Neuropathological Data Research Articles

Antiretroviral therapy reduces neurodegeneration in HIV infection.

To determine the effect of virally suppressive antiretroviral therapy (ART) on cortical neurodegeneration and associated neurocognitive impairment. Retrospective, postmortem observational study. Clinical neuropsychological and postmortem neuropathology data were analyzed in 90 HIV-infected volunteers from the general community who had never undergone ART (n = 7, 'naive') or who had undergone ART and whose plasma viral load was detectable (n = 64 'unsuppressed') or undetectable (n = 19, 'suppressed') at the last clinical visit before death. Individuals were predominately men (74/90, 82%) with a mean age of 44.7 years (SD 9.8). Cortical neurodegeneration was quantified by measuring microtubule-associated protein (MAP2) and synaptophysin (SYP) density in midfrontal cortex tissue sections. The suppressed group had higher SYP density than the naive group (P = 0.007) and higher MAP2 density than the unsuppressed group (P = 0.04). The suppressed group had lower odds of HIV-associated neurocognitive disorders than naive [odds ratio (OR) 0.07, P = 0.03]. Higher SYP was associated with lower likelihood of HIV-associated neurocognitive disorders in univariable (OR 0.8, P = 0.03) and multivariable models after controlling for ART and brain HIV p24 protein levels (OR 0.72, P = 0.01). We conclude that virally suppressive ART protects against cortical neurodegeneration. Further, we find evidence supporting the causal chain from treatment-mediated peripheral and central nervous system viral load suppression to reduced neurodegeneration and improved neurocognitive outcomes.

Fitting the epidemiology and neuropathology of the early stages of Alzheimer's disease to prevent dementia.

IntroductionRecent research on biomarkers has made possible the diagnosis of pre-dementia and even preclinical Alzheimer’s disease (AD), thus providing the ideal context for prevention. The aim of this study was to investigate the epidemiology of the early stages of AD by fitting neuropathologic and epidemiological data to assess the feasibility of prevention programs.MethodsThe study addressed primarily the construction of a discrete event simulation model of the stages of dementia. Age was included in the mathematical functions to combine the two competitive risks that determine the epidemiology of AD, that is, time to onset of dementia and time until death by other causes. Subsequently, this model was calibrated to reproduce the prevalence of pathological findings associated with AD. The beginning of the preclinical stage was taken to coincide with Thal phase 1 deposition of amyloid-beta. The duration of the prodromal stage, marked by mild cognitive impairment, was based on a 10% annual conversion rate from this level of impairment to dementia. The validation of prevalence figures also permitted estimation of the incidence and duration of preclinical and prodromal stages.ResultsIn Spain, half of the nearly 10 million people aged more than 60 years are in the early stages of AD; 35.9% are in a preclinical stage, and up to 14.2% are in a prodromal stage. However, dementia will develop in only 38% of this population. The weighted mean time to dementia was 22.0 years from the start of Thal phase 1 and 9.0 years from the start of phase 2. Results of simulation models showed a lack of correlation between clinical and pathological classifications.ConclusionsThese findings raise questions about the feasibility of drug-based prevention strategies. Currently, screening programs with biomarkers in the early stages of AD cannot be applied to the half of the general population older than 60 years. Hence, intensive research is needed regarding risk factors, so that more affordable strategies may be planned. More efficient criteria are also needed to select those subjects with mild cognitive impairment who have an increased probability of positive screening for biomarkers (prodromal stage).Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-014-0079-9) contains supplementary material, which is available to authorized users.

Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology.

