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1.  Neuropsychological Predictors of Dementia in Late-Life Major Depressive Disorder 
Major Depressive Disorder (MDD) is a likely risk factor for dementia, but some cases of MDD in older adults may actually represent a prodrome of this condition. The purpose of this study was to use neuropsychological test scores to predict conversion to dementia in a sample of depressed older adults diagnosed as nondemented at time of neuropsychological testing.
Longitudinal, with mean follow-up of 5.45 years.
Outpatient depression treatment study at Duke University
30 nondemented individuals depressed at time of neuropsychological testing and later diagnosed with incident dementia; 149 nondemented individuals depressed at time of neuropsychological testing and a diagnosis of cognitively normal.
All participants received clinical assessment of depression, were assessed to rule out prevalent dementia at time of study enrollment, completed neuropsychological testing at time of study enrollment, and were diagnosed for cognitive disorders on an annual basis.
Non-demented, acutely depressed older adults who converted to dementia during the study period exhibited broadly lower cognitive performances at baseline than acutely depressed individuals who remained cognitively normal. Discriminant function analysis indicated that 2 neuropsychological tests, CERAD Recognition Memory and Trail Making B, best predicted dementia conversion.
Depressed older adults with cognitive deficits in the domains of memory and executive functions during acute depression are at higher risk for developing dementia. Some cases of late-life depression may reflect a prodrome of dementia in which clinical manifestation of mood changes may co-occur with emerging cognitive deficits.
PMCID: PMC3376682  PMID: 23395197
geriatric depression; dementia; neuropsychology; memory; executive function
2.  Event-Related Functional Magnetic Resonance Imaging Changes during Relational Retrieval in Normal Aging and Amnestic Mild Cognitive Impairment 
The earliest cognitive deficits observed in amnestic mild cognitive impairment (aMCI) appear to center on memory tasks that require relational memory (RM), the ability to link or integrate unrelated pieces of information. RM impairments in aMCI likely reflect neural changes in the medial temporal lobe (MTL) and posterior parietal cortex (PPC). We tested the hypothesis that individuals with aMCI, as compared to cognitively normal (CN) controls, would recruit neural regions outside of the MTL and PPC to support relational memory. To this end, we directly compared the neural underpinnings of successful relational retrieval in aMCI and CN groups, using event-related functional magnetic resonance imaging (fMRI), holding constant the stimuli and encoding task. The fMRI data showed that the CN, compared to the aMCI, group activated left precuneus, left angular gyrus, right posterior cingulate, and right parahippocampal cortex during relational retrieval, while the aMCI group, relative to the CN group, activated superior temporal gyrus and supramarginal gyrus for this comparison. Such findings indicate an early shift in the functional neural architecture of relational retrieval in aMCI, and may prove useful in future studies aimed at capitalizing on functionally intact neural regions as targets for treatment and slowing of the disease course.
PMCID: PMC3864110  PMID: 22622022
Mild cognitive impairment; Aging; Memory; Functional MRI; Medial temporal lobe; Parietal lobe
3.  The Alzheimer’s associated 5′ region of the SORL1 gene cis-regulates SORL1 transcripts expression 
Neurobiology of Aging  2010;33(7):1485.e1-1485.e8.
SORL1 has been identified as a major contributor to Late-Onset Alzheimer’s disease (LOAD). We test whether genetic variability in the 5′of SORL1 gene modulates the risk to develop LOAD via regulation of SORL1-mRNA expression and splicing. Two brain structures, differentially vulnerable to LOAD pathology, were examined in 144 brain samples from 92 neurologically normal individuals. The temporal cortex, which is more susceptible to Alzheimer’s pathology, demonstrated ~2-fold increase in SORL1-mRNAs levels in carriers of the minor alleles at SNPs, rs7945931 and rs2298525, compared to non-carriers. No genetic effect on total-SORL1-mRNA levels was detected in the frontal-cortex. However, rs11600875 minor allele was associated with significantly increased levels of exon-2 skipping, but only in frontal cortex. No correlation of SORL1-mRNAs expression was found between frontal and temporal cortexes. Collectively, indicating the brain-region specificity of the genetic regulation of SORL1 expression. Our results suggest that genetic regulation of SORL1 expression plays a role in disease risk and maybe responsible for the reported LOAD-associations. Further studies to detect the actual pathogenic variant/s are necessary.
