Neuropathological Data Research Articles

ANTEMORTEM LONGITUDINAL MRI METRICS AS A BIOMARKER OF POSTMORTEM BRAAK NFT STAGING

The diagnosis of Alzheimer's disease (AD) can only be established through postmortem examination. The most widely used assessment method is “ABC staging”, involving the neuropathological gradation of diffuse amyloid plaques, neurofibrillary tangles (NFT), and neuritic plaques. NFT pathology is the strongest correlate of atrophy on structural magnetic resonance imaging (MRI) amongst all AD pathological features. Conversely, our goal was to identify regional MRI metrics for which longitudinal trajectories were the strongest predictors of postmortem neurofibrillary degeneration. We selected participants from three databases (ADNI, NACC and Rush Memory and Aging Project) providing up to 10 years of clinical and MRI longitudinal follow-up, as well as postmortem neuropathological data. After initial quality control, 104 subjects with at least two in vivo brain MRIs were retained, for a total of 402 scans. Bilateral surfaces, thicknesses and volumes from cortical and subcortical brain structures were extracted using FreeSurfer 5.3 (longitudinal processing pipeline). Yearly atrophy rates were then calculated for each of the resulting 232 measures. Nonparametric comparisons and correlation analyses using Kruskal-Wallis and Spearman's rank correlation tests were performed to screen for the best predictors of postmortem NFT staging as assessed by Braak score. There was a significant difference between Braak transentorhinal (I-II), limbic (III-IV) and isocortical (V-VI) stages for 75 radiological variables (p < .05). Most of these entities are part of the temporal lobe and ventricular system; were also present some limbic lobe structures such as the posterior cingulate cortex. When adjusted for multiple comparisons, only the annual atrophy rates of the left inferior temporal and right middle temporal volumes remained significantly different between Braak stages (p < .0002); these structures showed good correlations with the severity of NFT aggregation (-0.463 and -0.406, respectively). Trajectories of regional brain atrophy as detected by serial in vivo brain imaging reflect underlying severity and distribution of AD-associated neurofibrillary degeneration. In vivo MRI metrics may therefore be considered as a potential biomarker for the prediction of AD neuropathological staging in the living brain.

The Revised National Alzheimer's Coordinating Center's Neuropathology Form-Available Data and New Analyses.

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer's Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer's Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

Local volume fraction distributions of axons, astrocytes, and myelin in deep subcortical white matter

This study aims to statistically describe histologically stained white matter brain sections to subsequently inform and validate diffusion MRI techniques. For the first time, we characterise volume fraction distributions of three of the main structures in deep subcortical white matter (axons, astrocytes, and myelinated axons) in a representative cohort of an ageing population for which well-characterized neuropathology data is available. We analysed a set of samples from 90 subjects of the Cognitive Function and Ageing Study (CFAS), stratified into three groups of 30 subjects each, in relation to the presence of age-associated deep subcortical lesions. This provides volume fraction distributions in different scenarios relevant to brain diffusion MRI in dementia. We also assess statistically significant differences found between these groups. In agreement with previous literature, our results indicate that white matter lesions are related with a decrease in the myelinated axons fraction and an increase in astrocytic fraction, while no statistically significant changes occur in axonal mean fraction. In addition, we introduced a framework to quantify volume fraction distributions from 2D immunohistochemistry images, which is validated against in silico simulations. Since a trade-off between precision and resolution emerged, we also performed an assessment of the optimal scale for computing such distributions.

Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches.

Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia

Aim: To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). Methods: This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. Results: We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients – in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro­pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. Conclusions: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research.

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology.

White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04). This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis.

Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathological, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinical, pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathological data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group.

