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1.  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
2.  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.
doi:10.1371/journal.pgen.1004803
PMCID: PMC4256087  PMID: 25473830
3.  The relationship between cholesterol and cognitive function is homocysteine-dependent 
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.2147/CIA.S64766
PMCID: PMC4211868  PMID: 25364240
cholesterol; homocysteine; cognitive function
4.  Association of Apolipoprotein E Genotype and Alzheimer Disease in African Americans 
Archives of neurology  2006;63(3):431-434.
Background
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.
Objective
To determine the effect of apolipoprotein E (APOE) genotype on the risk of AD in elderly African Americans.
Design
Population-based longitudinal study of AD.
Setting
Indianapolis, Ind.
Participants
African Americans 65 years and older.
Main Outcome Measures
APOE genotype and diagnosis of AD.
Results
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).
Conclusions
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.
doi:10.1001/archneur.63.3.431
PMCID: PMC3203415  PMID: 16533971
5.  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.
doi:10.1007/s00401-014-1279-x
PMCID: PMC4059967  PMID: 24803225
DYT12; RDP; Rapid-onset dystonia-parkinsonism; Neuropathology
6.  Cognitive function, body mass index and mortality in a rural elderly Chinese cohort 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/2049-3258-72-9
PMCID: PMC3974191  PMID: 24666663
7.  Late Life Leisure Activities and Risk of Cognitive Decline 
Background.
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.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1093/gerona/gls153
PMCID: PMC3598354  PMID: 22879456
Cognitive function; Leisure activities; Mental activity; Physical activity; Social activity
8.  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.
doi:10.1016/j.neurobiolaging.2012.02.017
PMCID: PMC3743244  PMID: 22459598
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
9.  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.
doi:10.1111/j.1750-3639.2011.00481.x
PMCID: PMC3709456  PMID: 21435071
dementia; mutation; neurodegeneration; neuroserpin; progressive myoclonus epilepsy; seizures
10.  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.
doi:10.1038/ng.2466
PMCID: PMC3510344  PMID: 23143602
11.  Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans 
Importance
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.
Objective
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.
Results
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.
doi:10.1001/jama.2013.2973
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.
doi:10.1080/13854046.2012.666266
PMCID: PMC3349802  PMID: 22439633
Normative Study; Neuropsychological Test; Age; Gender; Education; Regression- Based Norms
BMC Psychiatry  2012;12:72.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1471-244X-12-72
PMCID: PMC3441866  PMID: 22759565
Archives of neurology  2011;68(4):488-497.
Objective
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.
Results
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.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
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
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1017/S1041610210001390
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.
doi:10.1038/ng.536
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.
doi:10.1002/ana.20694
PMCID: PMC2855121  PMID: 16278853
OBJECTIVES
To examine the association between hypertension and cognitive decline in older adults.
DESIGN
Prospective observational study.
SETTING
Four rural counties in China.
PARTICIPANTS
Two thousand rural Chinese aged 65 and older (median age 70, range 65–92) participated in a baseline evaluation. A follow-up evaluation of 1,737 subjects was conducted 2.5 years after baseline.
MEASUREMENTS
Cognitive function was assessed using the Community Screening Instrument for Dementia (CSID), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning and Recall Tests, Indiana University (IU) Story Recall Test, Animal Fluency Test, and IU Token Test. Hypertension was defined as the mean of two readings of systolic blood pressure (BP) of 140 mmHg or greater, diastolic BP of 90 mmHg or greater, or according to self-report. Cognitive decline was derived as the difference between baseline and follow-up scores. Analysis of covariance models were used to estimate the association between hypertension, BP, and cognitive decline, adjusting for other covariates.
RESULTS
Greater decline was found on the CERAD 10-Word List Learning (P<.001) and Recall (P =.01) scores for subjects with hypertension than for those without. In particular, significantly greater decline was seen in the group with hypertension that was not taking medication than in the group without hypertension. No significant difference on cognitive decline was found between subjects with hypertension who were taking medication and those without hypertention.