Hippocampal sclerosis of aging (HS-Aging) is a common high-morbidity neurodegenerative condition in elderly persons. To understand the risk factors for HS-Aging, we analyzed data from the Alzheimer's Disease Genetics Consortium and correlated the data with clinical and pathologic information from the National Alzheimer's Coordinating Center database. Overall, 268 research volunteers with HS-Aging and 2,957 controls were included; detailed neuropathologic data were available for all. The study focused on single-nucleotide polymorphisms previously associated with HS-Aging risk: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9). Analyses of a subsample that was not previously evaluated (51 HS-Aging cases and 561 controls) replicated the associations of previously identified HS-Aging risk alleles. To test for evidence of gene-gene interactions and genotype-phenotype relationships, pooled data were analyzed. The risk for HS-Aging diagnosis associated with these genetic polymorphisms was not secondary to an association with either Alzheimer disease or dementia with Lewy body neuropathologic changes. The presence of multiple risk genotypes was associated with a trend for additive risk for HS-Aging pathology. We conclude that multiple genes play important roles in HS-Aging, which is a distinctive neurodegenerative disease of aging.

Severe Neonatal Epileptic Encephalopathy and KCNQ2 Mutation: Neuropathological Substrate?

Background: Neonatal convulsions are clinical manifestations in a heterogeneous group of disorders with different etiology and outcome. They are attributed to several genetic causes.Methods: We describe a patient with intractable neonatal seizures who died from respiratory compromise during a status epilepticus.Results: This case report provides electroencephalogram (EEG), MRI, genetic analysis, and neuropathological data. Genetic analysis revealed a de novo heterozygous missense mutation in the KCNQ2 gene, which encodes a subunit of a voltage-gated potassium channel. KCNQ2 gene mutation is associated with intractable neonatal seizures. EEG, MRI, data as well as mutation analysis have been described in other KCNQ2 cases. Post-mortem neuropathological investigation revealed mild malformation of cortical development with increased heterotopic neurons in the deep white matter compared to an age-matched control subject. The new finding of this study is the combination of a KCNQ2 mutation and the cortical abnormalities.Conclusion: KCNQ2 mutations should be considered in neonates with refractory epilepsy of unknown cause. The mild cortical malformation is an important new finding, though it remains unknown whether these cortical abnormalities are due to the KCNQ2 mutation or are secondary to the refractory seizures.

69.: Neuropathological, imaging and clinical features of a patient with neurofibromatosis type 1 and multiple sclerosis

We present detailed histopathological and clinical characterisation of a young male patient with neurofibromatosis type 1 (NF1) and primary progressive multiple sclerosis (MS) and discuss the putative basis for association between these diseases. A young man with typical cutaneous stigmata of NF1 presented in his late 20s with a progressive myelopathy and pancerebellar disturbance. MRI demonstrated multifocal T2-weighted hyperintensities in the hemispheres, brainstem and spinal cord. Investigations revealed cerebrospinal fluid oligoclonal immunoglobulin G bands, and absent visual evoked responses. Clinical progression was rapid and non-remitting. Within 4 years he was wheelchair-bound. He died following an aspiration event 6 years after presentation. Histopathologically, extensive multifocal, and sometimes confluent, areas of demyelination were seen with perivascular inflammation and astrogliosis in the hemispheres and spinal cord. Abundant corpora amylacea deposition in areas of white matter degeneration was present. NF1 is an autosomal dominant neurocutaneous disorder caused by mutation in the Neurofibronin gene. It is unclear if the concurrence of MS and NF1 occurs by chance but early hypotheses of causal associations followed the discovery that the oligodendrocyte myelin glycoprotein gene is embedded within the NF1 gene. Approximately 27 patients with MS and NF1 have been described but none with detailed neuropathologic data, to our knowledge. In this patient, the rapidly progressive phenotype, severity of tissue injury histopathologically and extensive presence of corpora amylacea are of interest. Clinicians should be vigilant for the development of central nervous system demyelinating disease in patients with NF1.

Spreading of amyloid, tau, and microvascular pathology in Alzheimer's disease: findings from neuropathological and neuroimaging studies.

