Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer's disease and primary age-related tauopathy.

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disease that, in some cases, is associated with cognitive impairment and tau accumulation. Consequently, we explored the tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify tau prion seeding activity present in brain homogenates based on conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Prions exhibit seeding barriers, whereby a specific assembly structure cannot serve as a template for a native monomer if the amino acids are not compatible. We recently exploited the tau prion species barrier to define tauopathies by systematically substituting alanine (Ala) in the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. The Ala scan precisely classified the conformation of tau seeds from diverse tauopathies. We next studied 18 ET patient brains with tau pathology. Only one case had concurrent high amyloid-ß plaque pathology consistent with Alzheimer's disease (AD). We detected robust tau seeding activity in 9 (50%) of the patients. This predominantly localized to the temporal pole and temporal cortex. We examined 8 ET cases with the Ala scan and determined that the amino acid requirements for tau monomer incorporation into aggregates seeded from these ET brain homogenates were identical to those of AD and primary age-related tauopathy (PART), and completely distinct from other tauopathies such as corticobasal degeneration, chronic traumatic encephalopathy, and progressive supranuclear palsy. Based on these studies, tau assembly cores in a pathologically confined subset of ET cases with high tau pathology are identical to AD and PART. This could facilitate more precise diagnosis and therapy for ET patients with cognitive impairment.

Purkinje Cell Dendritic Swellings: A Postmortem Study of Essential Tremor and Other Cerebellar Degenerative Disorders.

Under stress, Purkinje cells (PCs) undergo a variety of reactive morphological changes. These can include swellings of neuronal processes. While axonal swellings, "torpedoes", have been well-studied, dendritic swellings (DS) have not been the centerpiece of study. Surprisingly little is known about their frequency or relationship to other morphological changes in degenerating PCs. Leveraging a large brain bank, we (1) examined the morphology of DS, (2) quantified DS, and (2) examined correlations between counts of DS versus 16 other PC morphological changes in a broad range of cerebellar degenerative disorders. There were 159 brains - 100 essential tremor (ET), 13 Friedreich's ataxia, and 46 spinocerebellar ataxia (SCA) (14 SCA1, 7 SCA2, 13 SCA3, 5 SCA6, 5 SCA7, and 2 SCA8). DS were a feature of PCs across all these disorders, with varying morphologies and changes elsewhere in the dendritic arbor. On Luxol fast blue/hematoxylin and eosin-stained sections, the median number of DS per PC ranged from 0.001 in ET to 0.025 in SCA8. Bielschowsky-stained sections yielded higher counts, from 0.003 in ET to 0.042 in SCA6. Torpedo counts exceeded DS counts by one order of magnitude. DS counts were more robustly correlated with torpedo counts than with counts for any of the other PC morphological changes. In summary, DS ranged in prevalence across cerebellar degenerative disorders, from 1/1,000 to 42/1,000 PCs. Across disorders of cerebellar degeneration, these swellings of the dendritic compartment were most robustly correlated with swellings of the axonal compartment, suggesting a similar type of cellular response to duress.

Subjective Sleep Disturbance and Lewy Pathology: Data from a Cohort of Essential Tremor Brain Donors.

INTRODUCTION: Sleep disturbances have been associated with essential tremor (ET). However, their pathophysiological underpinnings remain unknown. In this exploratory study, we examined the association between subjective sleep disturbances and the presence of Lewy pathology (LP) on postmortem brain examination in ET cases. METHODS: Fifty-two ET cases enrolled in a prospective, longitudinal study were assessed over an average period of 42 months. Cases completed the Pittsburgh Sleep Quality Index (PSQI), which yields seven component scores (e.g., sleep quality, sleep latency). For each component score, we calculated the difference between the last score and the baseline score. Brains were harvested at death. Each had a complete neuropathological assessment, including extensive α-synuclein immunostaining. We examined the associations between baseline PSQI scores and the change in PSQI scores (last - first), and LP on postmortem brain examination. RESULTS: ET cases had a mean baseline age of 87.1 ± 4.8 years. LP was observed in 12 (23.1%) of 52 cases; in 7 of these 12, LP was observed in the locus coeruleus (LC). Change in time needed to fall asleep (last - first sleep latency component score) was associated with presence of LP on postmortem brain examination - greater increase in sleep latency was associated with higher odds of LP (odds ratio = 2.98, p = 0.02). The greatest increase in sleep latency was observed in cases with LP in the LC (p = 0.04). CONCLUSION: In ET cases, increases in sleep latency over time could be a marker of underlying LP, especially in the LC.

