The long term cognitive outcome in PARKIN-PD patients is unknown. This data may be meaningful when counseling PARKIN-PD patients.
Among early-onset PD (EOPD) patients with long disease durations, we assessed cognitive and motor performances, comparing compound heterozygote/homozygote PARKIN carriers to non-carriers
Cross sectional study
Seventeen movement disorders centers
Forty-four participants in the Consortium on Risk for Early-Onset PD (CORE-PD) with PD duration greater than median (>14 years), including PARKIN compound heterozygotes/homozygotes combined (n=21), and non-carriers (n=23).
Main outcome measures
Unified Parkinson’s Disease Rating Scale Part III (UPDRS), Clinical Dementia Rating (CDR) and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.
Compound heterozygote/homozygote PARKIN mutation carriers had earlier AAO of PD (p<0.001) and were younger (p=0.004) at time of examination than non-carriers. They performed better on the MMSE (p=0.010) and were more likely to receive lower scores on the CDR (p=0.003). In multivariate analyses, PARKIN compound heterozygotes/homozygotes performed better on the UPDRS Part III (p=0.017), and on tests of attention (p=0.022), memory (p=0.025) and visuospatial (p=0.024) domains.
Conclusions and Relevance
Cross-sectional analyses demonstrate better cognitive and motor performance in compound heterozygote/homozygote PARKIN EOPD carriers than non-carriers with long disease duration, suggesting slower disease progression. Longitudinal follow up is required to confirm these findings.
Immune response plays an important role in the development of hepatic fibrosis. In
the present study, we investigated the effects of quercetin on hepatitis and hepatic
fibrosis induced by immunological mechanism. In the acute hepatitis model, quercetin
(2.5 mg/kg) was injected iv into mice 30 min after concanavalin A
(Con A) challenge. Mice were sacrificed 4 or 24 h after Con A injection, and
aminotransferase tests and histopathological sections were performed. Treatment with
quercetin significantly decreased the levels of alanine aminotransferase (ALT) and
aspartate aminotransferase (AST). Consistent with this observation, treatment with
quercetin markedly attenuated the pathologic changes in the liver. A hepatic fibrosis
model was also generated in mice by Con A challenge once a week for 6 consecutive
weeks. Mice in the experimental group were treated with daily iv
injections of quercetin (0.5 mg/kg). Histopathological analyses revealed that
treatment with quercetin markedly decreased collagen deposition, pseudolobuli
development, and hepatic stellate cells activation. We also examined the effects of
quercetin on the nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) and transforming growth factor beta (TGF-β) pathways by immunohistochemistry
and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). NF-κB and
TGF-β production was decreased after treatment with quercetin, indicating that the
antifibrotic effect of quercetin is associated with its ability to modulate NF-κB and
TGF-β production. These results suggest that quercetin may be an effective
therapeutic strategy in the treatment of patients with liver damage and fibrosis.
Quercetin; Concanavalin A; Acute hepatitis; Hepatic fibrosis; Liposome
We have conducted a comprehensive case–control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A*0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A*0206, HLA-B*3802 alleles plus the A*0207–B*4601 and A*3303–B*5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P<0.0001). HLA alleles that associate with low risk for NPC include HLA-A*1101, B*27, and B*55 with a combined OR of 0.42 (P<0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.
HLA; nasopharyngeal carcinoma; haplotype; stratified analysis
To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD).
We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration–matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed.
Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale–III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004).
GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.
Vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) are constantly exposed to haemodynamic forces, including blood flow-induced fluid shear stress and cyclic stretch from blood pressure. These forces modulate vascular cell gene expression and function and, therefore, influence vascular physiology and pathophysiology in health and disease. Epigenetics, including DNA methylation, histone modification/chromatin remodelling and RNA-based machinery, refers to the study of heritable changes in gene expression that occur without changes in the DNA sequence. The role of haemodynamic force-induced epigenetic modifications in the regulation of vascular gene expression and function has recently been elucidated. This review provides an introduction to the epigenetic concepts that relate to vascular physiology and pathophysiology. Through the studies of gene expression, cell proliferation, angiogenesis, migration and pathophysiological states, we present a conceptual framework for understanding how mechanical force-induced epigenetic modifications work to control vascular gene expression and function and, hence, the development of vascular disorders. This research contributes to our knowledge of how the mechanical environment impacts the chromatin state of ECs and VSMCs and the consequent cellular behaviours.