Primary pathologies including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) develop many years before the onset of dementia symptoms in Alzheimer's disease (AD). Age-related small vessel disease (SVD) is common in elderly subjects and may contribute to the clinical syndrome of AD. Each type of pathology shows a specific spatio-temporal sequence of spreading in the brain. Here, we review neuropathological and neuroimaging findings (PET tracers of Aβ and NFT, MRI markers of SVD) to assess whether staging of these primary pathologies is useful to predict clinical symptoms in AD. On the basis of neuropathological data, early stages of Aβ plaque and NFT pathology distribution occur in preclinical AD, but advanced stages with spreading into further brain regions are associated with dementia symptoms. Amyloid PET presumably detects Aβ in advanced neuropathological Aβ stages, and increased global amyloid PET uptake is associated with clinical worsening in non-demented subjects. Tau PET may provide additional predictive value by detecting NFT in the allocortex. There is weak evidence that SVD is related to amyloid or NFT pathology. Global volume of MRI-assessed white matter hyperintensities (WMH) contribute in addition to biomarker levels of Aβ to predict cognitive decline. Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers.

Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome.

Several biochemical, neuropathological, and experimental data suggest a possible role of nitric oxide (NO) in the pathophysiology of restless legs syndrome (RLS). Two single nucleotide polymorphisms (SNPs) neuronal nitric oxide synthase (nNOS or NOS1) gene (rs7977109 and rs693534) have been found to be associated with the risk for RLS in Germans, although only one of them (rs7977109) remained as significant after multiple comparison tests. The aim of our study was to replicate the possible association between these SNPs and risk for RLS in the Spanish population. We studied the allelic and genotype frequencies of the SNPs rs7977109 and rs693534 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. The rs7977109 and rs693534 genotypes and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, ferritin levels, and response to dopaminergic or gabaergic agents. The rs7999109GA genotype was overrepresented in RLS patients with positive family history of RLS, and in patients with symptomatic response to clonazepam. The results of our study suggest that these two NOS1 SNPs are not related to the overall risk for RLS in the Spanish population.

P23 * MANAGEMENT AND OUTCOME OF ADULT MEDULLOBLASTOMAS: ARE WE FOLLOWING RECOMMENDED GUIDELINES?

INTRODUCTION: Medulloblastomas are very rare tumours in adults compared to children. Clinical pathways for medulloblastoma are well established for children. The purpose of this study was to analyse clinical outcome of adult medulloblastomas. METHOD: Single centre retrospective case review from 1995 - 2012. Clinical, radiological and neuropathological data were gathered and analysed. RESULTS: 13 patients (9 male, 4 female) were identified; median age 24 years (range: 17-64). Annual incidence in our region is 0.2 cases per million per year. Headache was the most common presenting symptom, mean duration before diagnosis was 8 weeks. Tumours were located in lateral cerebellum (n = 10) and vermis (n = 3). All patients had localized disease at presentation and underwent surgical resection and tissue biobanking followed by cranio-spinal irradiation. Three patients also received adjuvant chemotherapy. MRI spine and CSF analysis were only completed after surgery in all cases. Median follow-up was 32 months (range: 3-126). Mean overall survival (OS) was 92 months (95%CI 62-122 months) with 5 year OS of 55%. Progression free survival (PFS) was 77% with median follow-up of 32 months falling to 56% at 5 years. Three of 13 cases (23%) recurred at a mean of 38 months. All patients who received adjuvant chemotherapy remained recurrence free. CONCLUSION: Diagnosis of adult medulloblastoma is often only made after surgery. Staging MRI should occur pre-operatively to minimize artifact. In our series, surgery and craniospinal radiotherapy was the primary treatment and the role of chemotherapy could be further beneficial. There may be a role for regional management of these very rare tumours.

Modeling cognitive reserve in healthy middle-aged and older adults: the Tasmanian Healthy Brain Project.

Cognitive reserve (CR) is a protective factor that supports cognition by increasing the resilience of an individual's cognitive function to the deleterious effects of cerebral lesions. A single environmental proxy indicator is often used to estimate CR (e.g. education), possibly resulting in a loss of the accuracy and predictive power of the investigation. Furthermore, while estimates of an individual's prior CR can be made, no operational measure exists to estimate dynamic change in CR resulting from exposure to new life experiences. We aimed to develop two latent measures of CR through factor analysis: prior and current, in a sample of 467 healthy older adults. The prior CR measure combined proxy measures traditionally associated with CR, while the current CR measure combined variables that had the potential to reflect dynamic change in CR due to new life experiences. Our main finding was that the analyses uncovered latent variables in hypothesized prior and current models of CR. The prior CR model supports multivariate estimation of pre-existing CR and may be applied to more accurately estimate CR in the absence of neuropathological data. The current CR model may be applied to evaluate and explore the potential benefits of CR-based interventions prior to dementia onset.