Pathologically based criteria to distinguish essential tremor from controls: analyses of the human cerebellum.

OBJECTIVE: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. METHODS: Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. RESULTS: Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. INTERPRETATION: These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.

Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1.

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration.

Reduced Bergmann glial process terminations and lateral appendages in essential tremor.

OBJECTIVE: Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum. METHODS: We applied the Golgi-Kopsch method and used computerized three-dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well. RESULTS: Essential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume. INTERPRETATION: These findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.

Decreased Synaptic Vesicle Glycoprotein 2A Binding in the Human Postmortem Essential Tremor Cerebellum: Evidence of Reduction in Synaptic Density.

OBJECTIVE: Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases. METHODS: The current study utilized autoradiography with the SV2A radioligand [18F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls. RESULTS: Using [18F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls. CONCLUSION: In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.

Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium 'leak' in tremor pathophysiology.

Essential Tremor (ET) is a prevalent neurological disease characterized by an 8-10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca2+) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a "leaky channel" biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This 'leaky' RyR1 signature was not seen in control or Parkinson's disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca2+ leak via RyR1 may contribute to tremor pathophysiology.

Decreased Synaptic Vesicle Glycoprotein 2A Binding in the Human Postmortem Essential Tremor Cerebellum: Evidence of Reduction in Synaptic Density.

Objective Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and that a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases. Methods The current study utilized autoradiography with the SV2A radioligand [ 18 F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls. Results Using [ 18 F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls. Conclusion For the first time, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.

Patterns of TDP-43 Deposition in Brains with LRRK2 G2019S Mutations.

OBJECTIVE: To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation. BACKGROUND: LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers. METHODS: Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration. RESULTS: TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change. CONCLUSIONS: Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society.

Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains.

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich's ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson's disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50). We generated data on 37 quantitative morphologic metrics, grouped into 8 broad categories: Purkinje cell (PC) loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes. Principal component analysis of z scored raw data across all diagnoses (11,651 data items) revealed that diagnostic groups were not uniform with respect to pathology. Dystonia and PD each differed from controls in only 4/37 and 5/37 metrics, respectively, whereas ET differed in 21, FA in 10, SCA3 in 10, MSA in 21, and SCA1/2/6/7/8/14 in 27. Pathological changes were generally on the milder end of the degenerative spectrum in ET, FA and SCA3, and on the more severe end of that spectrum in SCA1/2/6/7/8/14. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. In summary, we present a robust and reproducible method that identifies somewhat distinctive signatures of degenerative changes in the cerebellar cortex that mark each of these disorders.

Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.

Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis. We previously performed a transcriptome analysis in ET cerebellar cortex, identifying candidate genes and several dysregulated pathways. To directly target PCs, we purified RNA from PCs isolated by laser capture microdissection and performed the first ever PC-specific RNA-sequencing analysis in ET versus controls. Frozen postmortem cerebellar cortex from 24 ETs and 16 controls underwent laser capture microdissection, obtaining ≥2000 PCs per sample. RNA transcriptome was analyzed via differential gene expression, principal component analysis (PCA), and gene set enrichment analyses (GSEA). We identified 36 differentially expressed genes, encompassing multiple cellular processes. Some ET (13/24) had greater dysregulation of these genes and segregated from most controls and remaining ETs in PCA. Characterization of genes/pathways enriched in this PCA and GSEA identified multiple pathway dysregulations in ET, including RNA processing/splicing, synapse organization/ion transport, and oxidative stress/inflammation. Furthermore, a different set of pathways characterized marked heterogeneity among ET patients. Our data indicate a range of possible mechanisms for the pathogenesis of ET. Significant heterogeneity among ET combined with dysregulation of multiple cellular processes supports the notion that ET is a family of disorders rather than one disease entity.

Characterizing Lewy Pathology in 231 Essential Tremor Brains From the Essential Tremor Centralized Brain Repository.

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases.

Is essential tremor a degenerative disorder or an electric disorder? Degenerative disorder.