CONCLUSION
Untreated hypertension was associated with greater cognitive decline in this Chinese cohort. Better hypertension detection and treatment in elderly people, especially in developing countries, may offer protection against cognitive decline
PMCID: PMC2849159  PMID: 19507297
cognitive aging; cardiovascular risk factor; elderly
Public health nutrition  2009;12(12):2371-2376.
Objective
Se is an essential trace element in human nutrition associated with antioxidant activity. Previous studies on predictors of toenail Se or serum Se have mostly concentrated on demographic factors such as age and gender. The present paper examines the association between apoE genotype and Se levels in nail samples in a rural elderly Chinese cohort.
Design
Two thousand Chinese aged 65 years and over from four counties in China were enrolled in a cohort to study the association of Se with cognitive decline. Nail samples were collected from each participant and analysed for Se levels. Dietary Se intake was estimated from an FFQ using Se contents measured in food items collected from each village. Blood samples on filter cards were collected and analysed for apoE genotype. Mixed-effect models were constructed with nail Se level as the dependent variable and each village as the random effect, which controlled for the potential confounding effect from correlation in Se measures obtained from participants residing in the same village.
Results
In this elderly Chinese cohort, carriers of the apoE ε4 allele had significantly lower Se levels measured in nail samples than non-carriers after adjusting for other significant covariates and controlling for estimated dietary Se intake. There was no significant difference between the two genotypes on estimated Se dietary intake (P=0·6451).
Conclusions
Future studies are needed to examine the mechanism underlying the association between the apoE ε4 allele and Se levels, including the role of oxidative stress and that of reduced lipid metabolism in the apoE ε4 carriers.
doi:10.1017/S1368980009005102
PMCID: PMC2842076  PMID: 19278567
Selenium; Nail samples; Dietary intake; apoE ε4
SUMMARY
Objective
Late life depression has been studied in many populations around the world. However, findings on risk factors for late life depression have remained inconsistent.
Methods
A cross-sectional survey of 1737 rural Chinese age 65 and over from two provinces in China was conducted assessing cognitive functions using various cognitive instruments and collecting information on demographic characteristics and medical history. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Analysis of covariance and logistic regression models were used to identify factors associated with the continuous GDS score, mild or severe depression.
Results
In this cohort, 26.5% (95% CI: 24.4–28.6%) met the criteria for mild depression and 4.3% (95% CI: 3.4–5.4%) for severely depression. Living alone, history of heart attack, head injury, and fracture were associated with higher depressive symptoms. Alcohol consumption and higher cognitive function were associated with lower depressive symptoms. Living alone, not attended school, history of head injury, fracture, and low cognitive function were associated with increased probability of mild depression. Living alone, history of stroke or heart attack, and low cognitive function were associated with severe depression.
Conclusions
Depression, particularly mild depression, is common in rural elderly Chinese. Among a number of factors identified in this cohort as being significantly associated with depressive symptoms, living alone and lower cognitive function were the most consistent factors associated with depressive symptoms, mild and severe depression. History of stroke, heart attack, and fracture were also risk factors for depressive symptoms.
doi:10.1002/gps.2271
PMCID: PMC2833291  PMID: 19347839
depressive symptoms; Geriatric Depression Scale; Elderly Chinese
Frontotemporal lobar degenerations are a group of disorders characterized by circumscribed degeneration of the frontal and temporal lobes and diverse histopathological features. We report clinical, neuropathological, ultrastructural, biochemical and genetic data on seven individuals with a four-repeat (4R) tauopathy characterized by the presence of globular glial inclusions (GGIs) in brain white matter. Clinical manifestations were compatible with the behavioral variant of frontotemporal dementia (FTD) and included motor neuron symptoms; there was prominent neuronal loss in the frontal and temporal cortex, subiculum and amygdala. The surrounding white matter showed abundant GGIs composed of abnormal filaments present mostly in oligodendrocytes. The severity of white matter tau abnormalities correlated with a reduction in myelin and axons and with microglial activation. Western blotting of sarkosyl-insoluble tau demonstrated the presence of two major tau bands of 64 and 68 kDa. No mutations in the microtubule-associated protein tau (MAPT) gene were detected in two affected individuals. We propose that 4R tau-immunoreactive GGIs are the neuropathologic hallmark of a distinct sporadic tauopathy with variable clinical presentations that include FTD and occasionally upper motor neuron disease. This type of tauopathy with GGIs expands the group of neurodegenerative disorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders.