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects

Background and PurposeThe etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. Materials and MethodsThirty-five patients were prospectively included (multiple-system atrophy, n=5; Parkinson's disease, n=15; progressive supranuclear palsy, n=9; vascular parkinsonism, n=6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinson's disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. ResultsStatistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p=0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p=0.01).Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinson's disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. ConclusionClinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.

BRAINS FOR DEMENTIA RESEARCH: CONCORDANCE OF CLINICAL AND NEUROPATHOLOGICAL DIAGNOSES IN DECEASED PARTICIPANTS

Brains for Dementia Research (BDR) is a project involving planned brain donation following regular standardised assessments of cognition, mood, behaviour and activities of daily living. Six years on the project has 2470 living participants and 68 participants have died where full assessment and neuropathological data is available. This investigation looks at agreement between clinical judgement, assessment score-based and neuropathological diagnoses in the deceased. Tissue and data from BDR participants is available to researchers. The neuropathological diagnosis is the primary diagnosis by the BDR neuropathologist (grouped into normal/control [C], Alzheimer's disease [AD], cerebrovascular disease [CVD] and other dementias [OD]), secondary diagnoses were ignored for this study. Braak staging (grouped 0-2, 3, 4-6) was available. The assessment-derived clinical diagnosis was based on the last interview before death (78% within one year of death) and divided into control/MCI and dementia using MMSE (>23) and CDR memory domain(≤ 0.5) as a cut off. This was compared to the practical, clinical judgement diagnosis used by the field team. The results (Table 1) indicate for a recent clinical diagnosis of control/MCI; the neuropathological diagnoses were control (12), AD (2), moderate/severe CVD (4) and OD (2). The fieldworker identified both cases that subsequently proved to have AD as suffering from dementia and also both OD cases. but none of the CVD group. Only 1 person identified probable dementia by the fieldworker was diagnosed neuropathologically as a control. Within the clinical dementia group by MMSE and CDR memory domain, 7 had a neuropathological diagnosis of control, 2 of which were identified as control by the field team. The present report highlights concordance between clinical and neuropathological diagnosis in the BDR cohort, possibly reflecting the serial and standardised assessments undertaken typically within a year of death as part of the project. Assessment data and post-mortem tissue can be freely requested by researchers world-wide.

GENOME-WIDE ASSOCIATION STUDY USING ALZHEIMER-RELATED PATHOLOGICAL BIOMARKERS

Genome-wide association study (GWAS) is a powerful technique to identify polymorphisms associated with a particular disease. However, standard case-control study can often be disappointing because no SNPs reach genome-wide significance. Another way to highlight potential disease-modifying SNPs is to perform the study with pathology-specific biomarkers. This method was applied for late-onset Alzheimer's disease (LOAD). GWAS was performed with Illumina 550-Quad BeadChip using DNA samples from Quebec Founder Population (QFP). A total of 629 French Canadians (384 LOAD patients and 245 age-matched control subjects) were recruited for the study. DNA was extracted either from blood samples or directly from available brain tissues (from the Douglas - Bell Canada Brain Bank). For a subset of post-mortem samples, the density of senile plaques (SP) and neurofibrillary tangles (NFT) were evaluated by a neuropathologist. Single nucleotide polymorphisms (SNPs) significantly associated with the disease, the age of onset or with neuropathological data will be assessed for replication in the population from the Alzheimer's Disease Neuroimaging Initiative (ADNI). With the standard case-control analysis, only four SNPs reached genome-wide significance (p< 5 x 10 -8). These four SNPs (rs429358, rs2075650, rs405509 and rs8106922) were all located on chromosome 19 near APOE gene. The strongest SNP (rs429358, p= 4.1 x 10 -24) also correlated with the age of onset (p= 2.4 x 10 -4), the density of SP in the frontal cortex (p= 6.5 x 10 -8) and in the CA1 region of the hippocampus (p= 3.6 x 10 -3), and the density of NFT in the frontal cortex (p= 7.3 x 10 -7) and in the CA1 region of the hippocampus (p= 4.6 x 10 -3). A second analysis is currently being performed in an effort to find other SNPs that correlate with pathology-related biomarkers. SNPs will be selected based on P values and the number of significant correlations with different biomarkers from our study and the ADNI database. The contribution of APOE to late-onset Alzheimer's disease has already been well established. The present study will help to identify genes never before associated with the disease.

