The H1 haplotype of the microtubule-associated protein tau gene (
MAPT
) is associated with an increased risk of Parkinson disease (PD) compared with the H2 haplotype, but its effect on Lewy body ...(LB) formation is unclear. In this study, we compared the
MAPT
haplotype frequency between pathologically confirmed PD patients (
n
= 71) and controls (
n
= 52). We analyzed Braak LB stage, Braak neurofibrillary tangle (NFT) stage, and CERAD amyloid score by haplotype. We further tested the association between
MAPT
haplotype and semi-quantitative counts of LBs, NFTs, and neuritic plaques (NPs) in multiple neocortical regions. Consistent with previous reports, PD cases had an increased likelihood of carrying an H1/H1 genotype compared to controls (OR = 5.72, 95 % CI 1.80–18.21,
p
= 0.003). Braak LB, Braak NFT and CERAD scores did not differ by haplotype. However, H1/H1 carriers had higher LB counts in parietal cortex (
p
= 0.02) and in overall neocortical LBs (
p
= 0.03) compared to non-H1/H1 cases. Our analyses suggest that PD patients homozygous for the H1 haplotype have a higher burden of neocortical LB pathology.
Abstract Background Essential tremor (ET) is a progressive disorder, worsening gradually with time in most patients. Yet there are few data on the factors that influence rate of progression. ET is a ...highly familial disorder, and physicians often care for patients who have other affected family members. Do ET families differ from one another with respect to rate of progression? Are some families slower progressors and other families faster progressors? We are unaware of published data. Methods ET probands and relatives were enrolled in a cross-sectional genetic study at Columbia University. Rate of progression was calculated as total tremor score ÷ log disease duration. Results There were 100 enrollees (28 probands, 72 relatives). Data from 78 enrollees (23 probands, 55 relatives) were selected for final analysis. The mean familial rate of progression ranged from as little as 8.4 to as much as 34.3, a > 4-fold difference. In an analysis of variance, we found significant evidence of heterogeneity in the log rate of progression across families ( p < 0.001), with more than one-half (i.e., 55.4%) of the total variance in the log rate of progression explained by the family grouping. Conclusions Familial factors seem to affect rate of tremor progression in ET. There was a 4-fold difference across families in observed mean rate of progression; thus, some families seemed to be more rapid progressors than others. We hope these data may be used by clinicians to provide basic prognostic and family guidance information to their patients and families with ET.
Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients.
Among patients with early-onset PD of ...long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers.
Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers.
Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.
Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains.
In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.
A Drosophila Model of Essential Tremor Smith, Philip; Arias, Ronald; Sonti, Shilpa ...
Scientific reports,
05/2018, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, ...we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K
channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K
channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.
Essential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of ...surprisingly little scholarship.
To fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable.
Overall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered "yes" or "do not know" to the question, "is ET the same or different from the type of tremor that many normal people can get when they become old and frail?" A similar proportion did not know whether children could get ET or they responded "no." Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable.
We targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their family members without ET. Overall, however, knowledge of ET was very limited and this lack of knowledge encompassed all aspects of the disease including its underlying causes, the nature of the symptoms and signs, its natural history and its treatment. Further ET awareness education and programs targeting both families of ET patients and the public would help alleviate this gap in knowledge.
Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence ...of ESR2 polymorphisms on age at onset of AD in a multiethnic cohort of women.
To determine whether gene variants would affect risk for AD differently in women of different population ancestries.
Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), association with risk for AD was assessed for 20 ESR2 single-nucleotide polymorphisms (SNPs) using multivariate logistic regression, adjusting for age at time of study enrollment, presence of an APOE ε4 allele, years of education, and body mass index.
Increased risk for AD was associated with four ESR2 SNPs in women of predominantly Caucasian AIMS-defined ancestry: rs944045, rs1256062, rs10144225, and rs2274705 (OR range 1.6-1.9, empiric p-value range 0.002-0.004). A separate SNP (rs10137185) was associated with decreased risk for AD in women who identified themselves as Black (OR 0.6, 95% CI = 0.4-0.9). When vascular risk factors were included in the model, a separate SNP (rs1256059) was associated with increased risk for AD in women of admixed/Hispanic ancestry (OR 1.5, 95% CI = 1.1-2.4).
ESR2 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry and self-identified ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid risk factors mediating SNP effect on risk for AD by group.
The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence, it is unclear whether information about the age of onset in one family member can be used to ...predict the age of onset in others.
ET probands and relatives were enrolled in a genetic study at Columbia University.
Data from 26 probands and 52 relatives were analyzed. The probands' age of onset correlated significantly with their relatives' age of onset (r = 0.50, p = 0.001). In 57.7% of cases, the relative's age of onset was within 10 years of the proband's onset (i.e. a 20-year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset ≥20 years (p < 0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband.
In families containing multiple individuals with ET, the age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset.
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (
LINGO1
) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). ...Herein, we performed a comprehensive study of
LINGO1
and its paralog
LINGO2
in ET and PD by sequencing both genes in patients (ET,
n
= 95; PD,
n
= 96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET,
n
= 1,247; PD,
n
= 633) and controls (
n
= 642). The sequencing study identified six novel coding variants in
LINGO1
(p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in
LINGO2
(p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the
LINGO1
locus and 21 at the
LINGO2
locus. One variant in
LINGO1
(rs9652490) displayed evidence of an association with ET (odds ratio (OR) = 0.63;
P
= 0.026) and PD (OR = 0.54;
P
= 0.016). Additionally, four other tSNPs in
LINGO1
and one in
LINGO2
were associated with ET and one tSNP in
LINGO2
associated with PD (
P
< 0.05). Further analysis identified one tSNP in
LINGO1
and two in
LINGO2
which influenced age at onset of ET and two tSNPs in
LINGO1
which altered age at onset of PD (
P
< 0.05). Our results support a role for
LINGO1
and
LINGO2
in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.
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