Mean Age At Onset Research Articles

Non-parametric Survival Analysis of EPG5 Gene with Age at Onset of Alzheimer's Disease.

Non-parametric methods such as Wilcoxon test have the advantages of no assumptions for the underlying survival distributions. Alzheimer's disease (AD) is a chronic neurodegenerative disease while the ectopic P-granules autophagy protein 5 homolog (EPG5 gene) is highly expressed in human brain and may implicate in the pathogenesis of neurodegenerative disorders. The present study explored the associations of 26 single-nucleotide polymorphisms (SNPs) in the EPG5 gene with the age at onset (AAO) of AD using a family-based association test (FBAT)-Wilcoxon statistic in a family-based study. Then a replication study using a case-control sample was conducted to perform Wilcoxon test in Kaplan-Meier survival analysis of AAO. The results from FBAT-generalized estimating equations (FBAT-GEE) statistics and FBAT-Wilcoxon test showed that seven SNPs (top SNP rs495078 with p=1.29×10-3) were significantly associated with the risk of AD, and eight SNPs (top SNP rs11082498 with p=3.55×10-4) were associated with the AAO of AD in the family-based study (p<0.05). In the replicated data, three SNPs were associated with AAO by using the Wilcoxon test, where the mean AAO was approximately 2.2years earlier in individuals who had at least one minor allele of the top AAO-associated SNP rs9963463 (p=0.0018) compared with those who were homozygous for the major allele. These findings from non-parametric survival analyses provide evidence for several genetic variants in EPG5 influencing the AAO of AD and will serve as a resource for replication in other populations.

Eating disorders: What age at onset?

Age at onset (AAO) of eating disorders has classically been described in adolescence. We analyzed data from 806 subjects with anorexia nervosa (AN) or bulimia nervosa (BN) and performed a normal distribution admixture analysis to determine their AAO. No significant differences were found concerning the AAO functions of AN and BN subjects. Both groups had a mean AAO of about 18 years. Most of the subjects with AN (75.3%) and BN (83.3%) belonged to the early onset group. The definition of AAO for ED may be crucial for planning treatment modalities, with specific consideration of their clinical history and course.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Using admixture analysis to examine birth-cohort effects on age at onset of bipolar disorder.

It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania.

A Clinical Profile of 125 Patients with Writer's Cramp

Background: The characteristics of writer's cramp (WC) may vary according to native languages and scripts. We report the clinical profile of a large cohort of patients with WC from India. Methods: A chart review of 125 patients (F:M = 16:109) with WC seen over 10 years at the National Institute of Mental Health and Neurosciences (NIMHANS), India. Results: The mean age of patients was 36.8 ± 14.3, the mean age at onset (AAO) of symptoms was 31.5 ± 2.7 and the mean duration of difficulty in writing was 5.3 ± 6.3. The most common presenting complaint while writing was pain in the forearm (56%), followed by tremulousness of hand (28.8%) and abnormal posturing of hand (15.2%). Along with writing difficulty, 5.6% had difficulty in typing. The mean AAO of writing difficulty was significantly earlier in women than in men (22.8 ± 3.5 vs. 32.8 ± 4.2 years, p < 0.001). While writing, excessive extension (41.6%) of wrist was the most common abnormality, followed by excessive flexion (37.6%) and extension (19.2%) of index finger. Conclusions: Women with WC have a significantly earlier age of onset than men. Excessive extension of wrist with flexion of thumb and index finger were the most common abnormalities noted in WC.

Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic characterization.

