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1.  Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians 
Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer’s disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
PMCID: PMC4822513  PMID: 26519441
African Continental Ancestry Group; CD2-associated protein; cystathionine beta-synthase; genome-wide association study; homocysteine; metabolic networks and pathways; metabolomics
3.  [11C]PiB PET in Gerstmann-Sträussler-Scheinker disease 
Gerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [11C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [11C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [11C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [11C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [11C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [11C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.
PMCID: PMC4749507  PMID: 27069768
[11C]Pittsburgh compound B (PiB) positron emission tomography (PET); Gerstmann-Sträussler-Scheinker disease (GSS); prion disease; neuroimaging; amyloid
4.  Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals 
JAMA neurology  2015;72(11):1313-1323.
Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.
To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.
Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.
The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.
The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.
To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
PMCID: PMC4641052  PMID: 26366463
5.  Association of Apolipoprotein E Genotype and Alzheimer Disease in African Americans 
Archives of neurology  2006;63(3):431-434.
Alzheimer disease (AD) is the most frequent cause of dementia. Even though the incidence of AD in the African American population is similar to or higher than that in persons of European descent, AD in African Americans is understudied. Identification of genetic risk factors in African Americans is essential for understanding the etiology of AD.
To determine the effect of apolipoprotein E (APOE) genotype on the risk of AD in elderly African Americans.
Population-based longitudinal study of AD.
Indianapolis, Ind.
African Americans 65 years and older.
Main Outcome Measures
APOE genotype and diagnosis of AD.
The APOE genotype was determined in 1822 samples. Of these, 690 were clinically evaluated: 318 were normal, and 162 had a diagnosis of AD. The presence of APOE ε4 was significantly associated with increased risk of AD (ε3/ε4: OR, 2.32; 95% confidence interval [CI], 1.41–3.82; and ε4/ε4: OR, 7.19; 95% CI, 3.00–17.29, compared with the ε3/ε3 genotype). There was also a significant protective effect with APOE ε2 (ε2/ε2 and ε2/ε3: OR, 0.42; 95% CI, 0.20–0.89).
These findings are in marked contrast to the lack of association between APOE and AD in the Ibadan, Nigeria, sample of this project. These results suggest that other genetic factors and different environmental influences may play a role in the risk for AD in individuals of African ancestry.
PMCID: PMC3203415  PMID: 16533971
6.  Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein 
Stem Cell Reports  2015;5(1):83-96.
Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients’ brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.
Graphical Abstract
•FTD-iPSC-derived neurons show TAU pathology and disturbed neurite function•FTD neurons are vulnerable to oxidative stress and show an activation of the unfolded protein response•FTD neurons demonstrate distinct alterations in whole-genome gene expression•Validation of distinct disease phenotypes in post-mortem brain tissue of FTD patients
In this article, Hargus and colleagues generated iPSC-derived neurons from individuals carrying frontotemporal dementia-associated mutations in MAPT, the microtubule-associated protein TAU. These neurons showed pronounced TAU pathology, decreased neurite extension, an increased but reversible oxidative stress response, an activation of the unfolded protein response, and altered whole-genome expression profiles demonstrating distinct, mutant MAPT-associated neurodegenerative changes in these cells.
PMCID: PMC4618448  PMID: 26143746
7.  Mild Cognitive Impairment, Incidence, Progression, and Reversion: Findings from a Community-based Cohort of Elderly African Americans 
To examine the long-term outcomes of community-based elderly African Americans by following their transitions from normal cognition to mild cognitive impairment (MCI), and to dementia.
Participants were from the community-based Indianapolis Dementia Project. A total of 4104 African Americans were enrolled in 1992 or 2001 and followed until 2009 with regularly scheduled evaluation of cognitive assessment. A two-stage sampling was used at each evaluation to select individuals for extensive clinical assessment following the results of stage one cognitive testing. Age and gender specific incidence, progression and reversion rates for MCI were derived using the person-year method in a dynamic cohort and predicted probabilities from weighted multinomial logistic models of transitional probabilities among normal cognition, MCI and dementia.
Annual overall incidence rate for MCI is 5.6% (95% CI: 4.6–6.6%). Annual progression rate from MCI to dementia is 5.9% (95% CI: 5.3–6.5%) and annual reversion rate from MCI to normal is 18.6% (95% CI: 16.7–20.4%). Both MCI incidence rates and MCI to dementia progression rates increase with age, while reversion rates from MCI to normal decrease with age.