Epigenetics; Mechanotransduction; Shear stress; Endothelial cells; Smooth muscle cells
Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-phosphate uridylyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism. While the neonatal morbidity and mortality of the disease are now mostly prevented by newborn screening and galactose restriction, long-term outcome for older children and adults with this disorder remains unsatisfactory. The pathophysiology of Classic Galactosemia is complex, but there is convincing evidence that galactose-1-phosphate (gal-1P) accumulation is a major, if not the sole pathogenic factor. Galactokinase (GALK) inhibition will eliminate the accumulation of gal-1P from both dietary sources and endogenous production, and efforts towards identification of therapeutic small molecule GALK inhibitors are reviewed in detail. Experimental and computational high-throughput screenings of compound libraries to identify GALK inhibitors have been conducted, and subsequent studies aimed to characterize, prioritize, as well as to optimize the identified positives have been implemented to improve the potency of promising compounds. Although none of the identified GALK inhibitors inhibit glucokinase and hexokinase, some of them cross-inhibit other related enzymes in the GHMP small molecule kinase superfamily. While this finding may render the on-going hit-to-lead process more challenging, there is growing evidence that such cross-inhibition could also lead to advances in antimicrobial and anti-cancer therapies.
Mutations in parkin are a known genetic risk factor for early-onset Parkinson’s disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives.
We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second degree relatives without PD.
Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n=4), and not heterozygotes, had significantly increased risk of depressed mood (OR=14.1; 95% CI 1.2–163.4), moderate to severe depression (OR=17.8; 95% CI 1.0–332.0), depression (score ≥15) on the Beck Depression Inventory II (BDI-II) (OR=51.9; 95% CI 4.1–657.4), and BDI-II total depression score (β=8.4; 95% CI 2.4–11.3) compared to those without parkin mutations.
Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD.
genetics; depression; parkin; Parkinson’s disease; neuropsychiatry; early onset Parkinson’s disease
Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.
The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans.
Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10).
We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Exome sequencing; Genetic epidemiology; Genetics; Lipids; Next-generation sequencing; Obesity; Type 2 diabetes
The biosyntheses of isoprenoids is essential for the survival in all living organisms, and requires one of the two biochemical pathways: (a) Mevalonate (MVA) Pathway or (b) Methylerythritol Phosphate (MEP) Pathway. The latter pathway, which is used by all Gram-negative bacteria, some Gram-positive bacteria and a few apicomplexan protozoa, provides an attractive target for the development of new antimicrobials because of its absence in humans. In this report, we describe two different approaches that we used to identify novel small molecule inhibitors of Escherichia coli and Yersinia pestis 4-diphosphocytidyl-2-C-methyl D-erythritol (CDP-ME) kinases, key enzymes of the MEP pathway encoded by the E. coli ispE and Y. pestis ipk genes, respectively. In the first approach, we explored existing inhibitors of the GHMP kinases while in the second approach; we performed computational high-throughput screening of compound libraries by targeting the CDP-ME binding site of the two bacterial enzymes. From the first approach, we identified two compounds with 6-(benzylthio)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile and (Z)-3-methyl-4-((5-phenylfuran-2-yl)methylene)isoxazol-5(4H)-one scaffolds which inhibited Escherichia coli CDP-ME kinase in vitro. We then performed substructure search and docking experiments based on these two scaffolds and identified twenty three analogs for structure-activity relationship (SAR) studies. Three new compounds from the isoxazol-5(4H)-one series have shown inhibitory activities against E. coli and Y. pestis CDP-ME kinases with the IC50 values ranging from 7μM to 13μM. The second approach by computational high-throughput screening (HTS) of two million drug-like compounds yielded two compounds with benzenesulfonamide and acetamide moieties which, at a concentration of 20μM, inhibited 80% and 65%, respectively, of control CDP-ME kinase activity.