PMCID: PMC3117021  PMID: 21185108
SORL1; Alzheimer’s disease; mRNA; splicing; correlation to gene expression
4.  Midlife Activity Predicts Risk of Dementia in Older Male Twin Pairs 
Prospective study of dementia to elucidate mechanisms of disease risk factors amenable to modification and specifically to determine whether midlife cognitive and physical leisure activities are associated with delayed onset or reduced risk of dementia within older male twin pairs.
Co-twin control design using prospectively collected exposure information to predict risk of dementia 20–40 years later.
Community-dwelling and nursing home residents living throughout the continental United States.
147 male twin-pairs who were discordant for dementia or age of dementia onset and were members of the NAS-NRC Twin Registry of World War II veterans and participants in the Duke Twins Study of Memory in Aging.
Main Outcome Measure
Diagnosed dementia using a two-stage screen and full clinical evaluation. Conditional odds ratios were estimated for the association between midlife leisure activities and late life dementia.
Greater midlife cognitive activity was associated with a 26% risk reduction for dementia onset. Protective effects were most robust in monozygotic twin-pairs, where genetic and early-life influences were most tightly controlled, and for activities that were often cognitive and social in nature. Cognitive activity was particularly protective among monozygotic twin-pairs carrying the APOE4 allele, with a 30% risk reduction. Midlife physical activity did not modify dementia risk.
Participation in a range of cognitively and socially engaging activities in midlife reduced risk for dementia and AD in twins discordant for onset, particularly among twin-pairs at elevated genetic risk, and may be indicative of an enriched environment.
PMCID: PMC3673771  PMID: 18790459
dementia; midlife activity; leisure activity; twins
5.  Incidence of Dementia and Cognitive Impairment Not Dementia in the United States 
Annals of neurology  2011;70(3):418-426.
Estimates of incident dementia, and cognitive impairment, not dementia (CIND) (or the related mild cognitive impairment (MCI)) are important for public health and clinical care policy. In this paper, we report US national incidence rates for dementia and CIND.
Participants in the Aging, Demographic and Memory Study (ADAMS) were evaluated for cognitive impairment using a comprehensive in-home assessment. A total of 456 individuals age 72 and older, who were not demented at baseline were followed longitudinally from August 2001 to December 2009. An expert consensus panel assigned a diagnosis of normal cognition, CIND, or dementia and its subtypes. Using a population-weighted sample, we estimated the incidence of dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and CIND by age. We also estimated the incidence of progression from CIND to dementia.
The incidence of dementia was 33.3 (s.e. = 4.2) per 1000 person-years and 22.9 (s.e. =2.9) per 1000 person-years for AD. The incidence of CIND was 60.4 (s.e.= 7.2) cases per 1000 person-years. An estimated 120.3 (s.e.=16.9) individuals per 1000 person-years progressed from CIND to dementia. Over a 5.9 year period, about 3.4 million individuals aged 72 and older in the US developed incident dementia; of which approximately 2.3 million developed AD and about 637,000 developed VaD. Over this same period, almost 4.8 million individuals developed incident CIND.
The incidence of CIND is greater than the incidence of dementia, and those with CIND are at high risk of progressing to dementia, making CIND a potentially valuable target for treatments aimed at slowing cognitive decline.
PMCID: PMC3139807  PMID: 21425187
6.  Metabolomic changes in autopsy confirmed Alzheimer's disease 
Metabolomics, the global science of biochemistry, provides powerful tools to map perturbations in the metabolic network and enables simultaneous quantification of a large number of metabolites to identify metabolic perturbances that might provide insights into disease. In this pilot study we take a targeted electrochemistry based metabolomics approach where liquid chromatography followed by coulometric array detection enables quantification of over thirty metabolites within key neurotransmitter pathways (dopamine and serotonin) and pathways involved in oxidative stress.
