Gene expression profiling of brain samples from patients with Lewy body dementia.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative disorder in the elderly. The development and progression of DLB remain unclear. In this study we used next generation sequencing to assess RNA expression profiles and cellular processes associated with DLB in the anterior cingulate cortex, a brain region affected by DLB pathology. The expression measurements were made in autopsy brain tissues from 8 DLB subjects and 10 age-matched controls using AmpliSeq technology with ion torrent sequencing. The analysis of RNA expression profiles revealed 490 differentially expressed genes, among which 367 genes were down-regulated and 123 were up-regulated. Functional enrichment analysis of genes differentially expressed in DLB indicated downregulation of genes associated with myelination, neurogenesis, and regulation of nervous system development. miRNA binding sites enriched in these mRNAs yielded a list of candidate miRNAs participating in DLB pathophysiology. Our study provides a comprehensive picture of gene expression landscape in DLB, identifying key cellular processes associated with DLB pathology.

Self-Administered Gerocognitive Examination: longitudinal cohort testing for the early detection of dementia conversion.

BACKGROUND: Significant cognitive changes as individuals' age are not being identified in a timely manner, delaying diagnosis and treatments. Use of brief, multi-domain, self-administered, objective cognitive assessment tools may remove some barriers in assessing and identifying cognitive changes. We compared longitudinal Self-Administered Gerocognitive Examination (SAGE) test scores to non-self-administered Mini-Mental State Examination (MMSE) scores in 5 different diagnostic subgroups. METHODS: A cohort study evaluating annual rates of change was performed on 665 consecutive patients from Ohio State University Memory Disorders Clinic. Patients with at least two visits 6 months apart evaluated with SAGE and MMSE and classified according to standard clinical criteria as subjective cognitive decline (SCD), mild cognitive impairment (MCI), or Alzheimer's disease (AD) dementia were included. The pattern of change in SAGE scores was compared to MMSE. One way and repeated measures ANOVA and linear regression models were used. RESULTS: Four hundred twenty-four individuals (40 SCD, 94 MCI non-converters to dementia, 70 MCI converters to dementia (49 to AD dementia and 21 to non-AD dementia), 220 AD dementia) met inclusion criteria. SAGE and MMSE scores declined respectively at annual rates of 1.91 points/year (p < 0.0001) and 1.68 points/year (p < 0.0001) for MCI converters to AD dementia, and 1.82 points/year (p < 0.0001) and 2.38 points/year (p < 0.0001) for AD dementia subjects. SAGE and MMSE scores remained stable for SCD and MCI non-converters. Statistically significant decline from baseline scores in SAGE occurred at least 6 months earlier than MMSE for MCI converters to AD dementia (14.4 vs. 20.4 months), MCI converters to non-AD dementia (14.4 vs. 32.9 months), and AD dementia individuals (8.3 vs. 14.4 months). CONCLUSIONS: SAGE detects MCI conversion to dementia at least 6 months sooner than MMSE. Being self-administered, SAGE also addresses a critical need of removing some barriers in performing cognitive assessments. Limitations of our single-site cohort study include potential referral and sampling biases. Repetitively administering SAGE and identifying stability or decline may provide clinicians with an objective cognitive biomarker impacting evaluation and management choices.

Self-administered Gerocognitive Examination (SAGE): a brief cognitive assessment Instrument for mild cognitive impairment (MCI) and early dementia.

OBJECTIVES: To develop a self-administered cognitive assessment instrument to facilitate the screening of mild cognitive impairment (MCI) and early dementia and determine its association with gold standard clinical assessments including neuropsychologic evaluation. METHODS: Adults aged above 59 years with sufficient vision and English literacy were recruited from geriatric and memory disorder clinics, educational talks, independent living facilities, senior centers, and memory screens. After Self-administered Gerocognitive Examination (SAGE) screening, subjects were randomly selected to complete a clinical evaluation, neurologic examination, neuropsychologic battery, functional assessment, and mini-mental state examination (MMSE). Subjects were identified as dementia, MCI, or normal based on standard clinical criteria and neuropsychologic testing. RESULTS: Two hundred fifty-four participants took the SAGE screen and 63 subjects completed the extensive evaluation (21 normal, 21 MCI, and 21 dementia subjects). Spearman rank correlation between SAGE and neuropsychologic battery was 0.84 (0.76 for MMSE). SAGE receiver operating characteristics on the basis of clinical diagnosis showed 95% specificity (90% for MMSE) and 79% sensitivity (71% for MMSE) in detecting those with cognitive impairment from normal subjects. CONCLUSIONS: This study suggests that SAGE is a reliable instrument for detecting cognitive impairment and compares favorably with the MMSE. The self-administered feature may promote cognitive testing by busy clinicians prompting earlier diagnosis and treatment.