MCI progression to dementia is much more frequent in the older age groups than in the younger participants where reversion to normal cognition is more common. Future research is needed to determine factors related to the heterogeneous outcomes in MCI individuals.
PMCID: PMC3842367  PMID: 23831172
mild cognitive impairment; dementia; African Americans
8.  Rapidly progressive atypical parkinsonism associated with frontotemporal lobar degeneration and motor neuron disease 
To report the rare but distinct clinical and neuropathological phenotype of non-familial, rapidly progressive parkinsonism and dementia associated with frontotemporal lobar degeneration with motor neuron disease (FTLD-MND).
Subjects included two 70-year-old women presenting with rapidly progressive severe postural instability, axial-predominant parkinsonism, oculomotor dysfunction and frontal-predominant dementia with language impairment and pseudobulbar palsy. One had diffuse weakness without signs of lower motor neuron disease. Post-mortem evaluations included immunohistochemistry with antiphospho-TAR DNA-binding protein 43 (TDP-43) and genetic analysis of the TARDBP and PGRN genes.
Subjects died within 14 months from symptom onset. TDP-43-positive neuronal intracytoplasmic inclusions were prominent in the primary motor cortex, granule cell layer of the hippocampus, and several cranial and spinal cord nuclei. TDP-43 globular glial inclusions (GGI) were identified in one case. There were no mutations in PGRN or TARDBP genes.
FTLD-MND due to TDP-43-proteinopathy should be considered in patients with rapidly progressive parkinsonism and dementia phenotype, especially when aphasia and/or weakness are also present.
PMCID: PMC4449730  PMID: 20587488
9.  Cerebral hypometabolism and grey matter density in MAPT intron 10 +3 mutation carriers 
Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [18F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.
PMCID: PMC4299725  PMID: 25628962
Multiple system tauopathy with presenile dementia (MSTD); frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T); behavioral variant frontotemporal dementia; [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET); microtubule associated protein tau (MAPT); magentic resonance imaging (MRI); neuroimaging
10.  The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43 
PLoS Genetics  2014;10(12):e1004803.
Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups of neurodegenerative disease. Kinase hyperactivity may be a consistent feature of ALS and FTLD-TDP, as phosphorylated TDP-43 is not observed in the absence of neurodegeneration. By examining changes in TDP-43 phosphorylation state, we have identified kinases controlling TDP-43 phosphorylation in a C. elegans model of ALS. In this kinome-wide survey, we identified homologs of the tau tubulin kinases 1 and 2 (TTBK1 and TTBK2), which were also identified in a prior screen for kinase modifiers of TDP-43 behavioral phenotypes. Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. Furthermore, protein levels of TTBK1 and TTBK2 are increased in frontal cortex of FTLD-TDP patients, and TTBK1 and TTBK2 co-localize with TDP-43 inclusions in ALS spinal cord. These kinases may represent attractive targets for therapeutic intervention for TDP-43 proteinopathies such as ALS and FTLD-TDP.
Author Summary
Aggregated proteins are a hallmark of many neurodegenerative diseases. In ALS and FTLD-TDP, these aggregates contain abnormal TDP-43 modified by phosphorylation. Protein phosphorylation normally controls protein activity, stability, or location, but in some neurodegenerative diseases the phosphorylated proteins accumulate in excess. Kinases are the enzymes responsible for protein phosphorylation. We have identified two TDP-43 kinases, TTBK1 and TTBK2, using a novel approach combining reverse genetics and biochemical screening to identify the kinases responsible for changes in TDP-43 phosphorylation. We show TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro, and control TDP-43 phosphorylation in cellular and simple animal models of ALS. This has uncovered a molecular mechanism by which pathological phosphorylated TDP-43 can occur in disease. To determine whether changes in TTBK1/2 protein are contributing to TDP-43 pathology, we examined diseased brain and spinal cord tissue from patients with ALS or FTLD-TDP. We observed changes in the abundance of TTBK1 and TTBK2 in disease-affected neurons, and the coexistence of TTBK1/2 with phosphorylated TDP-43 aggregates in both FTLD-TDP and ALS. Therefore, increased abundance or activity of TTBK1 or TTBK2 may contribute to the neurodegeneration observed in ALS and FTLD-TDP.