In the past 2 years, 3 genes (SLC20A2, PDGFRB, and PDGFB) were identified as causative of primary familial brain calcification (PFBC), enabling genotype-specific phenotyping. To provide a systematic literature review on the neuroimaging and clinical phenotype of genetically confirmed PFBC and summarize known pathophysiological mechanisms, to improve and harmonize future phenotype description and reporting by addressing data gaps, and to develop uniform definitions for clinical characterization. We systematically searched the MEDLINE database among articles published from January 1, 2012, through May 31, 2014, for the 3 genes and selected 25 articles from all records (n=75) and from sources cited in the reference lists. Only genetically confirmed cases with individual clinical information were included, leaving 15 reports. Predefined categories for data extraction were different neurologic and psychiatric symptoms, imaging results, and age at onset (AAO). We also assessed availability of information to estimate possible bias. We included a total of 179 cases, 162 of which belong to 25 families. Availability of information ranged from 96.6% for ethnicity to 24.4% for AAO. All cases had calcifications on comprehensive cranial computed tomography, most frequently located in the basal ganglia (70.6%), subcortical white matter (40.8%), cerebellum (34.1%), or thalamus (28.5%). Mean (SD) AAO was 27.9 (22.3) years, and the AAO was comparable across genes (P=.77). The most frequently described signs were movement disorders, such as parkinsonism (12%) and dystonia (19%). Penetrance of the imaging phenotype was 100% compared with only 61% of the clinical phenotype. We propose a novel definition of disease status by specifying PFBC into genetic, clinical, and imaging phenotypes. Pathophysiological pathways converge on impaired phosphorus homeostasis and integrity of the blood-brain barrier. Especially in rare conditions, meta-analyses are the most suitable tool to extract reliable information on the natural course of a disease. For future analyses, we provide a minimal data set that can be used for systematic clinical and imaging data collection in PFBC and that will also improve informed counseling of patients.

Unravelling the epidemiology of late-onset and asymptomatic carriers of FAP ATTR V30M in a Portuguese population

Background Familial Amyloid Polyneuropathy (FAP ATTRV30M) is an AD systemic amyloidosis, due to a point mutation in the transthyretin (TTR) gene. Although in Portugal the disease has been characterized by its early onset (lower than 40yrs), a wider age-at-onset (AO) variability has been uncovered. The mean AO is 35.3, but more and more late-onset (higher than 50yrs) cases are being ascertained, often matched with older asymptomatic parents. Our aim now was to look into late-onset cases and agedasymptomatic carriers in order to unravel familial aggregation of late-onset and to characterize these families regarding their epidemiology.

I20 The Impact Of Lifestyle On The Onset Of Huntington Disease

<h3>Background</h3> A study of pre-morbid lifestyle in 154 individuals in Australasia published in 2010 made two findings. Firstly, a passive lifestyle can be a preclinical expression of HD. Secondly, and more importantly, the higher levels of lifestyle passivity associated with those showing an earlier age at onset (AO) is in part independent of the HD mutation, suggesting that overcoming the tendency to be passive may delay onset. <h3>Aims</h3> To undertake a replication study in a European cohort through EHDN. <h3>Methods</h3> The Australian questionnaire was modified to reflect cultural differences and translated into Czech, French, German, Italian, Norwegian, Polish, Spanish and Swedish. Trained interviewers in 30 centres gathered data from 194 individuals with early symptomatic HD to ascertain pre-morbid lifestyle, including participation in leisure and non-leisure activities (education, occupation and domestic duties). Activities were classified as physical, intellectual or passive, and scores were generated under the categories leisure, non-leisure and total lifestyle, and data were matched with the individual’s AO and HTT CAG repeat length. <h3>Results</h3> The mean AO was 44.4 years (range 16–71) There were strong inverse correlations between AO and both CAG repeat length (r=-0.68, p &lt; 0.001) and a lifestyle that includes higher levels of passive activity (r = -0.22, p &lt; 0.001), though not with higher levels of intellectual or physical activity. CAG repeat length and average pre-morbid lifestyle passivity were also strongly associated (r= + 0.32, p &lt; 0.001). Details of the breakdown into leisure and non-leisure aspects of lifestyle and into activity data for various life stages (teens, 20s/30s and 40s/50s) will be presented. <h3>Conclusions</h3> The data support the contention that passivity can be a pre-clinical manifestation of disease and that there may be a considerable impact of lifestyle on the age of onset.