SEARCH FOR RECESSIVE ALZHEIMER DISEASE LOCI IN AFRICAN AMERICANS BY GENOME-WIDE STUDY OF RUNS OF HOMOZYGOSITY

samples or directly from available brain tissues (from the Douglas Bell Canada Brain Bank). For a subset of post-mortem samples, the density of senile plaques (SP) and neurofibrillary tangles (NFT) were evaluated by a neuropathologist. Single nucleotide polymorphisms (SNPs) significantly associated with the disease, the age of onset or with neuropathological data will be assessed for replication in the population from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results: With the standard casecontrol analysis, only four SNPs reached genome-wide significance (p< 5 x 10 -8). These four SNPs (rs429358, rs2075650, rs405509 and rs8106922) were all located on chromosome 19 near APOE gene. The strongest SNP (rs429358, p1⁄4 4.1 x 10 -24) also correlated with the age of onset (p1⁄4 2.4 x 10 -4), the density of SP in the frontal cortex (p1⁄4 6.5 x 10 -8) and in the CA1 region of the hippocampus (p1⁄4 3.6 x 10 -3), and the density of NFT in the frontal cortex (p1⁄4 7.3 x 10 -7) and in the CA1 region of the hippocampus (p1⁄4 4.6 x 10 -3). A second analysis is currently being performed in an effort to find other SNPs that correlate with pathology-related biomarkers. SNPs will be selected based on P values and the number of significant correlations with different biomarkers from our study and the ADNI database. Conclusions: The contribution of APOE to late-onset Alzheimer’s disease has already been well established. The present study will help to identify genes never before associated with the disease.

Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology.

To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change. Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging-sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (β) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions. Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (β = -0.11; 95% confidence interval = -0.19, -0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change. Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.

A comparison of Aβ amyloid pathology staging systems and correlation with clinical diagnosis.

Current neuropathological Alzheimer's disease (AD) criteria from the National Institute on Aging-Alzheimer's Association (NIA-AA) incorporate two staging systems for Aβ pathology, namely the Thal Aβ phase (TAP) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) methods. The goal of this study was to compare and contrast results obtained with these two different staging systems for Aβ pathology since this is critical for future correlations of Aβ amyloid imaging data with Aβ neuropathology data based on immunohistochemical detection of Aβ deposits. A total of 123 cases, divided into 82 training and 41 validation cases, with a diagnosis of either unremarkable adult brain (normal) or AD and CERAD scores ranging from none to frequent were included. There was no clear and consistent relationship between CERAD and the TAP Aβ scores with the exception of scores for the highest plaque burdens (i.e., CERAD C3 and TAP A3) in the cases studied here. However, we developed an algorithm that relates CERAD scores to TAP scores with high agreement (94% in training and 98% in the validation set). In addition, TAP scores were a better predictor of dementia (sensitivity of 94% specificity 87.7%) than CERAD scores (sensitivity of 57% specificity 100%). Yet, further research is needed to define strategies to relate CERAD and TAP Aβ plaque scores to compare their utility and for determining the clinical associations of these different amyloid staging systems with aging and AD.

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.

