Papers by Claire Shepherd
Neurotoxicity Research, 2004
SIGLEAvailable from British Library Document Supply Centre-DSC:DXN027082 / BLDSC - British Librar... more SIGLEAvailable from British Library Document Supply Centre-DSC:DXN027082 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
Frontiers in Neurology, Jun 19, 2023
Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traum... more Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football during their youth would be more likely to have CTE-NC than those who did not play contact or collision sports, and (iii) there would be no association between CTE-NC and suicide as a manner of death. Methods: Brain tissue from 186 men and accompanying clinical information were obtained from the Lieber Institute for Brain Development. Manner of death was determined by a board-certified forensic pathologist. Information was obtained from next of kin telephone interviews, including medical, social, demographic, family, and psychiatric history. The 2016 and 2021 consensus definitions were used for CTE-NC. Two authors screened all cases, using liberal criteria for identifying "possible" CTE-NC, and five authors examined the 15 selected cases. Results: The median age at the time of death was 65 years (interquartile range = 57-75; range = 50-96). There were 25.8% with a history of playing American football and 36.0% who had suicide as their manner of death. No case was rated as definitively having "features" of CTE-NC by all five authors. Ten cases were rated as having features of CTE-NC by three or more authors (5.4% of the sample), including 8.3% of those with a personal history of playing American football and 3.9% of those who did not play contact or collision sports. Of those with mood disorders during life, 5.5% had features of CTE-NC compared to 6.0% of those who did not have a reported mood disorder. Of those with suicide as a manner of death, 6.0% had features of CTE-NC compared to 5.0% of those who did not have suicide as a manner of death.
Journal of Neuropathology & Experimental Neurology
BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic b... more BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescri...
Frontiers in Neuroscience
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, pathologically hallmarked b... more Parkinson’s disease (PD) is a progressive neurodegenerative disorder, pathologically hallmarked by the loss of dopamine neurons in the substantia nigra (SN) and alpha-synuclein aggregation. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a common target to treat the motor symptoms in PD. However, we have less understanding of the cellular changes in the STN during PD, and the impact of DBS on the STN and SN is limited. We examined cellular changes in the SN and STN in PD patients with and without STN-DBS treatment. Post-mortem brain tissues from 6 PD non-STN-DBS patients, 5 PD STN-DBS patients, and 6 age-matched controls were stained with markers for neurodegeneration (tyrosine hydroxylase, alpha-synuclein, and neuronal loss) and astrogliosis (glial fibrillary acidic protein). Changes were assessed using quantitative and semi-quantitative microscopy techniques. As expected, significant neuronal cell loss, alpha-synuclein pathology, and variable astrogliosis were obs...
The Lancet Neurology, 2018
npj Parkinson's Disease
In this article the Global Parkinson's Genetics Program (GP2) members names and affiliations were... more In this article the Global Parkinson's Genetics Program (GP2) members names and affiliations were missing in the main author list of the Original article which are listed in the below.
Assessments, Treatments and Modeling in Aging and Neurological Disease, 2021
Journal of Neuropathology and Experimental Neurology, 2019
To the Editor: We refer to the article “Performance of a Condensed Protocol That Reduces Effort a... more To the Editor: We refer to the article “Performance of a Condensed Protocol That Reduces Effort and Cost of NIAAA Guidelines for Neuropathologic Assessment of Alzheimer Disease” that uses 4 tissue blocks for Thal staging of amyloid-b (Ab) (1). In this protocol, the variable occipital visual cortex is recommended as the cortical region for examination of A1 (Thal phases 1 and 2), with the striatum being used to assess stage A2 (Thal phase 3) and midbrain and cerebellum used to assess stage A3 (Thal phase 4 for midbrain and phase 5 for cerebellum) (2–4). Indeed, according to Thal et al, Ab deposition occurs in the neocortex in 100% of phase 1 cases with only minor variability (temporal and/or occipital cortex affected in 5 of 6 cases, followed closely by frontal in 4 cases and parietal cortex in 2 cases) (4). However, in vivo amyloid imaging shows that amyloid is most consistently found in the inferior temporal, the anterior cingulate and the parietal opercular cortices followed by wi...
