MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Pick's disease presenting with corticobasal syndrome: A case report and clinicopathological review.

Pick's disease (PiD) is a rare form of frontal temporal lobar degeneration. The pathognomonic feature is atrophy of the frontotemporal lobes and intraneuronal deposits of 3R-τ inclusions, the Pick body. Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome with a heterogeneous spectrum of underlying pathologies. We report a case of clinically diagnosed CBS with a post-mortem diagnosis of PiD and conduct a clinicopathological review of the literature on this unusual presentation.

Impact of COVID-19 pandemic on neuropathology service: Experience at one Canadian center.

The COVID-19 pandemic has had a significant impact on medical services. Many countries postponed nonemergent procedures to preserve hospital resources for the unprecedented situation. Surgical backlogs caused by the COVID-19 pandemic have been evaluated by different groups. However, the impact of this pandemic on pathology and specifically neuropathology (NP) services has received limited attention. In this study, we reviewed all NP reports of the London Health Sciences Centre from January 2018 (2 years before the pandemic declaration) until the end of the year 2021. Demographic information and pathology details were collected. For tumors, site, histopathology types, and WHO grading were analyzed. In nontumoral specimens, pathological diagnoses were compared in pre- and postpandemic time. The total number of NP samples reached its lowest in April 2020, corresponding to the first Ontario provincial lockdown, and fluctuated throughout the studied period. Among the different types of NP surgical specimens, muscle and epilepsy-related specimens showed a more significant reduction, compared to neoplastic specimens. In 2020, the proportion of tumor specimens from patients older than 40 years of age increased. Similarly, the proportion of high-grade glioma and brain metastasis diagnoses also increased. Lastly, we observed a marked increase in biopsies for temporal arteritis and other inflammatory lesions.

Epilepsy-associated death in the Southwestern Ontario: A clinicopathological correlation study.

Patients with epilepsy are at elevated risk for premature mortality, of which sudden unexpected death in epilepsy (SUDEP) is one of the leading causes. SUDEP incidence varies significantly depending on the population and the methods used to document the cause of death. We performed retrospective case review at the London Health Sciences Centre for the period of 2000 to 2018. Clinical information, scene investigations, general pathology findings, toxicology, and neuropathology findings were obtained, examined, and confirmed by two neuropathologists and one epileptologist. The characteristics were compared and summarized. We also evaluated the impact of 2010 revision of Ontario Coroner Act Regulation, which significantly limited whole brain examination. Among the 12,206 cases reviewed, we identified 152 cases with a known history of epilepsy. Ninety-seven cases (64%) were classified as SUDEP. There were significantly more SUDEP decedents found dead unwitnessed at night in prone position, than non-SUDEP. Generalized seizures were strongly associated with SUDEP. A male predominance was observed in SUDEP group between 15 and 35 years old. Near half of the brains examined were "unremarkable." There was no difference in neuropathology findings between SUDEP and non-SUDEP groups. After implementation of the 2010 revision of Ontario Coroner Act Regulation, fixed whole brain examination was reduced from 88% to 7% of the epilepsy-related death investigation. Except a lower diagnosis rate of "inflammatory/infectious changes," there were no significant differences in neuropathology findings. This is the first detailed clinical-pathological study on epilepsy-related death based on a Canadian cohort. This study reinforces the previously reported findings in SUDEP and highlights the importance of clinicopathological correlation for accurate classification of epilepsy-related death.

White matter cellular changes in ischemic injuries.

OBJECTIVES: The white matter ischemic changes described in the literature are not specific and include white matter rarefaction, axonal damage, myelin degeneration, astrocytic fragmentation and beading of its processes (clasmatodendrosis), oligodendrocyte loss, and microglial activation. This morphological spectrum overlaps with morphological features of many other conditions. This retrospective study aims to describe the cellular changes (using immunohistochemical studies) in a spectrum of ischemic leukoencephalopathy. METHODS: We studied 24 white matter ischemic injury cases with a well-documented interval from the ischemic event of interest. The autopsy reports were reviewed for the clinical information and pathological features to select the most representative areas for other stains and immunostains: luxol fast blue with hematoxylin and eosin (LFB-HE), anti-amyloid precursor protein (APP), anti-glial fibrillary acidic protein (GFAP), and anti-human leukocyte antigen (HLA-DR) antibodies. RESULTS: The early changes detected in mild injury were axonal staining highlighted by APP immunostain and astrocytic and microglial reaction with no significant cellular loss. The most severe injury may lead to losing almost all cellular elements (complete infarct) and replacement by macrophages with time. Injuries in between resulted in a morphological spectrum of selective cellular injury (incomplete infarct), including apoptotic nuclei, axonal staining and swellings, clasmatodendrosis, and loss of ramified microglia. CONCLUSIONS: The pathological findings suggested that widespread axonal staining and swellings are early features followed or accompanied by loss of HLA-DR positive ramified microglia and then by astrocytes in ischemic leukoencephalopathy. The awareness of this morphological spectrum would prevent misdiagnosis, provide a better understanding of this condition and can guide future studies on this important and common subject.