PMCID: PMC4256087  PMID: 25473830
11.  The relationship between cholesterol and cognitive function is homocysteine-dependent 
Previous studies have identified hyperlipidemia as a potential risk factor for dementia and Alzheimer’s disease. However, studies on cholesterol measured in late-life and cognitive function have been inconsistent. Few studies have explored nonlinear relationships or considered interactions with other biomarker measures.
A cross-sectional sample of 1,889 participants from four rural counties in the People’s Republic of China was included in this analysis. Serum total cholesterol, high-density lipoprotein, triglycerides, and homocysteine levels were measured in fasting blood samples. A composite cognitive score was derived based on nine standardized cognitive test scores. Analysis of covariance models were used to investigate the association between biomarker measures and the composite cognitive scores.
There was a significant interaction between the homocysteine quartile group and the cholesterol quartile group on cognitive scores (P=0.0478). In participants with normal homocysteine levels, an inverse U-shaped relationship between total cholesterol level and cognitive score was found, indicating that both low and high cholesterol levels were associated with lower cognitive scores. In participants with high homocysteine levels, no significant association between cholesterol and cognition was found.
The relationship between cholesterol levels and cognitive function depends upon homocysteine levels, suggesting an interactive role between cholesterol and homocysteine on cognitive function in the elderly population. Additional research is required to confirm our findings in other populations, and to explore potential mechanisms underlying the lipid–homocysteine interaction.
PMCID: PMC4211868  PMID: 25364240
cholesterol; homocysteine; cognitive function
12.  Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings 
Acta Neuropathologica  2014;128(1):81-98.
Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1279-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4059967  PMID: 24803225
DYT12; RDP; Rapid-onset dystonia-parkinsonism; Neuropathology
13.  Cognitive function, body mass index and mortality in a rural elderly Chinese cohort 
Previous studies have shown that poor cognition and low body mass index were associated with increased mortality. But few studies have investigated the association between cognition and mortality across the entire cognitive spectrum while adjusting for BMI. The objective of this study is to examine the associations between cognitive function, BMI and 7-year mortality in a rural elderly Chinese cohort.
A prospective cohort of 2,000 Chinese age 65 and over from four rural counties in China were followed for 7-years. Cognitive function, BMI and other covariate information were obtained at baseline. Cox’s proportional hazard models were used to determine the effects of cognitive function and BMI on mortality risk.
Of participants enrolled, 473 (23.7%) died during follow-up. Both lower cognitive function (HR = 1.48, p = 0.0049) and lower BMI (HR = 1.6, p < 0.0001) were independently associated with increased mortality risk compared to individuals with average cognitive function and normal weight. Higher cognitive function was associated with lower mortality risk (HR = 0.69, p = 0.0312). We found no significant difference in mortality risk between overweight/obese participants and those with normal weight.
Cognitive function and BMI were independent predictors of mortality risk. Intervention strategies for increasing cognitive function and maintaining adequate BMI may be important in reducing morality risk in the elderly population.
PMCID: PMC3974191  PMID: 24666663
14.  Late Life Leisure Activities and Risk of Cognitive Decline 
Studies concerning the effect of different types of leisure activities on various cognitive domains are limited. This study tests the hypothesis that mental, physical, and social activities have a domain-specific protection against cognitive decline.
A cohort of a geographically defined population in China was examined in 2003–2005 and followed for an average of 2.4 years. Leisure activities were assessed in 1,463 adults aged 65 years and older without cognitive or physical impairment at baseline, and their cognitive performances were tested at baseline and follow-up examinations.
High level of mental activity was related to less decline in global cognition (β = −.23, p < .01), language (β = −.11, p < .05), and executive function (β = −.13, p < .05) in ANCOVA models adjusting for age, gender, education, history of stroke, body mass index, Apolipoprotein E genotype, and baseline cognition. High level of physical activity was related to less decline in episodic memory (β = −.08, p < .05) and language (β = −.15, p < .01). High level of social activity was associated with less decline in global cognition (β = −.11, p < .05). Further, a dose-response pattern was observed: although participants who did not engage in any of the three activities experienced a significant global cognitive decline, those who engaged in any one of the activities maintained their cognition, and those who engaged in two or three activities improved their cognition. The same pattern was observed in men and in women.