Analytical Chemistry, 2006
Formalin is a routine fixative facilitating tissue preservation and histopathology. Proteomic tec... more Formalin is a routine fixative facilitating tissue preservation and histopathology. Proteomic techniques require freshly frozen specimens, which are often difficult to procure, and methods facilitating proteomic analysis of archival formalin-fixed brain tissue are lacking. We employed antigen-epitope-retrieval principles to facilitate proteomic analysis of brain tissue that had been fixed and stored in formalin for 3-7 years. Twenty-micrometer-thick cryopreserved OCT-embedded sections from inferior temporal cortex of human (7 years in formalin) or mouse brain specimens (3 years in formalin) were hematoxylin-/eosin-stained. Approximately 16-64-mm2 areas of the tissue sections were manually scraped off slides, or approximately 2 mm2 of human brain cortex was captured off membrane-coated slides using laser microdissection. Tissue was treated using various pH and temperature conditions prior to trypsin digestion and nano-LC-MS/MS. The largest number of proteins were retrieved by solubilization at pH 9 at 95 degrees C for 1 h; treatments at pH 4 or 6 at 25 or 65 degrees C were generally ineffective. Three-year formalin-fixed murine tissue did not yield more proteins compared to human tissue. Use of formalin-fixed tissue for proteomics is an invaluable tool for medical research. The combination of proteomics and microdissection enables selective enrichment and identification of novel, unique, or abundant proteins that may be important in pathogenesis.
Journal of Neurotrauma, 2020
Collision sports are an integral part of Australian culture. The most common collision sports in ... more Collision sports are an integral part of Australian culture. The most common collision sports in Australia are Australian rules football, rugby union, and rugby league. Each of these sports often results in participants sustaining mild brain traumas, such as concussive and subconcussive injuries. However, the majority of previous studies and reviews pertaining to the neurological implications of sustaining mild brain traumas, while engaging in collision sports, have focused on those popular in North America and Europe. As part of this 2020 International Neurotrauma Symposium special issue, which highlights Australian neurotrauma research, this article will therefore review the burden of mild brain traumas in Australian collision sports athletes. Specifically, this review will first provide an overview of the consequences of mild brain trauma in Australian collision sports, followed by a summary of the previous studies that have investigated neurocognition, ocular motor function, neuroimaging, and fluid biomarkers, as well as neuropathological outcomes in Australian collision sports athletes. A review of the literature indicates that although Australians have contributed to the field, several knowledge gaps and limitations currently exist. These include important questions related to sex differences, the identification and implementation of blood and imaging biomarkers, the need for consistent study designs and common data elements, as well as more multi-modal studies. We conclude that although Australia has had an active history of investigating the neurological impact of collision sports participation, further research is clearly needed to better understand these consequences in Australian athletes and how they can be mitigated.
ABSTRACT The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the b... more ABSTRACT The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.
Alzheimer's & Dementia, 2018
Background: We aimed to determine the Centiloid unit (CL) thresholds for sparse and moderate dens... more Background: We aimed to determine the Centiloid unit (CL) thresholds for sparse and moderate density neuritic plaques. Methods: Amyloid PET results in CL for 49 subjects were compared with post-mortem neuritic plaque density, visual read, and final clinicopathological diagnosis. A Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL yielded highest accuracy in detecting moderate or frequent plaque density (ROC AUC 0.97). A threshold of 9.5 CL was optimal for detecting sparse, moderate or frequent plaques (ROC AUC 0.96). Those cases with a final clinicopathological diagnosis of Alzheimer’s disease yielded a median CL result of 87.7 (IQR ±42.2) with 94% > 45 CL. Positive visual read agreed highly with results >26 CL. Conclusions: In this cohort, values <9.5 CL accurately reflected the absence of any neuritic plaques, and >20.1 CL indicated the presence of at least moderate plaque de...
Neuropathology and Applied Neurobiology, 2019
Are mutations in MAPT associated with GGT type III? Globular glial tauopathy (GGT) is the most re... more Are mutations in MAPT associated with GGT type III? Globular glial tauopathy (GGT) is the most recently described pathological subtype of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau) [1]. It is a rare disorder with approximately 70 cases described in the literature and has been reported to occur as a concomitant pathology in elderly patients with Alzheimer's disease [2]. Further pathological subtypes (GGT Type I-III) are recognized based on the density and morphology of tau-immunopositive inclusions, and regional involvement of pathology [1].
Neurobiology of Disease, 2019
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common ge... more Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
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Papers by Claire Shepherd