Intracerebral retina-like pigmented tissue in a stillborn fetus with holoprosencephaly.

A stillbirth fetus with semilobar holoprosencephaly was induced at 24 weeks gestational age. While the eyes appeared unremarkable externally, there was an absence of optic nerves. At the ventral hypothalamicdiencephalic region there was an area of bilateral epithelioid cells containing melanin. Immunohistochemical characterization revealed the cells to be of neuroepithelial origin with features of retinal pigment epithelium. These findings reflect abnormalities in eye development in holoprosencephaly, especially when coupled with other structural defects in the visual system.

Distinct subcortical tau burden: The tau pallido-claustral ratio separates progressive supranuclear palsy and corticobasal degeneration.

Neuropathological diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) requires interpretation of tau morphology based on extensive brain sampling. Here we report subcortical tau burden is sufficient to distinguish PSP and CBD, regardless of the tau morphology. The tau pallido-claustral ratio is a promising diagnostic indicator for PSP and CBD.

Neuropathology of Perry Syndrome: Evidence of Medullary and Hypothalamic Involvement.

BACKGROUND: Perry syndrome is a rare genetic parkinsonian disorder with TAR DNA binding protein 43 (TDP-43) pathology clinically presenting with parkinsonism, neuropsychiatric features, weight loss, and central hypoventilation. As respiratory complications are often the cause of death, studies likely show the early stage of the neurodegenerative process. Because of the rarity of this condition, few studies exist, and each case provides insight into pathological findings in this neurodegenerative condition. OBJECTIVE: To study the clinical and pathological correlations of an autopsy case of Perry syndrome. METHODS: The patient was a woman in her 50s with Perry syndrome and a DCTN1 gene mutation. Between October 2016 and July 2019, she underwent postmortem and pathological examination at University Hospital in London, Ontario, Canada. Data were obtained through clinical pathological examination. RESULTS: Microscopy showed significant neuronal loss with pigmentary incontinence and gliosis in the substantia nigra. There was no atrophy elsewhere, including the frontal and cingulate cortex. Intraneuronal cytoplasmic TDP-43 inclusions and neurites were noticed in a moderate number in the substantia nigra and midbrain and were sparsely noticed in the basal ganglia, thalamus, thoracic motor neuron, posterior nucleus of the hypothalamus, and rostral ventral medulla. ß-Amyloid, Lewy body, and tau pathologies were absent. Rare axonal swelling was identified at the rostral ventrolateral medulla. CONCLUSIONS AND RELEVANCE: This study confirms that Perry syndrome is characterized by TDP-43 pathology with absent Lewy bodies or tau pathology. These findings support the hypothesis of dysfunctional neurons in the medulla and hypothalamus, which may respectively correlate to the clinical symptoms of hypoventilation and weight loss in Perry syndrome.

Vagus nerve stimulation does not alter brainstem nuclei morphology in patients with refractory epilepsy.

OBJECTIVE: To describe morphological characteristics of the brainstem nuclei in response to chronic vagus nerve stimulation (VNS) in patients with refractory epilepsy. BACKGROUND: VNS is a treatment option for individuals with medically refractory epilepsy. While treatment with VNS may achieve up to 50% seizure reduction and is protective against sudden unexpected death in epilepsy (SUDEP), its mechanism of action is not fully understood. Long-term structural and cellular changes in response to VNS have rarely been addressed in humans. METHODS: Four autopsy cases with history of chronic epilepsy treated with VNS (VNS+) and 4 age- and sex-matched chronic epilepsy-related death cases without VNS (VNS-) were included. Detailed clinical and postmortem data were obtained. Serial horizontal sections of the brainstem were prepared and stained with hematoxylin, eosin, and luxol fast blue (HE/LFB). Three regions of interest (ROIs) were delineated, including nucleus tractus solitarius (NTS), locus coeruleus (LC), and the rostral pontine group of raphe nuclei (rRN). Immunohistochemistry studies were performed using antibodies to GFAP, NeuN, HLA-DR, and IBA-1. Immunolabeling index was analyzed. RESULTS: Three of the 4 VNS+ patients and all 4 control (VNS-) patients died of SUDEP. There was no laterality difference in the NeuN, GFAP, HLA-DR and IBA-1 expression in LC and NTS of VNS+ patients. Similarly, there was no difference in the rRN, LC, and NTS between the VNS+ and VNS- groups. CONCLUSION: This study represents the first histopathological study of the long-term effects of VNS therapy in the human brain. There was no difference observed in the neuronal cell number, degree of astrocytosis, and neuroinflammation in the main brainstem vagal afferent nuclei after prolonged VNS treatment in patients with refractory epilepsy.

