Maria Kataki

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.

Self-administered Gerocognitive Examination (SAGE) A Brief Cognitive Assessment Instrument for Mild Cognitive Impairment (MCI) and Early Dementia

ObjectivesTo 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. MethodsAdults 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. ResultsTwo 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. ConclusionsThis 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.

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

INTRODUCTION Differential diagnosis of dementia with Lewy bodies (DLB), Parkinsons disease with dementia (PDD), Parkinsons disease (PD) and Alzheimers 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 Parkinsons 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 Alzheimers disease (AD) and Parkinsons 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.

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.

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 Alzheimers 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 Alzheimers 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 Alzheimers 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.

Memory profiles differ between parkinsonian dementia syndromes and Alzheimer's disease

efits, and general ethics of disclosing apolipoprotein (APOE) genotype to older adults. Knowledge that one carries the APOE e 4 allele risk factor for Alzheimer’s disease (AD) was recently found to have little short-term psychological risk. However, the impact of this knowledge on subjective ratings of memory and objective memory test performance of older adults is unknown. Methods:We administered objective verbal and visual memory tests, and self-rating scales of memory function, to 144 older adults (ages 52-89) with known APOE genotype who knew (e 4+: n 1⁄4 25; e 4-: n 1⁄4 49) or did not know (e 4+: n 1⁄4 25; e 4-: n 1⁄4 45) their genotype and genetic risk for AD prior to neuropsychological evaluation. Results: Although APOE genotype did not have an overall main effect on subjective self-ratings or objective memory scores, we observed significant genotype X disclosure interaction effects on several memory rating scales and tests of immediate and delayed verbal recall (all p’s<.05). Older adults who knew their e 4+ genotype tended to judge their memory more harshly and performed worse on an objective verbal memory test than did e 4+ adults who did not know. In contrast, older adults who knew their e 4genotype judged their memory more positively than did e 4adults who did not know, but these groups did not differ in objective memory test performance. The participant groups did not differ significantly in age, level of education, gender distribution, global ratings of depression (i.e., Geriatric Depression Scale) or global cognitive performance (i.e., Mini-Mental State Exam, Mattis Dementia Rating Scale). Conclusions: These results indicate that informing older adults that they have an APOE genotype associated with increased risk of AD can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. Therefore, clinicians and researchers should consider knowledge of genotype when evaluating older adults who may or may not be at risk for developing dementia. Similar implications can be drawn for those individuals who have knowledge of AD related risk based on neuroimaging or cerebrospinal fluid biomarkers.

Self Administered Gerocognitive Examination (SAGE) score changes over time in worried well, Mild Cognitive Impairment (MCI), dementia converter, and Alzheimer patients

decline is a hallmark of Alzheimer’s disease (AD), describing both risks and benefits in terms of changes in function is a logical choice for such an exercise and requires understanding the temporal relationship of changes in cognition and function. The objective of this study was to co-vary the individual items with Disability Assessment in Dementia (DAD) with measures of cognition and time to identify the temporal order associated with disease progression. Methods: 337 subjects (196 AD, 70 mild cognitive impairment, 71 cognitively healthy volunteers) were enrolled at 40 study sites across the US and Europe during 2006 and 2007 for an 18-month non-interventional study (ELN-AIP-901), sponsored by Elan Pharmaceuticals and Wyeth Research. Recruitment criteria were similar to those used in the ADNI study. DAD was performed at baseline and at 6-months intervals. DAD item scale scores were co-varied with Mini-Mental State Examination (MMSE) score using survival analysis. Results: Using median MMSE survival, patients were unable to perform activities for all items of the sub-domains for finance, medication, and outings at higher scores than for items in other sub-domains. The specific activities ‘‘organize finance’’ and ‘‘adequately organize correspondence’’ exhibited the shortest MMSE survival, ie, ‘‘lost’’ earlier in the course of the disease. The inability to perform items in the sub-domains of personal hygiene, dressing, eating, and continence occurred at lowest MMSE survivals, ie, ‘‘lost’’ at the later stages of AD progression. Seven items ‘‘lost’’ late in the course of the disease, lowest median MMSE survival, were from 3 of the 10 sub-domains, specifically dressing (4 items), eating (2 items), and continence (1 item). Conclusions: Inability to perform instrumental functional activities occurred earlier in the course of the disease, as measured by MMSE score, than basic functional activities. DAD items exhibit a hierarchical loss progression associated with cognitive decline, by MMSE. These findings support the use of DAD items that correlate with AD progression as a method for characterizing benefit and risk.