Essential tremor (ET) is a highly prevalent neurologic disease and is the most common of the many tremor disorders. ET is a progressive condition with marked clinical heterogeneity, associated with a spectrum of both motor and non-motor features. However, its disease mechanisms remain poorly understood. Much debate has centered on whether ET should be considered a degenerative disorder, with underlying pathological changes in brain causing progressive disease manifestations, or an electric disorder, with overactivity of intrinsically oscillatory motor networks that occur without underlying structural brain abnormalities. Converging data from clinical, neuroimaging and pathological studies in ET now provide considerable evidence for the neurodegenerative hypothesis. A major turning point in this debate is that rigorous tissue-based studies have recently identified a series of structural changes in the ET cerebellum. Most of these pathological changes are centered on the Purkinje cell and connected neuronal populations, which can result in partial loss of Purkinje cells and circuitry reorganizations that would disturb cerebellar function. There is significant overlap in clinical and pathological features of ET with other disorders of cerebellar degeneration, and an increased risk of developing other degenerative diseases in ET. The combined implication of these studies is that ET could be degenerative. The evidence in support of the degenerative hypothesis is presented.

Clinicopathological correlates of pyramidal signs in multiple system atrophy.

OBJECTIVE: Pyramidal signs are common but often under-recognized in multiple system atrophy (MSA). The clinicopathological correlates of pyramidal signs in MSA are not well characterized. The present study aims to understand the role of pyramidal signs in MSA. METHODS: We examined 40 autopsy-confirmed MSA cases in New York Brain Bank. The pyramidal signs were quantified by an established rating scale, summarized as the pyramidal score. We assessed whether pyramidal scores are associated with autonomic, parkinsonism, and cerebellar features and survival. We also examined whether the density of glial cytoplasmic inclusions (GCIs) in the motor cortex and its underlying white matter is associated with the pyramidal score. RESULTS: MSA parkinsonian type cases have higher pyramidal scores compared to cerebellar type cases (p = 0.017). MSA cases with high pyramidal scores are more likely to have laryngeal stridor (OR = 4.89, p = 0.022), but less likely to have orthostatic hypotension (OR = 0.11, p = 0.006) and erectile dysfunction (OR = 0.05, p = 0.018). MSA cases with high pyramidal scores do not differ from those with low pyramidal scores in terms of bowel dysfunction, dry eyes and mouth, and survival. Finally, MSA cases with more GCIs in the motor cortex have higher pyramidal scores compared to those with few GCIs (p = 0.017). INTERPRETATION: Pyramidal signs in MSA are associated with the parkinsonian subtype, laryngeal stridor, and certain autonomic dysfunction.

The distribution and density of Huntingtin inclusions across the Huntington disease neocortex: regional correlations with Huntingtin repeat expansion independent of pathologic grade.

Huntington disease is characterized by progressive neurodegeneration, especially of the striatum, and the presence of polyglutamine huntingtin (HTT) inclusions. Although HTT inclusions are most abundant in the neocortex, their neocortical distribution and density in relation to the extent of CAG repeat expansion in the HTT gene and striatal pathologic grade have yet to be formally established. We immunohistochemically studied 65 brains with a pathologic diagnosis of Huntington disease to investigate the cortical distributions and densities of HTT inclusions within the calcarine (BA17), precuneus (BA7), motor (BA4) and prefrontal (BA9) cortices; in 39 of these brains, a p62 immunostain was used for comparison. HTT inclusions predominate in the infragranular cortical layers (layers V-VI) and layer III, however, the densities of HTT inclusions across the human cerebral cortex are not uniform but are instead regionally contingent. The density of HTT and p62 inclusions (intranuclear and extranuclear) in layers V-VI increases caudally to rostrally (BA17 < BA7 < BA4 < BA9) with the median burden of HTT inclusions being 38-fold greater in the prefrontal cortex (BA9) than in the calcarine cortex (BA17). Conversely, intranuclear HTT inclusions prevail in the calcarine cortex irrespective of HTT CAG length. Neocortical HTT inclusion density correlates with CAG repeat expansion, but not with the neuropathologic grade of striatal degeneration (Vonsattel grade) or with the duration of clinical disease since motor onset. Extrapolation of these findings suggest that HTT inclusions are at a regionally-contingent, CAG-dependent, density during the advanced stages of HD. The distribution and density of HTT inclusions in HD therefore does not provide a measure of pathologic disease stage but rather infers the degree of pathogenic HTT expansion.

