Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains.

Neuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4-8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48-21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83-23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein. To elucidate the molecular basis of HD, we extended the polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an expanded human HD CAG repeat, creating mutant HdhneoQ50 and HdhQ50 alleles that express reduced and wild-type levels of altered huntingtin, respectively. Mice homozygous for reduced levels displayed characteristic aberrant brain development and perinatal lethality, indicating a critical function for Hdh in neurogenesis. However, mice with normal levels of mutant huntingtin did not display these abnormalities, indicating that the expanded CAG repeat does not eliminate or detectably impair huntingtin's neurogenic function. Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism.

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease.

All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

Increased number of Purkinje cell dendritic swellings in essential tremor.

BACKGROUND AND PURPOSE: Essential Tremor (ET) is among the most prevalent neurologic disorders. Growing clinical and neuro-imaging evidence implicates cerebellar dysfunction in the pathogenesis of ET and emerging postmortem studies have identified structural changes in the cerebellum, particularly in Purkinje cells. In this study we systematically quantified focal Purkinje cell dendritic swellings (DS) in 20 ET vs. 19 control brains. METHODS: In each brain, a standard parasagittal neocerebellar tissue block was harvested. DS were quantified in one 7-µm thick section stained with Luxol Fast Blue/Hematoxylin and Eosin (LH&E) and one section stained with Bielschowsky method. RESULTS: The number of DS were higher in cases than controls by LH&E (1.50 ± 1.79 vs. 0.05 ± 0.23, P = 0.002) and Bielschowsky methods (2.70 ± 3.10 vs. 0.37 ± 0.50, P = 0.002). The number of DS was correlated with the number of torpedoes and marginally inversely correlated with the number of Purkinje cells. CONCLUSION: The current study documents and quantifies an additional structural abnormality in the ET cerebellum, adding to the growing list of such changes in this disease. The mechanisms that underlie this and other structural changes observed in ET are currently unknown, and they deserve additional exploration.

Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease.

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.

Memory performance is related to amyloid and tau pathology in the hippocampus.

OBJECTIVE: To determine the relation of amyloid and tau pathology in the hippocampal formation to decline in memory and other cognitive functions in Alzheimer's disease (AD). METHODS: Regression models were used to relate semiquantitative measurements of amyloid plaques, neurofibrillary tangles (NFTs) and neuropil threads (NTs) at autopsy with antemortem performance in memory, abstract/visuospatial and language domains in two independent samples (n = 41, n = 66) that had repeated neuropsychological measurements before death. RESULTS: In both groups, the number of NFTs in the entorhinal cortex, subiculum and CA1 region was inversely associated with memory performance at the last visit before death. However, the number of amyloid plaques and NTs in the entorhinal cortex was also inversely related to poor memory function. Moreover, as the number of plaques or NTs increased in any region of the hippocampal formation, there was a more rapid decline in memory performance over time; a similar decline was associated with increasing numbers of NFTs in the CA1 or subiculum. In contrast, there was no association between amyloid plaques, NFTs or NTs in the frontal or parietal lobe and performance in memory, nor was there an association between plaques, NFTs or NTs in the hippocampal formation and cognitive functions unrelated to memory. DISCUSSION: This study implicates both amyloid deposition and tau pathology in the hippocampus as an early and late cause of decline in memory function over time in AD. Memory performance appears to be specifically related to the amount of amyloid plaques, NFTs and NTs in the entorhinal cortex and hippocampus.

Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain.

The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH2-terminal polyglutamine region in huntingtin. An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.

Rapid induction of Alzheimer A beta amyloid formation by zinc.

A beta 1-40, a major component of Alzheimer's disease cerebral amyloid, is present in the cerebrospinal fluid and remains relatively soluble at high concentrations (less than or equal to 3.7 mM). Thus, physiological factors which induce A beta amyloid formation could provide clues to the pathogenesis of the disease. It has been shown that human A beta specifically and saturably binds zinc. Here, concentrations of zinc above 300 nM rapidly destabilized human A beta 1-40 solutions, inducing tinctorial amyloid formation. However, rat A beta 1-40 binds zinc less avidly and is immune to these effects, perhaps explaining the scarcity with which these animals form cerebral A beta amyloid. These data suggest a role for cerebral zinc metabolism in the neuropathogenesis of Alzheimer's disease.

Inactivation of the mouse Huntington's disease gene homolog Hdh.