Leisure activities in old age may protect against cognitive decline for both women and men, and different types of activities seem to benefit different cognitive domains.
PMCID: PMC3598354  PMID: 22879456
Cognitive function; Leisure activities; Mental activity; Physical activity; Social activity
15.  Screening for C9ORF72 repeat expansion in FTLD 
Neurobiology of aging  2012;33(8):1850.e1-1850.11.
In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TDP-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
PMCID: PMC3743244  PMID: 22459598
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
16.  Encephalopathy with Neuroserpin Inclusion Bodies Presenting as Progressive Myoclonus Epilepsy and Associated with a Novel Mutation in the Proteinase Inhibitor 12 Gene 
Neuroserpin encephalopathy is an autosomal-dominant degenerative disease associated with mutations in the Proteinase Inhibitor 12 (PI12) gene. A 26-year-old male presented with progressive myoclonus epilepsy and declining mental status. He had failed in university studies because of impaired attention, memory and concentration. Generalized seizures started to occur approximately once a month, and he developed myoclonus and progressive gait disturbances. Neuroimaging revealed mild atrophy and multiple periventricular white matter lesions, consistent with demyelination. He progressively declined and died at age 34. Neuropathologic examination revealed widespread involvement of the cerebral cortex by numerous round eosinophilic inclusions in neuronal perikarya and neuropil, predominantly within the deep cortical layers. Numerous inclusions were also found in the basal ganglia, thalamus, hippocampus, brain stem, spinal gray matter, and dorsal root ganglia. They were essentially absent from the cerebellum. The inclusions were immunopositive for antibodies raised against neuroserpin. The white matter lesions showed histologic features compatible with multiple sclerosis. Genetic analysis revealed a nucleotide substitution in codon 47 in one allele of the PI12 gene, resulting in a proline for leucine amino acid substitution (L47P). In summary, we report a case of neuroserpin encephalopathy associated with a novel PI12 mutation and complicated by coexistent multiple sclerosis.
PMCID: PMC3709456  PMID: 21435071
dementia; mutation; neurodegeneration; neuroserpin; progressive myoclonus epilepsy; seizures
17.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
18.  Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans 
Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
PMCID: PMC3667653  PMID: 23571587
The Clinical Neuropsychologist  2012;26(4):641-653.
Normative information is important for appropriate interpretation of cognitive test scores as a critical component of dementia diagnosis in the elderly population. A cross-sectional evaluation of 1826 participants aged 65 years and older from four rural counties in China was conducted using six cognitive instruments including tests of global cognitive function (the Community Screening Instrument for Dementia), Memory (Word List Learning and Recall tasks from the Consortium to Establish a Registry for Alzheimer’s Disease, IU Story), Language (Animal Fluency Test), and executive function (IU Token). Multiple regression models adjusting for demographic variables were used to provide standardized residuals z-scores and corresponding percentile ranking for each cognitive test. In all cognitive tests, older age was associated with worse test performance while exposure to education was related to better cognitive test performance. We also detected a significant gender difference with men scoring better than women and a significant gender by education interaction on two tests. The interaction indicates that gender difference in test scores was much smaller in participants with more education than those who had less or no education. These demographically adjusted, regression-based norms can be a useful tool to clinicians involved with differential diagnosis of cognitive and memory disorders in older adults in rural China.
PMCID: PMC3349802  PMID: 22439633
Normative Study; Neuropsychological Test; Age; Gender; Education; Regression- Based Norms
BMC Psychiatry  2012;12:72.
Selenium is considered a protective agent against free radicals through the maintenance of better enzyme activity. The few studies examining the relationship between selenium and depression have yielded inconsistent results and none of these studies considered the role of cognitive function in this context.
A cross-sectional evaluation of 1737 rural Chinese age 65 and over from two provinces in China was conducted. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cognitive function was assessed using various cognitive instruments. Selenium measures were obtained from nail samples. Other information collected included demographic characteristics and medical history. Analysis of covariance models were used to identify factors associated with GDS score.