Human Polyomavirus 9-An Emerging Cutaneous and Pulmonary Pathogen in Solid Organ Transplant Recipients.

IMPORTANCE: We describe the first report to our knowledge of cutaneous and systemic pathogenicity of human polyomavirus 9 in solid organ transplant recipients. OBJECTIVE: Three solid organ transplant recipients developed a widespread, progressive, violaceous, and hyperkeratotic skin eruption. All died from pulmonary and multiorgan failure around 1 year from onset of the rash. Routine clinical diagnostic testing could not identify any causative agent; therefore, samples and autopsies were investigated for novel pathogens using high-throughput sequencing. DESIGN, SETTING, AND PARTICIPANTS: This case series, including 3 solid organ transplant recipients who developed characteristic pink, violaceous, or brown hyperkeratotic papules and plaques throughout the body, was conducted at the Columbia University Medical Center. Lesional skin biopsies were collected from all 3 patients and subjected to high-throughput illumina sequencing for identification of microbial pathogens. Human polyomavirus 9 was identified in lesional skin biopsies. We subsequently collected ocular swabs, oral swabs, urine samples, and blood samples from patients, and organ tissues at autopsy in 1 patient. We investigated these samples for the presence of human polyomavirus 9 using in situ hybridization and quantitative polymerase chain reaction (PCR) assays. MAIN OUTCOMES AND MEASURES: A description of the clinical and pathologic findings of 3 patients. RESULTS: This case series study found that human polyomavirus 9 was detected in the skin biopsies of all 3 patients by a capture-based high-throughput sequencing method platform (VirCapSeq-VERT). Human polyomavirus 9 was also detected in blood, oral, ocular swabs, and urine by real-time polymerase chain reaction (PCR) assay. In situ hybridization and quantitative PCR assays were performed on the skin biopsies from 3 patients and lung autopsy of 1 patient, which showed the presence of human polyomavirus 9 messenger RNA transcripts, indicating active viral replication and pathogenesis in the skin and lungs. CONCLUSIONS AND RELEVANCE: Human polyomavirus 9 was associated with the widespread cutaneous eruption. All 3 patients had progression of cutaneous disease, accompanied by clinical deterioration, pulmonary failure, and death. One patient underwent autopsy and human polyomavirus 9 was identified in the lungs and paratracheal soft tissue. These findings suggest that human polyomavirus 9 may be associated with cutaneous and possibly pulmonary infection and death in solid organ transplant recipients.

Pituitary corticotroph tumour with adrenocortical cells: A distinct clinicopathologic entity with unique morphology and methylation profile.

We describe a rare TPIT-positive corticotroph PitNET that is admixed with SF1-positive adrenocortical cells. This dimorphous population of cells showed no colocalisation between TPIT and SF1 by immunofluorescence, and an adrenocortical choristoma was favoured. Methylation array analysis revealed a novel methylation profile in relation to other pituitary neoplasms.

Tau Isoform Profile in Essential Tremor Diverges From Other Tauopathies.

Patients with essential tremor (ET) frequently develop concurrent dementia, which is often assumed to represent co-morbid Alzheimer disease (AD). Autopsy studies have identified a spectrum of tau pathologies in ET and tau isoforms have not been examined in ET. We performed immunoblotting using autopsy cerebral cortical tissue from patients with ET (n = 13), progressive supranuclear palsy ([PSP], n = 10), Pick disease ([PiD], n = 2), and AD (n = 7). Total tau in ET samples was similar to that in PSP and PiD but was significantly lower than that in AD. Abnormal tau levels measured using the AT8 phospho-tau specific (S202/T205/S208) monoclonal antibody in ET were similar to those in PSP but were lower than in PiD and AD. In aggregates, tau with 3 microtubule-binding domain repeats (3R) was significantly higher in AD than ET, while tau with 4 repeats (4R) was significantly higher in PSP. Strikingly, the total tau without N-terminal inserts in ET was significantly lower than in PSP, PiD, and AD, but total tau with other N-terminal inserts was not. Monomeric tau with one insert in ET was similar to that in PSP and PiD was lower than in AD. Thus, ET brains exhibit an expression profile of tau protein isoforms that diverges from that of other tauopathies.