Classic Galactosemia is a rare human disease associated with the accumulation of toxic level of galactose-1-phosphate (gal-1P) caused by the inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) activity. To reduce the toxic level of gal-1P in the patients, we have identified, via high-throughput screening, over 200 small molecule GALK inhibitors. We selected a 4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile scaffold for further structure-activity relationships characterization, lead optimization with regards to potency and efficacy to reduce gal-1P accumulation in patient cells.
galactokinase; galactose-1-phosphate; dihydrothiazinone; GHMP kinases; galactosemia
Ultrasound provides a valuable tool for medical diagnosis offering real-time imaging with excellent spatial resolution and low cost. The advent of microbubble contrast agents has provided the additional ability to obtain essential quantitative information relating to tissue vascularity, tissue perfusion and even endothelial wall function. This technique has shown great promise for diagnosis and monitoring in a wide range of clinical conditions such as cardiovascular diseases and cancer, with considerable potential benefits in terms of patient care. A key challenge of this technique, however, is the existence of significant variations in the imaging results, and the lack of understanding regarding their origin. The aim of this paper is to review the potential sources of variability in the quantification of tissue perfusion based on microbubble contrast-enhanced ultrasound images. These are divided into the following three categories: (i) factors relating to the scanner setting, which include transmission power, transmission focal depth, dynamic range, signal gain and transmission frequency, (ii) factors relating to the patient, which include body physical differences, physiological interaction of body with bubbles, propagation and attenuation through tissue, and tissue motion, and (iii) factors relating to the microbubbles, which include the type of bubbles and their stability, preparation and injection and dosage. It has been shown that the factors in all the three categories can significantly affect the imaging results and contribute to the variations observed. How these factors influence quantitative imaging is explained and possible methods for reducing such variations are discussed.
microbubble contrast agent; medical ultrasound; perfusion quantification; quantitative imaging; variation
To confirm in a cohort recruited in 1999–2001 our finding in a cohort recruited in 1992–1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD).
Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD.
The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4–2.9) and LOAD (1.6; 1.0–2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ∊4. This association was weaker when only AD – excluding cases of mixed dementia – was considered (hazard ratio = 1.3; 95% confidence interval = 0.8–2.2).
T2D is associated with LOAD. Cerebrovascular disease may be an important mediator.
Type 2 diabetes; Alzheimer's disease
Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor β-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.
reactive oxygen species; stem cell factor; protein kinase B; autocrine
To assess the frequency and clinical characteristics of carriers of previously identified mutations in six genes associated with early onset Parkinson disease (EOPD) and provide empirical data that can be used to inform genetic counseling.
Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2 and GBA were assessed in 953 individuals with EOPD ascertained based on age at onset (AAO) ≤50 years. Participants included 77 Hispanics and 139 of Jewish ancestry. A validated family history interview and the Unified Parkinson’s Disease Rating Scale (UPDRS) were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status.
One hundred and fifty eight (16.6%) had mutations including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA and one (0.2%) DJ1. Mutation carriers were more frequent among cases with AAO ≤30 than among cases with AAO between 31 and 50 (40.6% vs. 14.6% p<0.001), Jews compared to non-Jews (32.4% vs. 13.7% p<0.001) and those reporting a first degree family history of PD than among those who did not (23.9% versus 15.1% p=0.012). Hispanics were more likely to be PRKN carriers than non-Hispanics (15.6% versus 5.9% p=0.003). The GBA L444P mutation was associated with a higher mean UPDRS-III score after adjustment for covariates.
EOPD individuals of Jewish or Hispanic ancestry, those with AAO ≤ 30, and those with a family history of PD in a first-degree relative may benefit from genetic counseling.
Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson’s disease (EOPD). Results from a multi-center study of cases with PD systematically sampled by age at onset (AAO) have not been reported.
To determine risk factors associated with carrying mutations in the parkin gene.
Cross-sectional observational study
13 movement disorders centers
956 EOPD cases defined as AAO <51.
Main Outcome Measures
Presence of heterozygous, homozygous or compound heterozygous parkin mutations.
14.7% of cases reported a family history of PD in a first-degree relative using a previously validated interview. Sixty-four cases (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygotes, 2.2% compound heterozgyotes). Copy Number Variation (CNV) was present in 52.3% (31.6% of heterozygotes, 83.3% of homozygotes, 81.0% of compound heterozygotes). Deletions in exons 3–4 and 255delA, were common in Hispanics, and specifically, in the Puerto Rican population. Earlier AAO, Hispanic ethnicity (OR compared to White non-Hispanic 2.7 95% CI 1.3–5.7, p<0.009) and family history of PD in a first-degree relative (OR 2.8 95%CI 1.5–5.3, p<0.002) were associated with carrying any mutation in the parkin gene (heterozygous, homozygous, compound heterozygous). Hispanic ethnicity was associated with carrying a heterozygous mutation (OR compared to non-Hispanic Caucasian 2.8 95%CI 1.1–7.2, p<0.03) after adjustment for covariates.