Using samples from post-mortem ventricular cerebrospinal fluid (CSF) (15 AD and 15 non-demented subjects with autopsy confirmed diagnoses) and using regression models, correlations, Wilcoxon rank-sum tests and t-tests we identified alterations in tyrosine, tryptophan, purine, and tocopherol pathways in patients with AD. Reductions in norepinephrine and its related metabolites were also seen, consistent with prior literature. These data support further investigation of metabolomics in larger samples of clinical AD as well as in those with preclinical disease for utility as biomarkers.
PMCID: PMC3061205  PMID: 21075060
metabolomics; Alzheimer's; biomarkers; diagnosis; staging; tryptophan; tyrosine; purine
7.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Academic medical centers
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
PMCID: PMC3058918  PMID: 21059987
8.  The effect of SNCA 3′ region on the levels of SNCA-112 splicing variant 
Neurogenetics  2010;12(1):59-64.
Genetic variability at the 3′ region of SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson’s disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However, the mechanism through which the 3′ region of SNCA gene modulates the risk to develop sporadic PD remained elusive. We studied the effect of PD risk-associated variants at SNCA 3′ regions on SNCA112-mRNA (exon 5 in-frame skipping) levels in vivo in 117 neuropathologically normal, human brain frontal cortex samples. SNPs tagging the SNCA 3′ showed significant effects on the relative levels of SNCA112-mRNA from total SNCA transcripts levels. The “risk” alleles were correlated with increased expression ratio of SNCA112-mRNA from total. We provide evidence for functional consequences of PD-associated SNCA gene variants at the 3′ region, suggesting that genetic regulation of SNCA splicing plays an important role in the development of the disease. Further studies to determine the definite functional variant/s within SNCA 3′ and to establish their association with PD pathology are necessary.
PMCID: PMC3030669  PMID: 21046180
SNCA-mRNA; SNCA112; Splicing; Parkinson’s disease; Functional variants; eSNP
9.  Caspase-2-mediated cleavage of Mdm2 creates p53-induced positive feedback loop 
Molecular cell  2011;43(1):57-71.
Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.
PMCID: PMC3160283  PMID: 21726810
p53; Mdm2; tumor suppressor; Caspase-2; DNA damage; Lrdd; PIDDosome; cancer
10.  Metabolomics in Early Alzheimer's Disease: Identification of Altered Plasma Sphingolipidome Using Shotgun Lipidomics 
PLoS ONE  2011;6(7):e21643.
The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility.
Methods and Findings
We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics [1], [2] to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences.
In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.
PMCID: PMC3136924  PMID: 21779331
11.  Temporal lobe functional activity and connectivity in young adult APOE e4 carriers 
To determine if the APOE e4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTL) during successful memory encoding in young adults.
Twenty-four healthy young adults, twelve carriers and twelve non-carriers of the APOE e4 allele, were scanned in a subsequent memory paradigm, using event-related functional magnetic resonance imaging (fMRI). The neuroanatomical correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTL, as well as whole brain functional connectivity with the MTL, were assessed.
In the absence of demographic or performance differences, APOE e4 allele carriers exhibited greater bilateral MTL activity relative to the non-carriers to accomplish the same encoding task. Additionally, while e4 carriers demonstrated greater functional connectivity of ESA-related MTL activity with the posterior cingulate (PCC) and other peri-limbic regions, overall connectivity reductions were found across anterior and posterior cortices.
These results suggest that the APOE e4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTL to other regions implicated in memory encoding. Enhanced functional connectivity of the MTL with the PCC in young adult e4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease long before late-onset dementia is a practical risk or consideration. It is also possible that these functional connectivity differences reflect pleiotropic effects of APOE during early development.
PMCID: PMC2891943  PMID: 19744893
fMRI; Memory; Genetics; Alzheimer's disease; Functional Connectivity; APOE
12.  The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases 
Journal of Amino Acids  2011;2011:265084.
Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases.
PMCID: PMC3268222  PMID: 22312459
13.  Cognitive performance and informant reports in the diagnosis of cognitive impairment and dementia in African Americans and whites 
The diagnosis of cognitive impairment and dementia must reflect an increasingly diverse and aging United States population. This study compared direct testing and informant reports of cognition with clinical diagnoses of cognitive impairment and dementia between African Americans and whites.