Fetal neuroaxonal dystrophy: a new etiology of fetal akinesia

Neuroaxonal Dystrophies (NAD) are neurodegenerative diseases characterized by axonal “spheroids” occurring in different age groups. The identification of mutations delineated new molecular entities in these disorders. We report neuropathological data of a new form of NAD, characterized by a precocious prenatal onset, different from classical and connatal Infantile Neuroaxonal Dystrophy (INAD).We studied 5 fetuses examined after pregnancy termination and 2 term neonates deceased just after birth, 4/7 from consanguineous parents. All subjects presented severe fetal akinesia sequence with microcephaly. In 4/7 cases, a molecular study was performed. In all cases, “spheroids” with typical immunohistochemical features were identified, with variable spreading in the central and peripheral nervous system. Basal ganglia, brainstem, cerebellum and spinal cord involvement was constant. Associated CNS malformations, unusual in INAD, were associated including hydrocephalus (2), callosal agenesis/hypoplasia (2), olfactory agenesis (1), cortical (3) and retinal (1) anomalies. None cases demonstrated mutations in PLA2G6, found in INAD.The clinical and neuropathological features of these fetal cases are different from those of “classical” INAD. The absence of mutations of PLA2G6, in addition, suggests that the fetal NAD is a new entity, distinct from INAD, with different molecular basis. Associated malformations suggest a wide phenotypic spectrum and probable genetic heterogeneity. Finally, fetal NAD is an additional etiology of fetal akinesia.

Memory complaints, dementia, and neuropathology in older blacks and whites.

To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons. A total of 4,015 community-based persons (28% black; 74% women; mean baseline age = 78 years) were enrolled in 1 of 4 longitudinal cohort studies, and another 2,937 in a population-based cohort. Memory scores, assessed using 2 questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and 5 cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1,350 deceased subjects with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology. Baseline memory complaints (n = 1,310; 33% of 4,015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032, standard error = 0.004, p < 0.0001), during a mean follow-up of 6 (standard deviation = 2) years. Persons with memory complaints had higher dementia risk (hazard ratio = 1.64, 95% confidence interval [CI] = 1.42-1.89) and odds of pathologic Alzheimer disease (odds ratio [OR] = 1.96, 95% CI = 1.51-2.54), neocortical Lewy bodies (OR = 2.47, 95% CI = 1.54-3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2,937 older persons in a population-based cohort with similar data, the population-attributable risk for incident dementia due to memory complaints was 14.0% (95% CI = 2.6-23.0), and did not vary between the black and white groups. Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. Ann Neurol 2018;83:718-729.

An image registration protocol to integrate electrophysiology, MRI and neuropathology data in epileptic patients explored with intracerebral electrodes

BackgroundSeveral attempts have been made to coregister in vivo MRI with the histopathology of surgical samples, aiming to validate new MRI biomarkers and improve the detection of epileptogenic lesions. As a further implementation, we propose a method to reconstruct the anatomical localization of the intracerebral electrodes on the histological sections, developing a coregistration protocol to match the in vivo MRI onto the ex vivo MRI obtained from the surgical specimen. New methodSince the ex vivo MRI is natively in geometrical correspondence with histology slices, the goal of the coregistration process is to compute the transform function mapping the clinical MRI space to the ex vivo MRI. Electrodes and leads, identified in CT-MRI, can then be segmented and translated onto the histological slices. ResultsStep-by-step, qualitative visual inspection showed an improved matching of the anatomical structures or boundaries and electrodes positions between the two modalities. The quantitative evaluation of the coregistration protocol reported a mean error ranging between 0.82 and 1.27 mm when a sufficient number of landmarks, particularly in the core of the specimen, were clearly identified. Comparison with existing methodsBecause histology was performed according to ex vivo MRI geometry we chose to transform the in vivo onto the ex vivo MRI, differently from other methods. ConclusionsInteresting applications of the method will include correlating the locally-generated pathological electrical activity with the subtle morphological alterations of the tissue, and histologically validating the origin of signal alterations or quantitative parameter variations in MRI studies.

Leptomeninges-Derived Induced Pluripotent Stem Cells and Directly Converted Neurons From Autopsy Cases With Varying Neuropathologic Backgrounds.

Patient-specific stem cell technology from skin and other biopsy sources has transformed in vitro models of neurodegenerative disease, permitting interrogation of the effects of complex human genetics on neurotoxicity. However, the neuropathologic changes that underlie cognitive and behavioral phenotypes can only be determined at autopsy. To better correlate the biology of derived neurons with age-related and neurodegenerative changes, we generated leptomeningeal cell lines from well-characterized research subjects that have undergone comprehensive postmortem neuropathologic examinations. In a series of proof of principle experiments, we reprogrammed autopsy leptomeningeal cell lines to human-induced pluripotent stem cells (hiPSCs) and differentiated these into neurons. We show that leptomeningeal-derived hiPSC lines can be generated from fresh and frozen leptomeninges, are pluripotent, and retain the karyotype of the starting cell population. Additionally, neurons differentiated from these hiPSCs are functional and produce measurable Alzheimer disease-relevant analytes (Aβ and Tau). Finally, we used direct conversion protocols to transdifferentiate leptomeningeal cells to neurons. These resources allow the generation of in vitro models to test mechanistic hypotheses as well as diagnostic and therapeutic strategies in association with neuropathology, clinical and cognitive data, and biomarker studies, aiding in the study of late-onset Alzheimer disease and other age-related neurodegenerative diseases.