doi:10.1097/NEN.0b013e318187a80f
PMCID: PMC2785030  PMID: 18800011
Dementia; Frontotemporal lobar degeneration; Tau; Tauopathy; White matter
American journal of epidemiology  2007;165(8):955-965.
Selenium is a trace element associated with antioxidant activity and is considered to be a protective agent against free radicals through enhanced enzyme activity. Studies on selenium and cognitive function or Alzheimer’s disease have yielded inconsistent results. A cross-sectional survey of 2,000 rural Chinese aged 65 years or older from two provinces in the People’s Republic of China was conducted from December 2003 to May 2005 by use of the Community Screening Instrument for Dementia, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning Test, the Indiana University Story Recall Test, the Animal Fluency Test, and the Indiana University Token Test. Over 70% of the study participants have lived in the same village since birth. Nail samples were collected and analyzed for selenium contents. Analysis-of-covariance models were used to estimate the association between quintile selenium levels measured in nail samples and cognitive test scores, with adjustment for other covariates. Lower selenium levels measured in nail samples were significantly associated with lower cognitive scores (p < 0.0087 for all tests) except the Animal Fluency Test (p = 0.4378). A dose-response effect of selenium quintiles was also seen for those significant associations. Results in this geographically stable cohort support the hypothesis that a lifelong low selenium level is associated with lower cognitive function.
doi:10.1093/aje/kwk073
PMCID: PMC2760949  PMID: 17272290
aged; Asian continental ancestry group; cognition; selenium
Background
Trace elements are involved in metabolic processes and oxidation-reduction reactions in the central nervous system and could have a possible effect on cognitive function. The relationship between trace elements measured in individual biological samples and cognitive function in an elderly population had not been investigated extensively.
Methods
The participant population is part of a large cohort study of 2000 rural elderly Chinese persons. Six cognitive assessment tests were used to evaluate cognitive function in this population, and a composite score was created to represent global cognitive function. Trace element levels of aluminum, calcium, cadmium, copper, iron, lead, and zinc were analyzed in plasma samples of 188 individuals who were randomly selected and consented to donating fasting blood. Analysis of covariance models were used to assess the association between each trace element and the composite cognitive score adjusting for demographics, medical history of chronic diseases, and the apolipoprotein E (APOE) genotype.
Results
Three trace elements—calcium, cadmium, and copper—were found to be significantly related to the composite cognitive score. Increasing plasma calcium level was associated with higher cognitive score (p < .0001). Increasing cadmium and copper, in contrast, were significantly associated with lower composite score (p = .0044 and p = .0121, respectively). Other trace elements did not show significant association with the composite cognitive score.
Conclusions
Our results suggest that calcium, cadmium, and copper may be associated with cognitive function in the elderly population.
PMCID: PMC2728120  PMID: 18559640
Trace element; Cognitive function; Calcium; Copper; Cadmium
Neuro-Degenerative Diseases  2008;5(3-4):215-217.
Background
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
Objective
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
Methods
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
Results
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Conclusion
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
doi:10.1159/000113706
PMCID: PMC2826454  PMID: 18322394
Frontotemporal dementia and parkinsonism linked to chromosome 17; Tau; Ubiquitin; TDP-43; Neuropathology

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