To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of ...Pick disease and 910 neurologically healthy controls and performed case-control association analysis.
Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.
No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing (
< 0.0021, considered significant). However, nominally significant (
< 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio OR 4.78,
= 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82,
= 0.021).
Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (
C9orf72)
have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be ...the most common genetic cause of both neurodegenerative diseases. Genetic variants at
TMEM106B
influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that
TMEM106B
is a genetic modifier of FTLD-TDP caused by progranulin (
GRN
) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with
C9orf72
expansions (
n
= 14), with the major allele correlated with later age at death (
p
= 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with
C9orf72
expansions (
n
= 75), again finding that the major allele associates with later age at death (
p
= 0.016), as well as later age at onset (
p
= 0.019). In contrast,
TMEM106B
genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for
GRN
mutations or
C9orf72
expansions. Thus,
TMEM106B
is a genetic modifier of FTLD with
C9orf72
expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in
C9orf72
expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
Background
Genetic mutations in the microtubule‐associated protein tau (MAPT) cause frontotemporal lobar degeneration (FTLD‐MAPT), associated with severe frontotemporal atrophy antemortem, and highly ...heterogeneous tau immunoreactivity postmortem, with differential involvement of 3‐repeats (3R) or 4‐repeats (4R) tau isoforms. To date, there are limited data objectively measuring tau burden in FTLD‐MAPT, or directly comparing specific mutation groups. These novel data can help elucidate patterns of regional spread and associated neuronal loss, and shed light on pathologic heterogeneity in tauopathies.
Method
We digitally quantified burden of AT8‐positive tau pathology using validated digital methods in a cohort of 35 FTLD‐MAPT autopsy cases with 9 different mutations (4R mutations: P301L=16, IVS10+16=4, N279K=1; 3R mutations: G272V=5; L266V=2; 3R+4R mutations: R406W=3; L315R=2; G389R=1; S320F=1). We examined the relationship between quantitative measurements of tau burden and ordinal scores of neuronal loss (0‐3) in a maximum of nine available grey matter (GM) regions. Regional analysis of tau burden was performed in a subset of six regions with most available data using linear mixed‐effects modeling, adjusting for disease duration and neuronal loss.
Result
Overall, digitally quantified GM tau burden correlated positively with neuronal loss (beta=1.7, p<0.001), however a subset of GM samples (39/179, 22%) showed relatively low tau pathology in combination with severe neuronal loss. This was particularly prominent in specific mutations (χ2=33.0, p<0.001) irrespective of region, i.e. in 7/11 (64%) GM samples of L315R, 11/24 (46%) of G272V, and 2/6 (33%) of S320F, and showed some regional variability (χ2=34.9, p<0.001) across the cohort, occurring most frequently in the frontal (6/8, 75%) and temporal (9/20, 45%) pole. Regional analysis of tau burden in all FTLD‐MAPT found that maximally affected regions were the parahippocampal gyrus (PHG), anterior cingulate cortex (ACC) and temporal pole (TP) (F=53.5, p<0.001). Sub‐analyses found that 4R mutations were most affected in PHG and TP (F=29.7, p<0.001), while 3R mutations in ACC (F=13.0, p<0.001), and 3R+4R mutations in ACC and inferior parietal lobule (F=53.6, p<0.001).
Conclusion
Heterogeneity in severity and distribution of pathology in FTLD‐MAPT may in part be related to underlying mutation and tau isoform conformation, which may help improve the understanding of disease pathogenesis and progression.
Tauopathies are a major group of neurodegenerative proteinopathies characterized by the accumulation of abnormal and hyperphosphorylated tau proteins in the brain. Tau pathology is characterized as ...3R (repeat) or 4R predominant or mixed 3R and 4R type. Here we report three cases lacking mutations in the microtubule associated protein tau (MAPT) gene with unusual tau pathology. The age at onset and duration of illness, respectively, were 63 and 20 years (male), 67 and 5 years (female) and 72 and 20 years (female). The clinical presentation was compatible with a diagnosis of progressive supranuclear palsy (PSP) in two subjects and with cognitive decline in all three subjects. Common neuropathological features included neuronal loss in the hippocampus and dentate gyrus associated with spherical basophilic Pick body‐like inclusions showing 4R tau immunoreactivity, which was supported by the detection of predominantly 4R tau species by Western blot examination. In addition, accumulation of tau immunoreactive argyrophilic astrocytes in the hippocampus and amygdala and oligodendroglial coiled bodies in the hippocampal white matter were observed. These morphologies appeared in combination with Alzheimer disease‐related pathology and subcortical tau pathology compatible with PSP. Together with a single case report in the literature, our observations on these three cases expand the spectrum of previously described tauopathies. We suggest that this tauopathy variant with hippocampal 4R tau immunoreactive spherical inclusions might contribute to the cognitive deficits in the patients reported here. The precise definition of the clinicopathological relevance of these unusual tau pathologies merits further study.
Intestinal metaplasia of the gastric mucosa is an important component in the pathway to adenocarcinoma. The mechanisms that induce the progression from intestinal metaplasia to cancer have not been ...elucidated. High dietary salt has been known as one of the risk factors for gastric cancer development in humans. Therefore, we investigated the role of high salt diet on gastric epithelial cell proliferation and differentiation, using our mouse model that ectopically expressed Cdx2 homeodomain transcription factor and induced an intestinal metaplastic phenotype in the gastric epithelia. Sixty Cdx2 transgenic and sixty age-matched wild-type littermates were studied. Fifty-percent Cdx2 transgenic and wild type mice were administered a high-salt diet and the other fifty-percent was fed a standard diet starting at 12 weeks after birth. At 10, 20 and 40 weeks after initiation of the diets, histopathological changes were determined by Hemotoxylin and Eosin, alcian blue, and periodic acid-Schiff (PAS) staining. Cell types and cell kinetics were assessed by immunohistochemistry. At 52 weeks, significant alterations in pathology were observed in the Cdx2 transgenic mice fed a high-salt diet, including elongation of gastric pits, reduction of the glandular zone in the gastric corpus, and deepening of glands in the antrum. In the Cdx2 transgenic mice fed a high salt diet, the parietal and chief cells were significantly decreased in the gastric corpus. A significant increase in cell proliferation and apoptosis in the corpus and antrum were observed in Cdx2 transgenic mice fed a high-salt diet as compared to wild-type littermates. Taken together, these data implicate that intestinal metaplasia in concert with a high-salt diet induces epithelial proliferation, apoptosis, and alters cellular types in the gastric mucosa of mice. Alteration in the composition of the gastric epithelium may play a role in influencing the microenvironment to engender susceptibility to carcinogens.
Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis ...Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center.
To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants.
All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research.
Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%).
We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization.
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