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

α-tropomyosin gene (TPM3) mutation in an infant with nemaline myopathy.

We report a case of neonatal nemaline myopathy with a de novo TPM3 mutation, which has been classified as a likely pathogenic mutation. With the expanding use of genetic testing in congenital myopathies, genotype-phenotype descriptions of novel variants are important to inform clinical care, diagnosis, genetic counseling, and management of disease.

Serotonin transporter protein in autopsied brain of chronic users of cocaine.

RATIONALE: The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug. OBJECTIVE AND METHODS: Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11). RESULTS: We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid. CONCLUSION: Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.

Clinicopathological overlap of neurodegenerative diseases: A comprehensive review.

Clinical and neuropathological overlap of two or more neurodegenerative diseases (ND) is not an uncommon occurrence yet is still underdiagnosed in clinical neurological and neuropathological. The authors present a clinicopathological overview of the current understanding of overlapping ND's with the hope that this review will encourage further studies that are required to investigate the effect of such overlaps on clinical presentations and how often clinical presentations raise the suspicion of multiple ND's. The authors suggest that as more patients with overlapping ND's come to light, traditional classification system of ND's may need to be modified.

Concentration, distribution, and influence of aging on the 18 kDa translocator protein in human brain: Implications for brain imaging studies.

Positron emission tomography (PET) imaging of the translocator protein (TSPO) is widely used as a biomarker of microglial activation. However, TSPO protein concentration in human brain has not been optimally quantified nor has its regional distribution been compared to TSPO binding. We determined TSPO protein concentration, change with age, and regional distribution by quantitative immunoblotting in autopsied human brain. Brain TSPO protein concentration (>0.1 ng/µg protein) was higher than those reported by in vitro binding assays by at least 2 to 70 fold. TSPO protein distributed widely in both gray and white matter regions, with distribution in major gray matter areas ranked generally similar to that of PET binding in second-generation radiotracer studies. TSPO protein concentration in frontal cortex was high at birth, declined precipitously during the first three months, and increased modestly during adulthood/senescence (10%/decade; vs. 30% for comparison astrocytic marker GFAP). As expected, TSPO protein levels were significantly increased (+114%) in degenerating putamen in multiple system atrophy, providing further circumstantial support for TSPO as a gliosis marker. Overall, findings show some similarities between TSPO protein and PET binding characteristics in the human brain but also suggest that part of the TSPO protein pool might be less available for radioligand binding.

Loss of Ramified Microglia Precedes Axonal Spheroid Formation in Adult-Onset Leukoencephalopathy with Axonal Spheroids.

Two different pathological mechanisms have been suggested to underlie adult-onset leukoencephalopathy with axonal spheroids (ALAS). Pathological studies have suggested that ALAS involves primary axonopathy with secondary demyelination. However, the identification of mutations in Colony Stimulating Factor 1 Receptor (CSF1R), important for microglial survival, has suggested that ALAS is a microgliopathy. This study examines the correlation between microglial changes and axonopathy in ALAS. A total of 6 ALAS cases were studied. White matter lesions were classified into three evolving stages: 1) numerous axonal spheroids among well-myelinated fibers; 2) moderate loss of myelinated fibers with or without axonal spheroids; and 3) a leukodystrophy-like pattern of severe confluent axonal and myelin loss. Axonal spheroids and ramified microglia were semi-quantified and the lesions were assigned a score of 0-3. We found a strong correlation between the preponderance of axonal spheroids and ramified microglial loss. All areas with a predominance of axonal spheroids showed a near-complete absence of ramified microglia, which was also apparent in small cortical and white matter lesions. In contrast, some areas with no ramified microglia showed no axonal pathology. Our findings support the suggestion that ramified microglia loss precedes axonal spheroids formation. This observation will help to better understand the pathogenesis of ALAS and suggests a protective role of microglia.