magnetic Resonance Imaging (fMRI) is a popular noninvasive modality to investigate activation in the human brain. The end result of most fMRI experiments is an activation map corresponding to the given paradigm. These maps can vary greatly from one study to the next, so quantifying the reliability of identified activation over several fMRI studies is important. The percent overlap of activation (Rombouts et al., 1998; Machielsen et al., 2000) is a global reliability measure between activation maps drawn from any two fMRI studies. A slightly modified but more intuitive measure is provided by the Jaccard (1901) coefficient of similarity, whose use we study in this paper. A generalization of these measures is also proposed to comprehensively summarize the reliability of multiple fMRI studies. Finally, a testing mechanism to flag potentially anomalous studies is developed. The methodology is illustrated on studies involving left- and right-hand motor task paradigms performed by a right-hand dominant male subject several times over a period of two months, with excellent results., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Objective: Medial temporal lobe atrophy (MTA) can be used as a biomarker of pathology that affects mechanisms of episodic memory. The authors compared the strength of this biomarker with performance on four memory measures and examined the influence of demographic factors including age, level of education, and primary language (English or Spanish)., Methods: The Hopkins Verbal Learning Test-revised, Fuld Object Memory Evaluation (FOME), delayed memory for a story passage, and delayed visual reproduction of the Wechsler Memory Scale-revised tests were administered to 281 subjects who were diagnosed as having no cognitive impairment, mild cognitive impairment (MCI), impaired non-MCI, or dementia. MTA scores were obtained from visual ratings of the hippocampus, entorhinal cortex, and perirhinal cortex on coronal magnetic resonance imaging scans using a magnetization-prepared rapid gradient echo protocol., Results: Age was associated with scores on all memory measures and MTA. Level of educational attainment had no influence on FOME performance but had greater associations with scores on other memory measures. In regression models, FOME scores had the strongest relationship with MTA scores, accounting for 31% of the explained variability. Among subjects with MCI, an index representing the total number of memory tests that were impaired was also predictive of the severity of MTA scores., Conclusion: Among four common tests of memory, the FOME was highly associated with MTA, and it exhibited minimal influences of education. Impairment on more than one memory test was more predictive of MTA than impairment on a single memory test.