Participants in the Aging, Demographics, and Memory Study completed in-person dementia evaluations, and were assigned clinical diagnoses (by a consensus panel of dementia experts) of normal; cognitive impairment, not demented (CIND); and dementia. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total score and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were used to assess cognitive performance and reported cognitive decline.
A higher CERAD total score was associated with lower odds of CIND and dementia, at comparable ratios between African Americans and whites. Higher IQCODE scores were associated with increased odds of dementia in both African Americans and whites. Higher IQCODE scores were associated with increased odds of CIND among whites, but not among African Americans.
Cultural differences may influence informant reports of prevalent CIND and dementia. Our findings also highlight the need for more comparative research to establish the cultural validity of measures used to diagnose these conditions.
PMCID: PMC2805266  PMID: 19896583
CERAD; IQCODE; Cognitive decline; CIND; Dementia; African American
14.  Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer’s Disease 
Alzheimer’s disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer’s disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In line with previous reports, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.
PMCID: PMC2883723  PMID: 20061627
Alzheimer’s disease; copy number variation; dementia; genome-wide association study
15.  Neuroanatomical Correlates of Malingered Memory Impairment: Event-related fMRI of Deception on a Recognition Memory Task 
Brain injury : [BI]  2008;22(6):481-489.
Primary objective
Event-related, functional magnetic resonance imaging (fMRI) data were acquired in healthy participants during purposefully malingered and normal recognition memory performances to evaluate the neural substrates of feigned memory impairment.
Methods and procedures
Pairwise, between-condition contrasts of neural activity associated with discrete recognition memory responses were conducted to isolate dissociable neural activity between normal and malingered responding while simultaneously controlling for shared stimulus familiarity and novelty effects. Response timing characteristics were also examined for any association with observed between-condition activity differences.
Outcomes and results
Malingered recognition memory errors, regardless of type, were associated with inferior parietal and superior temporal activity relative to normal performance, while feigned recognition target misses produced additional dorsomedial frontal activation and feigned foil false alarms activated bilateral ventrolateral frontal regions. Malingered response times were associated with activity in the dorsomedial frontal, temporal, and inferior parietal regions. Normal memory responses were associated with greater inferior occipitotemporal and dorsomedial parietal activity, suggesting greater reliance upon visual/attentional networks for proper task performance.
The neural substrates subserving feigned recognition memory deficits are influenced by response demand and error type, producing differential activation of cortical regions important to complex visual processing, executive control, response planning, and working memory processes.
PMCID: PMC2875084  PMID: 18465389
fMRI; MRI, Functional; forensic psychiatry; deception; malingering; Deficits, Memory
16.  Cerebrovascular Smooth Muscle Actin Is Increased in Non-Demented Subjects with Frequent Senile Plaques at Autopsy: Implications for the Pathogenesis of Alzheimer Disease 
We previously found that vascular smooth muscle actin (SMA) is reduced in the brains of patients with late stage Alzheimer disease (AD) compared to brains of non-demented, neuropathologically normal subjects. To assess the pathogenetic significance and disease specificity of this finding, we studied 3 additional patient groups: non-demented subjects without significant AD type pathology (“Normal”, n = 20); non-demented subjects with frequent senile plaques at autopsy (“Preclinical AD”, n = 20); and subjects with frontotemporal dementia, (“FTD”, n = 10). The groups were matched for gender and age with those previously reported; SMA immunohistochemistry and image analysis were performed as previously described. Surprisingly, SMA expression in arachnoid, cerebral cortex and white matter arterioles was greater in the Preclinical AD group than in the Normal and FTD groups. The plaques were not associated with amyloid angiopathy or other vascular disease in this group. SMA expression in the brains of the Normal group was intermediate between the Preclinical AD and FTD groups. All 3 groups exhibited much greater SMA expression than in our previous report. The presence of frequent plaques and increased arteriolar SMA expression in the brains of non-demented subjects suggest that increased SMA expression might represent a physiologic response to neurodegeneration that could prevent or delay overt expression dementia in AD.