AAO, Hispanic ethnicity and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation in Hispanics warrants further study.
While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown.
To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives.
We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking.
Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001).
Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.
Amyloid β (Aβ) is a key pathophysiological feature of Alzheimer’s disease (AD). Baseline and change values of plasma Aβ have been associated with AD risk.
To determine if plasma Aβ levels: 1) can be linked to specific cognitive changes which constitute conversion to AD; and 2) correspond to cognitive change independent of dementia.
Northern Manhattan community.
Longitudinal study including three visits over ~4.5 years (2000–2006).
880 individuals, from a population based and ethnically diverse sample, who had two plasma Aβ measurements and were dementia-free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired at any point, and 70 converted to AD.
Main Outcome Measures
General Estimating Equations tested the association between plasma Aβ (baseline and change values) and cognitive change (composite score, and memory, language, and visuospatial indices).
High baseline plasma Aβ42 (p=.01)and Aβ40 (p=.01), and decreasing/relatively stable Aβ42 (p=.01) were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (p=.01) and decreasing/relatively stable plasma Aβ42 (p=.01) was associated with faster cognitive decline, primarily in memory.
The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elders also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.
To examine changes in levels of plasma amyloid-β (Aβ) peptides, Aβ42 and Aβ40, in relation to onset of Alzheimer disease (AD) in adults with Down syndrome (DS).
Plasma Aβ42 and Aβ40 were measured at initial examination and at follow-up in a community-based cohort of 225 adults with DS who did not have dementia at baseline and were assessed for cognitive/functional abilities and health status and followed at 14- to 20-month intervals. We used Cox proportional hazards modeling to estimate the cumulative incidence of AD by Aβ peptide change group (increasing, no change, or decreasing), adjusting for covariates.
Sixty-one (27.1%) of the participants developed AD. At follow-up, a decrease in Aβ42 levels, a decrease in the Aβ42/Aβ40 ratio, and an increase in Aβ40 levels were related to conversion to AD. Compared with the group with increasing levels of Aβ42, the likelihood of developing AD was 5 times higher for those whose plasma Aβ42 levels decreased over follow-up (hazard ratio [HR] = 4.9, 95% confidence interval [CI] 2.1–11.4). Decreasing Aβ42/Aβ40 was also strongly related to AD risk (HR = 4.9, 95% CI 1.8–13.2), while decreasing Aβ40 was associated with lower risk (HR = 0.4, 95% CI 0.2–0.9).
Among adults with DS, decreasing levels of plasma Aβ42, a decline in the Aβ42/Aβ40 ratio, or increasing levels of Aβ40 may be sensitive indicators of conversion to AD, possibly reflecting compartmentalization of Aβ peptides in the brain.
Fijian infants aged 6 weeks were stratified by ethnicity and randomized to receive 0, 1, 2, or 3 PCV-7 doses with or without the 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months. Strong booster effects for all 7 PCV-7 serotypes were elicited, and for 4/7 serotypes these responses were highest in the single PCV-7 group. There were fourfold rises in GMC for all non-PCV-7 serotypes. By 17 months the PPV-23 group still had significantly higher GMC (each p<0.001) for all serotypes. The PPV-23 was well tolerated and induced excellent responses for all serotypes which were greatest in the single PCV-7 group.
Pneumococcal; polysaccharide; booster
To determine whether leisure activities modify the risk for incident dementia.
Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated.
A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects’ leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities.
Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered.
The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.
To determine the motor phenotype of LRRK2 G2019S mutation carriers
LRRK2 mutation carriers were previously reported to manifest the tremor-dominant (TD) motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared to the postural instability gait difficulty (PIGD) phenotype.
Cross sectional observational study
13 movement disorders centers
925 Early Onset Parkinson Disease (EOPD) cases defined as age at onset (AAO) ≤50.
Main Outcome Measures
LRRK2 mutation status and PD motor phenotype: TD or PIGD
Demographic information, family history of PD (FHPD), and the Unified Parkinson Disease Rating Scale (UPDRS) were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish (AJ) ancestry, levodopa dose, and FHPD.
34 cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be AJ (55.9% vs. 11.9% p<0.001), but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (p=0.026) and were more likely to have a PIGD phenotype (92.3% vs. 58.9% p=0.003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and AJ (OR= 17.7, p< 0.001).