Huntington's disease (HD) is a dominant neurodegenerative disorder caused by expansion of a CAG repeat in the gene encoding huntingtin, a protein of unknown function. To distinguish between "loss of function" and "gain of function" models of HD, the murine HD homolog Hdh was inactivated by gene targeting. Mice heterozygous for Hdh inactivation were phenotypically normal, whereas homozygosity resulted in embryonic death. Homozygotes displayed abnormal gastrulation at embryonic day 7.5 and were resorbing by day 8.5. Thus, huntingtin is critical early in embryonic development, before the emergence of the nervous system. That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons.

The gene defective in Huntington's disease encodes a protein, huntingtin, with unknown function. Antisera generated against three separate regions of huntingtin identified a single high molecular weight protein of approximately 320 kDa on immunoblots of human neuroblastoma extracts. The same protein species was detected in human and rat cortex synaptosomes and in sucrose density gradients of vesicle-enriched fractions, where huntingtin immunoreactivity overlapped with the distribution of vesicle membrane proteins (SV2, transferrin receptor, and synaptophysin). Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites, rather than the more selective pattern of axon terminal labeling characteristic of many vesicle-associated proteins. At the ultrastructural level, immunoreactivity in cortical neurons was detected in the matrix of the cytoplasm and around the membranes of the vesicles. The ubiquitous cytoplasmic distribution of huntingtin in neurons and its association with vesicles suggest that huntingtin may have a role in vesicle trafficking.

Eosinophilic vasculitis in an isolated central nervous system distribution.

BACKGROUND: Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases; presentation in an isolated CNS distribution is rare. We present a case of eosinophilic vasculitis isolated to the CNS. CASE REPORT: A 39-year-old woman with a history of migraine without aura presented to an institution (located in the borough of Queens, New York, USA; no academic affiliation) in an acute confusional state with concurrent headache and left-sided weakness and numbness. Laboratory evaluation showed increased cerebrospinal fluid (CSF) protein level, but an otherwise unremarkable serological investigation. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over 2 weeks without residual deficit. After 18 months, later the patient presented with similar symptoms and neuroradiological findings involving territories different from those in her first episode. Again, the CSF protein level was high. She had a raised C reactive protein level and erythrocyte sedimentation rate. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates of medium-sized leptomeningeal arteries without granulomas. She improved, without recurrence, when treated with a prolonged course of corticosteroids. CONCLUSIONS: To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. Spontaneous resolution and recurrence of her syndrome is an unusual feature of the typical CNS vasculitis and may suggest an environmental epitope with immune reaction as the cause.

Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes.

OBJECTIVE: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. METHODS: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. RESULTS: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. CONCLUSION: PGRN mutations are not a common cause of ALS phenotypes.

Relationship of clinical efficacy to postmortem-determined anatomic subthalamic stimulation in Parkinson syndrome.

OBJECTIVE/BACKGROUND: Patients with medically refractory Parkinson's disease (PD) obtain significant clinical benefit from subthalamic nucleus (STN) stimulation. The degree to which a successful outcome relates to the anatomic location of the stimulating electrode has not yet been clearly established. Many studies have attempted to correlate the clinical result with the electrode location using postoperative magnetic resonance imaging (MRI) and there have been a few that used autopsy-determined locations. In this report, we describe long-term clinical follow-up in a patient with autopsy-determined electrode tip anatomic location. METHODS: A 67-year-old patient with a 27-year history of idiopathic PD complicated by disabling motor fluctuations and dopaminergic dyskinesias underwent bilateral STN deep brain stimulation (DBS). He was prospectively followed in a long-term clinical protocol until his death 40 months after electrode placement. Postoperative magnetic resonance (MR) imaging and postmortem studies of this patient's brain were performed to localize DBS tip locations. RESULTS: STN stimulation produced improvement of the patient's motor fluctuations, dyskinesias and clinical motor performance, especially appendicular tremors, rigidity and bradykinesia. MRI showed the electrode tips to be within 2 mm of the intended target. Postmortem brain analysis identified the right DBS tip location at the dorsomedial edge of the STN, with the left electrode in the vicinity (but not within) the STN. Chronic DBS elicited minor reactive changes were confined to the immediate vicinity of the electrode tracks. The pathological analysis demonstrated numerous cortical Lewy bodies and degenerative encephalopathy, establishing the diagnosis of transitional type diffuse Lewy body disease (DLBD) rather than simple PD. CONCLUSION: This patient obtained clinical benefit from STN stimulation typical of that seen for most PD patients. Both the MR analysis and the autopsy demonstrated electrode placement at or outside the boundaries of the STN, suggesting that that clinical efficacy may not depend on electrode location within the central region of the STN.

Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain.