PMCID: PMC2732426  PMID: 19287310
Alzheimer disease; Arterioles; Demented subjects; Image analysis; Non-demented subjects; Smooth muscle actin
17.  A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease 
Annals of neurology  2008;63(6):697-708.
To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion.
Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center (NPDPSC) for clinical, histopathological, immunohistochemical, genotypical and PrP characteristics.
Patients presented with behavioral and psychiatric manifestations on average at 62 years while mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern and the presence of micro-plaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. Following enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly four times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the NPDPSC. Although several subjects had family history of dementia, no mutations were found in the PrP gene open reading frame (ORF).
The distinct histopathological, PrP immunohistochemical and physical-chemical features along with the homogeneous genotype indicate that this is a previously unidentified type of disease involving the prion protein, which we designated “protease-sensitive prionopathy or PSPr”. PSPr is not very rare among prion diseases, and might be even more prevalent than our data indicate since PSPr cases are likely to be also classified within the group of non-Alzheimer dementias.
PMCID: PMC2767200  PMID: 18571782
18.  Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues 
PLoS ONE  2009;4(10):e7480.
Genetic variability across the SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson's disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However whether genetic variability in the SNCA gene modulates the risk to develop sporadic PD via regulation of SNCA expression remained elusive. We studied the effect of PD risk-associated variants at SNCA 5′ and 3′regions on SNCA-mRNA levels in vivo in 228 human brain samples from three structures differentially vulnerable to PD pathology (substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD-associated promoter polymorphism, Rep1, had an effect on SNCA-mRNA levels. Homozygous genotype of the ‘protective’, Rep1-259 bp allele, was associated with lower levels of SNCA-mRNA relative to individuals that carried at least one copy of the PD-risk associated alleles, amounting to an average decrease of ∼40% and >50% in temporal-cortex and substantia-nigra, respectively. Furthermore, SNPs tagging the SNCA 3′-untranslated-region also showed effects on SNCA-mRNA levels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the ‘decreased-risk’ alleles were correlated with increased SNCA-mRNA levels. Similar to Rep1 findings, no difference in SNCA-mRNA level was seen with different SNCA 3′SNP alleles in the frontal-cortex, indicating there is brain-region specificity of the genetic regulation of SNCA expression. We provide evidence for functional consequences of PD-associated SNCA gene variants in disease relevant brain tissues, suggesting that genetic regulation of SNCA expression plays an important role in the development of the disease.
PMCID: PMC2759540  PMID: 19834617
19.  Twin Pairs Discordant For Neuropathologically Confirmed Lewy Body Dementia 
Little is known about the concordance rate in twins for dementia with Lewy bodies (DLB). The rate of agreement between clinical and pathological diagnoses for DLB is typically low, necessitating confirmation of the diagnosis neuropathologically.
Participants were 17 twin pairs enrolled in the Duke Twins Study of Memory in Aging in which at least one member of the pair had an autopsy confirmed diagnosis of DLB, Alzheimer's disease (AD) with Lewy bodies, or fronto-temporal dementia with Lewy bodies. We assessed characteristics of those with dementia and examined rates of concordance for pathological confirmed dementia.
Four monozygotic twin pairs had a proband with neuropathologically confirmed pure DLB; all remained discordant for dementia for periods up to 16 years or more. Five of 13 pairs in which the proband had AD plus DLB were concordant for dementia, but only one pair was concordant for AD plus DLB, while the cotwins in the other four pairs had other types of dementia.
The present study indicates that even among twins, a diagnosis of DLB in one twin does not predict the same diagnosis in the other twin. Neuropathological discordance in type of dementia among monozygotic pairs hints at environmental or epigenetic factors playing a role in Lewy body pathology.
PMCID: PMC2758029  PMID: 19372291
Twin Studies; Dementia with Lewy Bodies; Autopsy; Neuropathology
20.  Identification of Chemical Inhibitors to Human Tissue Transglutaminase by Screening Existing Drug Libraries 
Chemistry & biology  2008;15(9):969-978.
Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the post-translational modification of intra- and extra-cellular proteins and involved in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (Lopac and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor and its metabolite ZM449829 were the most potent inhibitors with IC50 of 10 and 5 nM, respectively. In addition, two other inhibitors including Tyrphostin 47 and Vitamin K3 were found to have an IC50 in the µM range. These agents utilized in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intra-molecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.
PMCID: PMC2637080  PMID: 18804034
21.  Prevalence of Cognitive Impairment without Dementia in the United States 
Annals of internal medicine  2008;148(6):427-434.
Cognitive impairment without dementia is associated with increased risk for disability, increased health care costs, and progression to dementia. There are no population-based prevalence estimates of this condition in the United States.
To estimate the prevalence of cognitive impairment without dementia in the United States and determine longitudinal cognitive and mortality outcomes.
Longitudinal study from July 2001 to March 2005.
In-home assessment for cognitive impairment.
Participants in ADAMS (Aging, Demographics, and Memory Study) who were age 71 years or older drawn from the nationally representative HRS (Health and Retirement Study). Of 1770 selected individuals, 856 completed initial assessment, and of 241 selected individuals, 180 completed 16- to 18-month follow-up assessment.
Assessments, including neuropsychological testing, neurologic examination, and clinical and medical history, were used to assign a diagnosis of normal cognition, cognitive impairment without dementia, or dementia. National prevalence rates were estimated by using a population-weighted sample.
In 2002, an estimated 5.4 million people (22.2%) in the United States age 71 years or older had cognitive impairment without dementia. Prominent subtypes included prodromal Alzheimer disease (8.2%) and cerebrovascular disease (5.7%). Among participants who completed follow-up assessments, 11.7% with cognitive impairment without dementia progressed to dementia annually, whereas those with subtypes of prodromal Alzheimer disease and stroke progressed at annual rates of 17% to 20%. The annual death rate was 8% among those with cognitive impairment without dementia and almost 15% among those with cognitive impairment due to medical conditions.
Only 56% of the nondeceased target sample completed the initial assessment. Population sampling weights were derived to adjust for at least some of the potential bias due to nonresponse and attrition.
Cognitive impairment without dementia is more prevalent in the United States than dementia, and its subtypes vary in prevalence and outcomes.
PMCID: PMC2670458  PMID: 18347351
22.  BMS-345541Targets Inhibitor of κB Kinase and Induces Apoptosis in Melanoma: Involvement of Nuclear Factor κB and Mitochondria Pathways 
Constitutive activation of inhibitor of κB kinase (IKK) confers melanoma resistance to apoptosis and chemotherapy. Whether IKK is able to serve as a therapeutic target in melanoma is unknown. We explored the possibility of exploiting IKK as a therapeutic target in melanoma by using BMS-345541, a novel compound with a highly selective IKKβ inhibitory activity, to trigger melanoma cell apoptosis.
Experimental Design
Three human melanoma cell lines (SK-MEL-5, Hs 294T, and A375), all of which have high constitutive IKK activities, served as in vitro and in vivo melanoma models for treatment with BMS-345541. Two known antitumor drugs (temozolomide and bortezomib) were used as parallel controls for evaluation of the therapeutic efficiency and toxicity of BMS-345541. The effects of BMS-345541 on nuclear factor κB (NF-κB) signaling and on the apoptosis machinery were investigated.
Inhibition of constitutive IKK activity by BMS-345541 resulted in the reduction of NF-κB activity, CXCL1chemokine secretion by cultured melanoma cells and melanoma cell survival in vitro and in vivo. The effect of BMS-345541on tumor cell growth was through mitochondria-mediated apoptosis, based on the release of apoptosis-inducing factor, dissipation of mitochondrial membrane potential, and reduced ratio of B cell lymphoma gene-2 (Bcl-2)/Bcl-associated X protein (Bax) in mitochondria. The BMS-345541 execution of apoptosis was apoptosis-inducing factor – dependent, but largely caspase-independent.