Genetic Variants in the SORL1 Gene Are Associated with Age at Onset of Alzheimer Disease: A Survival Analysis

Few studies focused on the association of SORL1 with the age at onset (AAO) of Alzheimer disease (AD). This study investigated the association of 43 SNPs in SORL1 with the AAO of AD by using the Kaplan-Meier survival analysis and the Cox proportional hazards model in SAS version 9.2 and linear regression model in PLINK software (791 AD patients and 782 controls). Both logrank test and Cox regression model showed that five SNPs (rs1784934, rs676759, rs560573, rs593769, and rs11218313) were associated with the AAO of AD in the male sample, while one SNP (rs17125558) was associated with the AAO of AD in the female sample (P&lt;0.05). SNP rs560573, previously associated with the risk of late-onset AD, showed the most association with the AAO in the male sample (P=0.0077 for logrank test and P=0.0117 in the Cox model). The mean AAO was approximately 2.5 years earlier in individuals who were homozygous for the minor allele compared with those who had at least one major allele. Linear regression model showed that rs2282649 and rs726601 were associated with AAO in the whole sample (P=0.0374 and 0.0367, resp.). These findings provide evidence of several genetic variants in SORL1 influencing the AAO of AD.

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation.

C09 Age at onset of Huntington's disease: rater estimates versus data based extrapolation

BackgroundThe accurate determination of age at onset (AAO) of Huntington's disease is critical to develop and evaluate therapies that aim to delay it.Aim(1) To compare the raters' estimates of AAO...

A retrospective study of the impact of lifestyle on age at onset of Huntington disease

In transgenic mouse models of Huntington disease (HD) environmental enrichment significantly delays disease onset. A questionnaire-based survey of 154 adults with diagnosed HD (mean 4.2 years postdiagnosis) and a known IT15 CAG repeat length, explored whether premorbid lifestyle may relate to age-at-onset (AO). Participants were drawn from HD outpatient clinics in Australia and New Zealand. Premorbid physical, intellectual, and passive activity levels were used to generate scores in the categories of leisure, nonleisure (education, occupation and domestic duties) and total lifestyle. AO was associated with increased CAG repeat length as expected (r = -0.72, P < 0.001), but also with a lifestyle that included higher levels of passive activity (r = -0.38, P < 0.001). Multiple linear regression modeling showed lifestyle passivity to be a variable independent of CAG repeat length in predicting AO (R(2) = 0.54, b = -0.22, P = 0.005). Comparison of the mean AO across tertiles of lifestyle passivity scores showed onset 4.6 years (95% CI = 1.3-7.9) later in the least compared with the most passive tertile. CAG repeat length was also shown to predict lifestyle passivity (R(2) = 0.12, b = 1.08, P < 0.0005). Neither intellectual nor physical activity showed significant relationships to AO or CAG repeat length in this cohort. Our study leads to two conclusions: that a passive lifestyle may be a preclinical expression of HD, and that it actually contributes to the earlier onset of symptoms. Overcoming the tendency to be passive may substantially delay onset of HD. (c) 2010 Movement Disorder Society.

Age at onset in Sardinian bipolar I patients: evidence for three subgroups

We studied age at onset (AAO) in order to assess the presence of different subgroups in a homogeneous genetic population, such as the Sardinian population. Admixture analysis was applied in order to identify a model of separate normal distribution of AAO characterized by different means, variances and population proportions to allow for evaluation of different subgroups in a sample of 181 unrelated patients of Sardinian origin with bipolar disorder (BP) type I. The Mann-Whitney test was used to compare the means of AAO between subjects with a history of suicide attempts and subjects with no such history. The best-fitting model had three components with means (SD) of 18.1 (2.3), 24.3 (5.3) and 41 (11.5) years, comprising 36%, 39% and 25% of the sample, respectively. We obtained two cut-off points at 21 and 33 years, enabling the sample to be divided into three subgroups. The Mann-Whitney test revealed a difference between the mean AAO of subjects with a positive history of suicide attempts and that of subjects with no such history (p = 0.041). We found three AAO sub-groups in our sample of BP I patients of Sardinian origin. Our findings add further support to the hypothesis whereby AAO acts as a clinical marker of biological heterogeneity in BP.