Huntington's disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG-repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo-and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease.

We performed morphometric analysis of five standardized coronal brain slices at anterior frontal (AF), caudate-putamen-accumbens (CAP), globus pallidus (GP), lateral geniculate nucleus (LGN), and parieto-occipital fissure (OCP) levels in 30 patients with Huntington's disease (HD) and 13 controls. Associated with the 30% mean reduction in brain weight in HD patients (p less than 0.001) were significantly smaller overall cross-sectional areas of brain at all five levels studied, with striking losses in cerebral cortex (21-29%), white matter (29-34%), caudate (57%), putamen (64%), and thalamus (28%) (all p less than 0.005). In addition, the ventricular system was dilated up to 2.5 times normal at CAP, GP, and LGN levels, 9.5 times normal at the OCP level, and 13 times normal at the AF level. Higher grades of severity of HD had greater reductions in the cross-sectional area of the caudate, putamen, thalamus, and cerebral cortex (p less than 0.005-0.001), and larger ventricles (p = 0.08) compared to lower (less severe) grades of HD. The findings confirm and quantitate the severe atrophy of the neostriatum, in addition to demonstrating a severe loss of cerebral cortex and subcortical white matter in HD. The global atrophy of cerebral cortex and white matter observed in all degrees of HD may account for the cognitive and neuropsychiatric impairments which often precede the onset of chorea.

Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease.

Aggregation of N-terminal mutant huntingtin within nuclear inclusions and dystrophic neurites occurs in the cortex and striatum of Huntington disease (HD) patients and may be involved in neurodegeneration. We examined the prevalence of inclusions and dystrophic neurites in the cortex and striatum of 15 adult onset HD patients who had mild to severe striatal cell loss (grades 1, 2 or 3) using an antibody that detects the N-terminal region of huntingtin. Nuclear inclusions were more frequent in the cortex than the striatum and were sparse or absent in the striatum of patients with low-grade striatal pathology. Dystrophic neurites occurred in both regions. Patients with low-grade striatal pathology had numerous fibers with immunoreactive puncta and large swellings within the striatal neuropil, the subcortical white matter, and the internal and external capsules. In the globus pallidus of 3 grade 1 cases, N-terminal huntingtin markedly accumulated in the perinuclear cytoplasm and in some axons but not in the nucleus. Findings suggest that in the earlier stages of HD, accumulation of N-terminal mutant huntingtin occurs in the cytoplasm and is associated with degeneration of the corticostriatal pathway.

Decreased neuronal and increased oligodendroglial densities in Huntington's disease caudate nucleus.

Decreased density of neurons was found throughout the head of the caudate nucleus in Huntington's disease (HD), with the most severe neuronal loss early in the disease in the medial region. The density of reactive astrocytes is inversely proportional to the neuronal loss. In cases of mild Huntington's disease which had no identifiable abnormality on conventional neuropathologic evaluation (grade 0), there is a reduction in neuron density without an accompanying reactive astrocytosis. The pattern for decrease in neurons and accompanying astrocytosis suggests that the earliest changes occur in the most medial portion of the head of the caudate nucleus and subsequently sweep laterally across the caudate nucleus to the internal capsule. An increased density of oligodendrocytes is observed in the head of the caudate nucleus for the lower grades (0, 1 and 2). The decreased neuronal and increased oligodendroglial densities may be of significance in understanding the pathogenesis of HD. These altered densities, observed in the absence of reactive astrocytosis, suggest that these changes may not represent recent effects of disease, but rather that HD gene expression may influence brain cell densities from early in the life of the gene carrier.

Neuropathological classification of Huntington's disease.

In postmortem brain specimens from 163 clinically diagnosed cases of Huntington's disease (HD) the striatum exhibited marked variation in the severity of neuropathological involvement. A system for grading this severity was established by macroscopic and microscopic criteria, resulting in five grades (0-4) designated in ascending order of severity. The grade correlates closely with the extent of clinical disability as assessed by a rating scale. In five cases of clinically diagnosed HD there were no discernible neuropathological abnormalities (grade 0), suggesting that the anatomical changes lag behind the development of clinical abnormalities. In eight cases, neuropathological changes could only be recognized microscopically (grade 1). The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4; astrocytes are greatly increased in grades 2-4. These studies indicate that analyses of the CN in grade 4 would reflect mainly its astrocytic composition with a component of remote neurons projecting to the striatum. Because of the relative preservation of the lateral half of the head of the CN in grades 1-2, these regions would reflect early cellular and biochemical changes in HD.

Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury.

The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.