Higher selenium levels were associated with lower GDS scores adjusting for demographic and medical conditions (p = 0.0321). However, the association between selenium and depressive symptoms was no longer significant when cognitive function score was adjusted in the model (p = 0.2143).
Higher selenium level was associated with lower depressive symptoms without adjusting for cognition in this cohort. However, after cognition was adjusted in the model the association between selenium and depressive symptoms was no longer significant, suggesting that selenium’s association with depressive symptoms may be primarily through its association with cognitive function.
PMCID: PMC3441866  PMID: 22759565
Archives of neurology  2011;68(4):488-497.
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
PMCID: PMC3160280  PMID: 21482928
The literature on the association between apolipoprotein E (ApoE) and mortality across ethnic and age groups has been inconsistent. No studies have looked at this association in developing countries. We used data from the Indianapolis-Ibadan Dementia study to examine this association between APOE and mortality in 354 African-Americans from Indianapolis and 968 Yoruba from Ibadan, Nigeria. Participants were followed up to 9.5 years for Indianapolis and 8.7 years for Ibadan. Subjects from both sites were divided into 2 groups based upon age at baseline. A Cox proportional hazards regression model adjusting for age at baseline, education, hypertension, smoking history and gender in addition to time-dependent covariates of cancer, diabetes, heart disease, stroke, and dementia was fit for each cohort and age group. Having ApoE ε4 alleles significantly increased mortality risk in Indianapolis subjects under age 75 ( hazard ratio: 2.00; 95% CI: 1.19–3.35; p = 0.0089). No association was found in Indianapolis subjects 75 and older (hazard ratio: 0.71; 95% CI: 0.45–1.10; p = 0.1238), Ibadan subjects under 75 (hazard ratio: 1.04; 95% CI: 0.78 to 1.40; p = 0.7782), or Ibadan subjects over 75 (hazard ratio: 1.21; 95% CI: 0.83 to 1.75; p = 0.3274).
PMCID: PMC3212028  PMID: 14646029
Apolipoprotein E; survival analysis; African-Americans
The relationship between weight and dementia risk has not been investigated in populations with relatively low body mass index (BMI) such as the Yoruba. This study set out to achieve this objective using a prospective observational design.
The setting was Idikan Ward in Ibadan City, Nigeria. The participants were all aged 65 years or older and were enrolled in the Indianapolis-Ibadan Dementia Project. Repeated cognitive assessments and clinical evaluations were conducted to identify participants with dementia or MCI during 10 years of follow-up (mean duration: 5.97 years). BMI measures, information on alcohol, smoking history, cancer, hypertension, diabetes, heart attack, stroke and depression were collected at each follow-up evaluation. Mixed effect models adjusted for covariates were used to examine the differences in BMI among participants who developed dementia or MCI and those who remained cognitively normal during the follow-up.
This analysis included 1559 participants who had no dementia at their first BMI measurements. There were 136 subjects with incident dementia, 255 with MCI and 1168 with normal cognition by the end of the study. The mean BMI at baseline was higher for female participants (22.31; SD = 4.39) than for male (21.09; SD = 3.61, p < 0.001). A significantly greater decline in BMI was found in those with either incident dementia (p < 0.001) or incident MCI (p < 0.001) compared to normal subjects.
Decline in BMI is associated with incident MCI and dementia in elderly Yoruba. This observation calls for close monitoring of weight loss in elderly individuals which may indicate future cognitive impairment for timely detection and tailored interventions.
PMCID: PMC3044788  PMID: 20735893
body mass index; dementia; mild cognitive impairment; normal cognition
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
PMCID: PMC2828525  PMID: 20154673
Annals of neurology  2006;59(1):182-185.
Since 1992, research teams from Indiana University and the University of Ibadan have been collecting and comparing data from two diverse, elderly populations to identify risk factors for dementia and Alzheimer’s disease. Apolipoprotein E (APOE) was genotyped in 2,245 Nigerian samples. Of these, 830 had a diagnosis: 459 were normal, and 140 had dementia including 123 diagnosed with Alzheimer’s disease. In contrast with other populations, the APOE ε4 allele was not significantly associated with Alzheimer’s disease or dementia. This lack of association in the Yoruba might reflect genetic variation, environmental factors, as well as genetic/environmental interactions.
PMCID: PMC2855121  PMID: 16278853

Results 1-25 (33)