Allelic mRNA expression of sortilin-1 (SORL1) mRNA in Alzheimer's autopsy brain tissues.

Polymorphisms in the gene encoding SORL1, involved in cellular trafficking of APP, have been implicated in late-onset Alzheimer's disease, by a mechanism thought to affect mRNA expression. To search for regulatory polymorphisms, we have measured allele-specific mRNA expression of SORL1 in human autopsy tissues from the prefrontal cortex of 26 Alzheimer's patients, and 51 controls, using two synonymous marker SNPs (rs3824968 in exon 34 (11 heterozygous AD subjects and 16 controls), and rs12364988 in exon 6 (8 heterozygous AD subjects)). Significant allelic expression imbalance (AEI), indicative of the presence of cis-acting regulatory factors, was detected in a single control subject, while allelic ratios were near unity for all other subjects. We genotyped 7 SNPs in two haplotype blocks that had previously been implicated in Alzheimer's disease. Since each of these SNPs was heterozygous in several subjects lacking AEI, this study fails to support a regulatory role for SORL1 polymorphisms in mRNA expression.

Alpha-synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3'UTR.

BACKGROUND: Multiple variants in SNCA, encoding alpha-synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease. METHODS: We searched for cis-acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3'UTR (2,520 bp) luciferase reporter gene assay, translation in SH-SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome-wide association studies. RESULTS: Allelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3' untranslated region (3'UTR), but not at a marker at its start, suggesting regulation of 3'UTR processing. 3'UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3'UTR isoforms. A second 3'UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3'UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome-wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the "Genome Wide Association Study of Yoruba in Nigeria," rs356165 was associated with reduced memory performance. CONCLUSIONS: Here, we identify two cis-acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3'UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations.

Motor performance differentiates individuals with Lewy body dementia, Parkinson's and Alzheimer's disease.

INTRODUCTION: Differential diagnosis of dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Parkinson's disease (PD) and Alzheimer's disease (AD) is challenging. Comparative motor profiles of these neurodegenerative disorders may aid in earlier diagnosis but have not been extensively studied. METHODS: Groups were rigorously matched by age, education, and sex. DLB/PDD participants were matched by Mini-Mental State Examination Score to individuals with AD and by Unified Parkinson's Disease Rating Scale motor scores to individuals with PD. Gait, balance, dual task walking and hand dexterity measures were compared between a combined group (n=21) of individuals with Lewy body dementia (LBD) consisting of those with DLB (n=11) and PDD (n=10) to individuals with PD (n=21) or AD (n=21). RESULTS: Individuals at the same disease stage with LBD walked significantly slower with shorter stride lengths (p<0.05), demonstrated poorer balance on both the Tinetti and Berg Balance Scale, and poorer performance on dual-task and figure-of-eight walking compared to PD and AD (p<0.05 for all) groups. Upper extremity coordination on the 9-hole peg test differentiated LBD from both PD and AD and was the only motor test in which individuals with AD performed worse than those with PD. Tinetti balance subscores were significantly lower in PDD compared to DLB participants (10.4±2.3 versus 12.8±2.3; p=0.027). CONCLUSIONS: Motor features distinguish individuals with LBD from those with AD and PD. Measures of gait, balance and finger dexterity provide an additional means of differentiating individuals with LBD from those with AD and PD.

Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer's and Parkinson's Diseases.

Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder.

The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3'-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3'UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3'UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR = 2.1, p = 0.03). This result was replicated in a second bipolar/control population (OR = 1.65, p = 0.01), supporting a critical role for DAT regulation in bipolar disorder.

A method for estimating duration of illness in Alzheimer's disease.

BACKGROUND: We developed a set of questions for generating an estimate regarding the date of first symptoms to the nearest half-year. Physicians then revised this estimate in conjunction with medical record review and patient/informant interviews, and by testing the estimate by recall of life events. One experienced examiner rated 36 patients, and each was independently rated by a second, less experienced rater. The physician ratings were compared to each other and to an unstructured caregiver estimate of duration using Lin concordance coefficients. There was excellent agreement between independent physician raters (rho = 0.95, p < 0.001). Caregiver estimates of duration were usually shorter because of failure to relate the first symptoms to the onset of disease.