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.

Early onset familial Alzheimer's disease: Mutation frequency in 31 families.

Three causative genes have been identified for autosomal dominant AD. To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.

Study of anticipation in Chinese families with schizophrenia.

The anticipation phenomenon is an important aspect in several genetic disorders in which the age at onset (AAO) decreases and the severity of illness increases in successive generations. This phenomenon has been reported in several schizophrenic family studies, and expanded repeat mutations are implicated. In the present study, we investigate the anticipation phenomenon in Chinese schizophrenic families. We compare the AAO between two generations of 38 unilinear schizophrenic families. Intergenerational comparisons show that the AAO was significantly earlier in the offspring generation (mean AAO, 22.2 years) than that in the parental generation (mean AAO, 31.0 years) (P < 0.001). When only including the offspring generation who married, the AAO difference between the two generations was not significant (28.4 years vs 31.0 years, P = 0.151). Our findings suggest that a selection bias in the parental group might greatly impact the study of anticipation in schizophrenia. Other unavoidable biases associated with these analyses are discussed in the text.

A recommended method for obtaining the age at onset of dementia from the CSHA database.

In studies of dementia, the age at onset (AAO) of the disease is often described without indicating how it was obtained. We used the "CAMDEX algorithm," an ad hoc procedure, to compute the AAO of dementia from the CSHA database. An AAO could be calculated for 983 of 1,132 subjects with dementia. A similar procedure (the "clinical algorithm") was used to calculate a second AAO, which was compared to that obtained by the first algorithm. The CAMDEX and clinical algorithms produced mean AAOs of dementia of 80.5 years (SD = 9.2 years, n = 983) and 79.6 years (SD = 9.7 years, n = 829), respectively. The sample correlation coefficient between the CAMDEX and clinical algorithms was .899 while the intraclass correlation coefficient, ICC(2,1), was .898. This method could prove useful for researchers using the CSHA data who need an AAO for those subjects with dementia.

Anticipation in Japanese families with schizophrenia.

The identification of anticipation in schizophrenia is a recent focus in the genetic epidemiology of schizophrenia, although it involves some controversial methodological issues. We explored the evidence of anticipation among 44 Japanese two-generation pairs with schizophrenia found by reviewing nine years of admission records (1986-1994) at the Department of Neuropsychiatry, Nagasaki University Hospital and Michino-o Hospital, Nagasaki. The 44 pairs consisted of 27 two-generation pairs of first-degree relatives group (FDRG) and 17 pairs of second-degree relatives group (SDRG). On pairwise comparison and a life table analysis, the age at onset (AO) was significantly earlier in the lower generation (G2) than in the upper generation (G1) in all of the pairs and in the two subgroups, FDRG and SDRG. Earlier AO was shown in G2 even after minimizing some statistical biases for the study of anticipation in schizophrenia. A significant earlier mean AO was found in G2 even when a cohort effect was controlled for. There was no marked difference in AO between paternal and maternal transmission. These results provide further evidence for epidemiological anticipation, suggesting biological anticipation such as the involvement of trinucleotide repeats expansion in G2. The limitations of the study are also discussed.

Anticipation and imprinting in Spanish families with schizophrenia.

Evidence of imprinting and anticipation, two genetic phenomena that are correlated with clinical sequelae, was assessed in familial schizophrenia. A sample of patients (n=291) who fulfilled the ICD-9 criteria for schizophrenia and corresponding to the familial-type and sporadic-type of the disorder was recruited. Clinical anticipation and imprinting variables such as age at onset (AAO), schizophrenia subtype, course of disease and onset type were assessed over parental (G1) and filial (G2) generations in both schizophrenia types. Anticipation assessment indicated significant differences in mean AAO between parent-offspring pairs in unilineal families. These differences were not explained by a cohort effect. Imprinting assessment indicated non-significant differences in AAO between the offspring of affected mothers and the offspring of affected fathers. The results obtained for other clinical variables were non-conclusive. The results suggest that anticipation, but not imprinting, is operative in schizophrenia.