Gary Angelo

Autism-Related Routines and Rituals Associated With a Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Polymorphism

Evidence for a genetic association between autism and two single nucleotide polymorphisms (SNPs), rs2056202 and rs2292813, in the mitochondrial aspartate/glutamate carrier (SLC25A12) gene led us to ask whether any of the four previously identified familial traits in autism spectrum disorders (ASD) varied by these SNPs. In 355 ASD cases from 170 sibships we examined levels of the four traits in these SNPs using ANCOVA models. The primary models selected unrelated affected cases and used age and sex as covariates. An ancillary set of models used all affected siblings and included “sibship” as a random effects independent variable. We found significantly lower levels of routines and rituals associated with the presence of the less frequent A allele in rs2056206. No other significant differences were observed. The rs2056202 polymorphism may be associated with levels of routines and rituals in autism and related disorders.

Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele.

OBJECTIVE To examine the association of cholesterol with cognitive functioning in oldest old community dwelling individuals with and without the apolipoprotein e4 (APOE4) allele. METHOD One hundred eighty-five nondemented, community dwelling individuals (>or=85) were assessed with a broad neuropsychological battery. Bloods were drawn to assess total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol, as well as for APOE genotyping. RESULTS In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for noncarriers of the APOE4 allele. No significant associations between cognitive performance and lipid profile were found for carriers of the APOE4 allele. CONCLUSIONS In oldest old nondemented noncarriers of the APOE4 allele, high cholesterol is associated with better memory function. Further examination of the role of APOE genotype on the association between cholesterol and cognitive performance, especially in the oldest old is warranted.

C-reactive protein and memory function suggest antagonistic pleiotropy in very old nondemented subjects

SIR—A possible role of inflammation in the development of dementia [1] has led to investigations examining whether C-reactive protein (CRP), a systemic marker of inflammation, is associated with worse cognitive function and decline in old age. Elevated CRP has been associated with worse global and specific cognitive functioning [2–7], although other studies have found no relationship between CRP and cognition [8–10]. Most studies have examined samples averaging <75 years [3–6, 9, 10]. We hypothesised that elevated CRP would be related to worse cognitive function in very old cognitively healthy subjects.

Impact of APOE ε4 on the Cognitive Performance of a Sample of Non-Demented Puerto Rican Nonagenarians

APOE epsilon4 is a major risk factor for Alzheimers disease. It has also been associated with cognitive impairment and cognitive decline in young-olds, but the impact of the epsilon4 allele on cognitive function in very late life is still unclear. The object of this study was to evaluate the association of the epsilon4 allele of APOE with the cognitive performance of a sample of non-demented oldest-olds. Eighty-seven Spanish-speaking Puerto Rican non-demented nonagenarians were administered a complete neuropsychological assessment and provided a blood sample used for APOE genotyping. A factor analysis generated two factors: 1) verbal memory; and 2) visuo-spatial, naming and attention tasks, accounting for 43.6% of the overall variance in the 13 original neuropsychological variables. The multivariate analysis reflected, after controlling for gender, education, and age, the APOE epsilon4 carriers performed better in overall cognition (both factors analyzed together) than non-carriers (T;{2} = 0.082, F(2,80) = 3.289, p = 0.042). Neither gender nor the gender by APOE epsilon4 status interaction was associated with differences in cognition. In conclusion, the results of this study suggest that, among these Puerto Rican non-demented nonagenarians, being an APOE epsilon4 allele carrier is associated with better cognition.

Homocysteine and cognitive function in very elderly nondemented subjects

OBJECTIVES To examine the association of homocysteine with cognitive functioning in very elderly community-dwelling individuals (80 years or older). METHODS Two hundred twenty-eight nondemented community-dwelling individuals were assessed with a broad neuropsychological battery. Bloods were drawn to measure homocysteine, serum vitamin B12, and folate levels and APOE genotype. RESULTS Higher homocysteine levels were associated with poorer executive-language functioning scores (r = -0.311). The association persisted when serum B12 and folate levels were controlled for (r = -0.308). Homocysteine levels were not associated with memory score (r = 0.120). CONCLUSIONS In very elderly, nondemented community dwellers, high homocysteine levels are associated with poorer executive-language functioning but not with memory. This possible differential effect of homocysteine on cognitive functions suggests that it may affect only specific brain regions or mechanisms underlying healthy executive functioning.

Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.

A locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2–p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 Mb. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family members, although several polymorphisms were detected.

Heritability of Cognitive Functions in Families of Successful Cognitive Aging Probands from the Central Valley of Costa Rica

We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age). We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4 ± 3.0) and their offspring (n = 188; mean age = 66.4 ± 5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h² = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h² = 0.50), memory as a cognitive domain (h² = 0.53), and the overall neuropsychological summary (h² = 0.42). Heritabilities for sequencing (h² = 0.42), fluency (h² = 0.39), abstraction (h² = 0.36), and the executive functions cognitive domain (h² = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA.

Non-synonymous variants in the AMACR gene are associated with schizophrenia

BACKGROUND The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia. METHODS The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent. RESULTS AND CONCLUSION We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.

Mutation screening of PDZD2, GOLPH3, and MTMR12 genes in patients with schizophrenia.

Department of Psychiatry, Mount Sinai School of Medicine, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA, San Juan Veteran Affairs Medical Center and University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico Correspondence to Irina N. Bespalova, PhD, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, PO Box 1230, NY 10029, New York, USA Tel: + 1 212 659 8843; fax: + 1 212 659 5626; e-mail: irina.bespalova@mssm.edu

Mutation analysis of the C1QTNF3 gene in patients with schizophrenia.

We previously identified a small region on chromosome 5p13 related to schizophrenia in a Puerto Rican pedigree. We screened one of the positional candidate genes, C1QTNF3, for mutations in affected family members. The direct sequencing identified 10 sequence variants, including five shared by all affected family members. Genotyping of the shared variants in a Puerto Rican sample of 118 cases and 136 controls did not reveal either allelic or genotype association with schizophrenia.