BMS-345541down-regulation of IKK activity results in mitochondria-mediated apoptosis of tumor cells because the programmed cell death machinery in melanoma cells is highly regulated by NF-κB signaling. Therefore, IKK may serve as a potential target for melanoma therapy.
PMCID: PMC2668250  PMID: 16467110
23.  Job demands and dementia risk among male twin pairs 
Job characteristics may influence dementia risk, but some types of job complexity remain to be examined. Twin studies provide a useful methodology to examine job differences between pairs who share many environmental and genetic influences.
Members of the NAS-NRC Twins Registry of World War II Veterans received a clinical evaluation for dementia and had job ratings from the Dictionary of Occupational Titles.
Cotwin-control models (n = 220 pairs) indicated lower dementia risk with greater job demands of reasoning, mathematics, language, and vocational training, with comparable results in case-control models (n=425 cases). These effects were significant among twin pairs discordant for 6 or more years, but not among those discordant between 3–5 years. Results were similar for Alzheimer’s disease, and main effects were not further explained by zygosity or apolipoprotein E genotype.
Jobs that utilize data, academic skills, and extensive vocational training may protect against dementia; however, in twin pairs these effects only emerged among individuals who remained free of dementia several years after onset in their sibling.
PMCID: PMC2031862  PMID: 18591984
Dementia; Alzheimer’s disease; Twins; Occupation; Job complexity
24.  Alternative ion channel splicing in mesial temporal lobe epilepsy and Alzheimer's disease 
Genome Biology  2007;8(3):R32.
A novel microarray technology that permits the screening of alternative splice variants identifies disease-associated alternative splicing patterns in ion channel genes of patients with mesial temporal lobe epilepsy and Alzheimers disease.
Alternative gene transcript splicing permits a single gene to produce multiple proteins with varied functions. Bioinformatic investigations have identified numerous splice variants, but whether these transcripts are translated to functional proteins and the physiological significance of these alternative proteins are largely unknown. Through direct identification of splice variants associated with disease states, we can begin to address these questions and to elucidate their roles in disease predisposition and pathophysiology. This work specifically sought to identify disease-associated alternative splicing patterns in ion channel genes by comprehensively screening affected brain tissue collected from patients with mesial temporal lobe epilepsy and Alzheimer's disease. New technology permitting the screening of alternative splice variants in microarray format was employed. Real time quantitative PCR was used to verify observed splice variant patterns.
This work shows for the first time that two common neurological conditions are associated with extensive changes in gene splicing, with 25% and 12% of the genes considered having significant changes in splicing patterns associated with mesial temporal lobe epilepsy and Alzheimer's disease, respectively. Furthermore, these changes were found to exhibit unique and consistent patterns within the disease groups.
This work has identified a set of disease-associated, alternatively spliced gene products that represent high priorities for detailed functional investigations into how these changes impact the pathophysiology of mesial temporal lobe epilepsy and Alzheimer's disease.
PMCID: PMC1868939  PMID: 17343748
25.  Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions? 
Age  1998;21(1):25-30.
At least seven adult-onset neurodegenerative diseases, including Huntington’s disease (HD), are caused by genes containing expanded CAG triplets within their coding regions. The expanded CAG repeats give rise to extended stretches of polyglutamines (Qn) in the proteins expressed by the affected genes. Generally, n ≥40 in affected individuals and ≤36 in clinically unaffected individuals. The expansion has been proposed to confer a “toxic gain of function” to the mutated protein. Poly-Q domains have recently been shown to be excellent substrates of tissue transglutaminase. We investigated the effects of expression of glutathione S-transferase constructs containing poly-Q inserts of various lengths (GSTQn where n = 0, 10, 62 or 81) on the activity of some key metabolic enzymes in the host Escherischia coil-an organism not known to have transglutaminase activity. E. coil carrying the GSTQ62 construct exhibited statistically significant decreases in the specific activities of α-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC). Previous work has shown that KGDHC and PDHC activities are reduced in the brains of Alzheimer’s disease (AD) patients. Our results suggest that KGDHC and PDHC may be particularly susceptible to the effects of a number of disparate insults, including those associated with AD and HD.
PMCID: PMC3455770  PMID: 23604331

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