Slowly progressive dementia caused by MAPT R406W mutations: longitudinal report on a new kindred and systematic review

BackgroundThe MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer’s disease-like clinical features.MethodsWe compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes.ResultsFor all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer’s disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-β pathology was absent.ConclusionsDominance of 4R over three-repeat (exon 10−) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.

Chapter 13 - Collecting, storing, and mining research data in a brain bank

The Stanley Medical Research Institute Brain Collection distributes samples from specified cohorts that contain demographically matched groups of subjects with mental illnesses such as schizophrenia, bipolar disorder, and major depression, as well as unaffected controls. The groups are matched by age, sex, race, postmortem interval, pH, side of brain, and mRNA quality. The samples are distributed coded so that all data must be returned in order to obtain the demographic information. The database contains more than 5000 individual data sets, as well as data from high-throughput microarray, sequencing, and proteomic studies. While most data were generated from the frontal cortex and hippocampus, the cerebellum has the most data sets that differ significantly between diagnostic groups and controls. The database contains interactive features and statistical tools that enable online data mining and real-time data analysis. The decrease in density of parvalbumin-positive neurons in schizophrenia, one of the most replicated findings in the field, is used to illustrate features of the brain bank. We describe how this finding can be replicated and validated in this database. We also show how the density of parvalbumin-positive neurons is correlated with markers of immune activation in the neuropathology data sets, how it is correlated with immune-related genes in a microarray data set, and how it is associated with a single-nucleotide polymorphism in the immune complement system.

Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging.

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used [18F]AV-1451 and [11C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.SIGNIFICANCE STATEMENT Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.

Olfactory dysfunctions in drug-naïve Parkinson's disease with mild cognitive impairment

BackgroundEvaluation of olfactory function is valuable for the detection of pre-motor state of Parkinson's disease (PD). PD patients have an increased risk of associated dementia and one-third of PD patients have mild cognitive impairment (MCI) at the time of diagnosis. However, the characteristics of olfactory dysfunction in PD-MCI patients are unclear. This study examined the relationship between olfactory dysfunction and cognitive function in drug-naïve PD at the time of diagnosis with the patterns of olfactory function in PD-MCI patients using the Korean version of the Sniffin’ stick test II (KVSS II). MethodsA total of 66 drug-naïve PD patients were enrolled. A neuropsychiatric assessment battery and KVSS II were performed. For the statistical analyses, univariate, multivariable linear regression and Student's t-test were used to determine the relationship between the variables and olfactory function. ResultsOlfactory dysfunction was more prevalent in the PD-MCI group than in the PD-normal cognition (PD-CN) group. Each domains of odor threshold, discrimination, identification and total olfactory score were more impaired in the PD-MCI group than the PD-CN group. Whether cognitive impairment was single or multiple domain was not affected. ConclusionPD-MCI is more likely to be associated with severe olfactory impairment than PD-CN. There may be more extensive neurodegenerative processes affecting olfaction in PD-MCI patients. With further investigation and validation using neuropathological data, an objective olfactory function test could be used as a tool to evaluate disease progression. Further studies with prospective design investigating the prognostic value of olfactory dysfunction in PD-MCI patients are essential.

Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer\u2019s disease

BackgroundOligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer’s disease (AD) may be associated with dysmyelination and a breakdown of OL-axon communication.MethodsIn order to understand this phenomenon on a molecular level, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic and proteomic data obtained from human AD postmortem brain samples. We then validated these networks using gene expression datasets generated from mice with ablation of major gene expression nodes identified in our AD-dysregulated networks.ResultsThe robust OL gene coexpression networks that we identified were highly enriched for genes associated with AD risk variants, such as BIN1 and demonstrated strong dysregulation in AD. We further corroborated the structure of the corresponding gene causal networks using datasets generated from the brain of mice with ablation of key network drivers, such as UGT8, CNP and PLP1, which were identified from human AD brain data. Further, we found that mice with genetic ablations of Cnp mimicked aspects of myelin and mitochondrial gene expression dysregulation seen in brain samples from patients with AD, including decreased protein expression of BIN1 and GOT2.ConclusionsThis study provides a molecular blueprint of the dysregulation of gene expression networks of OL in AD and identifies key OL- and myelination-related genes and networks that are highly associated with AD.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.

GBA mutations in Parkinson disease: earlier death but similar neuropathological features.

Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi-quantitative scores for Lewy-type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.

Gender and Pathology-Specific Effect of Apolipoprotein E Genotype on Psychosis in Alzheimer's Disease.

Symptoms of psychosis is one of the common clinical manifestations of Alzheimer's disease (AD). However, the pathophysiology behind psychosis is unknown. The aim of the present study was to explore the relationship between Apolipoprotein E (APOE) genotype, Lewy body pathology, and psychosis in AD. The data was obtained from the National Alzheimer's disease Coordinating Centre (NACC), using the Uniform Data Set and the Neuropathology Data Set. Subjects with frequent neuritic plaque on CERAD, and Braak Stage of V or VI, corresponding to high probability of AD based on the NIA-AA Regan criteria were included in the analysis. Subjects with two copies of ε4 alleles were significantly more likely to develop psychosis, both delusions and/or hallucinations, during the course of their illness. This association was gender-specific, only reaching significance in females. Our findings further showed that presence of two copies of ε4 allele was positively associated with the formation of Lewy bodies. Only in females with Lewy bodies was the effect of two copies of ε4 allele significant, reaching an odd ratio of 4.5. The APOE ε4 allele has a female-specific effect in inducing psychosis in AD through the formation of Lewy bodies.

MEDIAL TEMPORAL ATROPHY AND ITS ASSOCIATION WITH AMYLOID STATUS AND NEUROPATHOLOGY

Converging evidence suggests the neurodegenerative process underlying Alzheimer's disease (AD) begins years before the onset of dementia symptoms. Quantitative neuroimaging has been shown to be a useful in vivo biomarker of AD pathology. There is evidence that neurodegeneration—as measured by atrophy in MRI—correlates with clinical impairment and progression from Mild Cognitive Impairment (MCI) to dementia better than amyloid plaque burden. Medial temporal lobe atrophy, in particular, is predictive of rapid conversion from MCI to dementia (Heister et al., 2011). Here we examined the relationship between a quantitative neuroimaging measure of hippocampal atrophy and amyloid pathology—assessed through PET imaging and at autopsy—to evaluate its ability to predict underlying pathology and potential utility in identifying subjects with the greatest likelihood for decline. Two cohorts with high-resolution structural MRI including 989 (AD=171, MCI=494, NL=324) subjects from ADNI with Florbetapir (AV-45) PET and 130 subjects from 6 ADCs in the NACC (U01 AG016976) with neuropathology data were assembled to examine the relationship between hippocampal occupancy (HOC—a measure of hippocampal atrophy) and amyloid pathology. Volumetric MRI analysis was used to derive volumes of cortical regions and subcortical structures for each individual, and age- and sex-adjusted normative percentiles of HOC (HOCP) were generated (Brewer, 2009). The relationship between HOCP and amyloid positivity was examined by applying various percentile cutoffs. 47% of non-demented individuals in ADNI were amyloid positive. 69% of those who converted to dementia had an HOCP≤15. In all non-demented individuals, 32% of those with an HOCP≤15 converted to dementia, versus 2% of those with an HOCP>85. In the NACC cohort, 87% of subjects with an HOCP≤15 were clinically diagnosed with dementia while alive, versus 29% of those subjects with an HOCP>15. HOCP was associated with the amount of AD pathology at autopsy when controlling for the time between the MRI and death (p=0.0489). Even in subjects with dementia, HOCP was found to be significantly lower in amyloid positive subjects than amyloid negative subjects (p=0.0398). HOCP may be used as a predictor of decline and underlying AD pathology, and has potential use in clinical trial enrichment.