EOPD G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.
Advanced prostate cancers are known to acquire not only invasive capabilities but also significant resistance to chemotherapy-induced apoptosis. To understand how microRNAs (miRNAs) may contribute to prostate cancer resistance to apoptosis, we compared microRNA expression profiles of a benign prostate cancer cell line WPE1-NA22 and a highly malignant WPE1-NB26 cell line (derived from a common lineage). We found that miR-205 and miR-31 are significantly downregulated in WPE1-NB26 cells, as well as in other cell lines representing advanced-stage prostate cancers. Antiapoptotic genes BCL2L2 (encoding Bcl-w) and E2F6 are identified as the targets of miR-205 and miR-31, respectively. By downregulating Bcl-w and E2F6, miR-205 and miR-31 promote chemotherapeutic agents-induced apoptosis in prostate cancer cells. The promoter region of the miR-205 gene was cloned and was found to be hypermethylated in cell lines derived from advanced prostate cancers, contributing to the downregulation of the gene. Treatment with DNA methylation inhibitor 5-aza-2′-deoxycytidine induced miR-205 expression, downregulated Bcl-w, and sensitized prostate cancer cells to chemotherapy-induced apoptosis. Thus, downregulation of miR-205 and miR-31 has an important role in apoptosis resistance in advanced prostate cancer.
miR-205; miR-31; E2F6; Bcl-w; apoptosis; prostate cancer
Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample.
A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI.
WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-ɛ4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains.
White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.
= Alzheimer disease;
= Boston Diagnostic Aphasia Examination;
= Benton Visual Retention Test;
= cerebral amyloid angiopathy;
= confidence interval;
= cerebrovascular disease;
= fluid-attenuated inverse recovery;
= mild cognitive impairment;
= odds ratio;
= Selective Reminding Test;
= Wechsler Adult Intelligence Scale–Revised;
= Washington/Hamilton Heights–Inwood Columbia Aging Project;
= white matter hyperintensity.
To investigate transcranial magnetic stimulation (TMS) measures as clinical correlates and longitudinal markers of amyotrophic lateral sclerosis (ALS).
We prospectively studied 60 patients with ALS subtypes (sporadic ALS, familial ALS, progressive muscular atrophy, and primary lateral sclerosis) using single pulse TMS, recording from abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. We evaluated three measures: 1) TMS motor response threshold to the ADM, 2) central motor conduction time (CMCT), and 3) motor evoked potential amplitude (correcting for peripheral changes). Patients were evaluated at baseline, compared with controls, and followed every 3 months for up to six visits. Changes were analyzed using generalized estimation equations to test linear trends with time.
TMS threshold, CMCT, and TMS amplitude correlated (p < 0.05) with clinical upper motor neuron (UMN) signs at baseline and were different (p < 0.05) from normal controls in at least one response. Seventy-eight percent of patients with UMN (41/52) and 50% (4/8) of patients without clinical UMN signs had prolonged CMCT. All three measures revealed significant deterioration over time: TMS amplitude showed the greatest change, decreasing 8% per month; threshold increased 1.8% per month; and CMCT increased by 0.9% per month.
Transcranial magnetic stimulation (TMS) findings, particularly TMS amplitude, can objectively discriminate corticospinal tract involvement in amyotrophic lateral sclerosis (ALS) from controls and assess the progression of ALS. While central motor conduction time and response threshold worsen by less than 2% per month, TMS amplitude decrease averages 8% per month, and may be a useful objective marker of disease progression.
= abductor digiti minimi;
= amyotrophic lateral sclerosis;
= analysis of variance;
= confidence interval;
= compound motor action potential;
= central motor conduction time;
= deep tendon stretch reflex;
= familial ALS;
= generalized estimation equations;
= lower motor neuron;
= motor evoked potential;
= primary lateral sclerosis;
= progressive muscular atrophy;
= sporadic ALS;
= tibialis anterior;
= transcranial magnetic stimulation;
= upper motor neuron.
To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study.
AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale.
The mortality rate was 10.7 per 100 person-years. Mortality rates were higher among those diagnosed at older ages, and among Hispanics compared to non-Hispanic whites. The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics.
Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension.
= Alzheimer disease;
= National Death Index;
= Washington Heights Inwood Columbia Aging Project.