IgG and Complement Deposition and Neuronal Loss in Cats and Humans With Epilepsy and Voltage-Gated Potassium Channel Complex Antibodies

Voltage-gated potassium channel complex (VGKC-complex) antibody (Ab) encephalitis is a well-recognized form of limbic encephalitis in humans, usually occurring in the absence of an underlying tumor. The patients have a subacute onset of seizures, magnetic resonance imaging findings suggestive of hippocampal inflammation, and high serum titers of Abs against proteins of the VGKC-complex, particularly leucine-rich, glioma-inactivated 1 (LGI1). Most patients are diagnosed promptly and recover substantially with immunotherapies; consequently, neuropathological data are limited. We have recently shown that feline complex partial cluster seizures with orofacial involvement (FEPSO) in cats can also be associated with Abs against VGKC-complexes/LGI1. Here we examined the brains of cats with FEPSO and compared the neuropathological findings with those in a human with VGKC-complex-Ab limbic encephalitis. Similar to humans, cats with VGKC-complex-Ab and FEPSO have hippocampal lesions with only moderate T-cell infiltrates but with marked IgG infiltration and complement C9neo deposition on hippocampal neurons, associated with neuronal loss. These findings provide further evidence that FEPSO is a feline form of VGKC-complex-Ab limbic encephalitis and provide a model for increasing understanding of the human disease.

HIV-1 Tat promotes premature brain aging

Background It is estimated that by 2015, about half of all HIV-positive individuals will be older than 50 due to the introduction of the HAART. Yet those over 50 progress to AIDS faster than adults in their 20s or 30s, and those in the younger age bracket still exhibit illnesses and clinical conditions commonly associated with older people, such as HIVassociated neurocognitive disorders (HAND), certain cancers, liver and bones diseases. For the most part, the reasons for this have remained a mystery. In support of the eradication failure, studies showed the persistence of HIV-1 in brain cells as well as the presence of viral proteins in CSF. This notion was supported by the compelling neuropathological data suggesting that the loss of Synaptic Plasticity occurs with the ongoing presence of virus and despite HAART. Clinically, these neuropathological data manifest by a gradual loss of working memory and learning disability that may manifest by symptoms similar to the ones observed in aged brain. Anatomically, working memory and learning ability functions are assured by neurons of the hippocampus, a brain area known-to-be affected by HIV-1 proteins such as gp120.

Are patients with Parkinson's disease blind to blindsight?

In Parkinson's disease, visual dysfunction is prominent. Visual hallucinations can be a major hallmark of late stage disease, but numerous visual deficits also occur in early stage Parkinson's disease. Specific retinopathy, deficits in the primary visual pathway and the secondary ventral and dorsal pathways, as well as dysfunction of the attention pathways have all been posited as causes of hallucinations in Parkinson's disease. We present data from patients with Parkinson's disease that contrast with a known neuro-ophthalmological syndrome, termed 'blindsight'. In this syndrome, there is an absence of conscious object identification, but preserved 'guess' of the location of a stimulus, preserved reflexive saccades and motion perception and preserved autonomical and expressive reactions to negative emotional facial expressions. We propose that patients with Parkinson's disease have the converse of blindsight, being 'blind to blindsight'. As such they preserve conscious vision, but show erroneous 'guess' localization of visual stimuli, poor saccades and motion perception, and poor emotional face perception with blunted autonomic reaction. Although a large data set on these deficits in Parkinson's disease has been accumulated, consolidation into one specific syndrome has not been proposed. Focusing on neuropathological and physiological data from two phylogenetically old and subconscious pathways, the retino-colliculo-thalamo-amygdala and the retino-geniculo-extrastriate pathways, we propose that aberrant function of these systems, including pathologically inhibited superior colliculus activity, deficient corollary discharges to the frontal eye fields, dysfunctional pulvinar, claustrum and amygdaloid subnuclei of the amygdala, the latter progressively burdened with Lewy bodies, underlie this syndrome. These network impairments are further corroborated by the concept of the 'silent amygdala'. Functionally being 'blind to blindsight' may facilitate the highly distinctive 'presence' or 'passage' hallucinations of Parkinson's disease and can help to explain handicaps in driving capacities and dysfunctional 'theory of mind'. We propose this synthesis to prompt refined neuropathological and neuroimaging studies on the pivotal nuclei in these pathways in order to better understand the networks underpinning this newly conceptualized syndrome in Parkinson's disease.