P P Zandi

Publications of P P Zandi

• The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

  Authors: P B Rosenberg, M M Mielke, D Han, J S Leoutsakos, C G Lyketsos, P V Rabins, P P Zandi, J C S Breitner, M C Norton, K A Welsh-Bohmer, I H Zuckerman, G B Rattinger, R C Green, C Corcoran, J T Tschanz

  International journal of geriatric psychiatry. 02/2012;

  OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association ofOBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications. Copyright © 2012 John Wiley & Sons, Ltd.

• Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia.

  Authors: J M Coughlin, K Ishizuka, S I Kano, J A Edwards, F T Seifuddin, M A Shimano, E L Daley, P P Zandi, F M Leweke, N G Cascella, M G Pomper, R H Yolken, A Sawa

  Molecular psychiatry. 02/2012;

• Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

  Authors: E R Gamazon, J A Badner, L Cheng, C Zhang, D Zhang, N J Cox, E S Gershon, J R Kelsoe, T A Greenwood, C M Nievergelt [......] J B Potash, P P Zandi, P B Mahon, M G McInnis, S Zöllner, P Zhang, D W Craig, S Szelinger, T B Barrett, C Liu

  Molecular psychiatry. 01/2012;

  We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variationWe conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.Molecular Psychiatry advance online publication, 3 January 2012; doi:10.1038/mp.2011.174.

• Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

  Authors: J A Badner, D Koller, T Foroud, H Edenberg, J I Nurnberger, P P Zandi, V L Willour, F J McMahon, J B Potash, M Hamshere [......] M Ayub, A Maclean, D Blackwood, C-Y Liu, E S Gershon, W McMahon, G J Lyon, R Robinson, J Ross, W Byerley

  Molecular psychiatry. 07/2011;

  Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information contentBecause of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ∼1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.Molecular Psychiatry advance online publication, 19 July 2011; doi:10.1038/mp.2011.89.

• A genome-wide association study of attempted suicide.

  Authors: V L Willour, F Seifuddin, P B Mahon, D Jancic, M Pirooznia, J Steele, B Schweizer, F S Goes, F M Mondimore, D F Mackinnon [......] S Cichon, H Gurling, S Purcell, J W Smoller, N Craddock, J R Depaulo, T G Schulze, F J McMahon, P P Zandi, J B Potash

  Molecular psychiatry. 03/2011;

  The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have beenThe heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.Molecular Psychiatry advance online publication, 22 March 2011; doi:10.1038/mp.2011.4.

• The 32-year relationship between cholesterol and dementia from midlife to late life.

  Authors: M M Mielke, P P Zandi, H Shao, M Waern, S Östling, X Guo, C Björkelund, L Lissner, I Skoog, D R Gustafson

  Neurology. 11/2010; 75(21):1888-95.

  Cellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clearCellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clear and may vary over the lifespan. The Prospective Population Study of Women, consisting of 1,462 women without dementia aged 38-60 years, was initiated in 1968-1969 in Gothenburg, Sweden. Follow-ups were conducted in 1974-1975, 1980-1981, 1992-1993, and 2000-2001. All-cause dementia was diagnosed according to DSM-III-R criteria and AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Cox proportional hazards regression examined baseline, time-dependent, and change in cholesterol levels in relation to incident dementia and AD among all participants. Analyses were repeated among participants who survived to the age of 70 years or older and participated in the 2000-2001 examination. Higher cholesterol level in 1968 was not associated with an increased risk of AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence interval [CI] 0.94-8.43) among those who survived to and participated in the 2000-2001 examination. While there was no association between cholesterol level and dementia when considering all participants over 32 years, a time-dependent decrease in cholesterol over the follow-up was associated with an increased risk of dementia (HR 2.35, 95% CI 1.22-4.58). These data suggest that midlife cholesterol level is not associated with an increased risk of AD. However, there may be a slight risk among those surviving to an age at risk for dementia. Declining cholesterol levels from midlife to late life may better predict AD risk than levels obtained at one timepoint prior to dementia onset. Analytic strategies examining this and other risk factors across the lifespan may affect interpretation of results.

• Occupational exposure to pesticides increases the risk of incident AD: the Cache County study.

  Authors: K M Hayden, M C Norton, D Darcey, T Ostbye, P P Zandi, J C S Breitner, K A Welsh-Bohmer

  Neurology. 05/2010; 74(19):1524-30.

  Commonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects onCommonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects on the nervous system. Few studies have examined the relationship of pesticide exposure and risk of dementia or Alzheimer disease (AD). We sought to examine the association of occupational pesticide exposure and the risk of incident dementia and AD in later life. Residents of the agricultural community of Cache County, UT, who were aged 65 years and older as of January 1995, were invited to participate in the study. At baseline, participants completed detailed occupational history questionnaires that included information about exposures to various types of pesticides. Cognitive status was assessed at baseline and after 3, 7, and 10 years. Standardized methods were used for detection and diagnosis of dementia and AD. Cox proportional hazards survival analyses were used to evaluate the risk of incident dementia and AD associated with pesticide exposure. Among 3,084 enrollees without dementia, more men than women reported pesticide exposure (p < 0.0001). Exposed individuals (n = 572) had more years of education (p < 0.01) but did not differ from others in age. Some 500 individuals developed incident dementia, 344 with AD. After adjustment for baseline age, sex, education, APOE epsilon4 status, and baseline Modified Mini-Mental State Examination scores, Cox proportional hazards models showed increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09-1.76, and for AD (HR 1.42, 95% CI 1.06-1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05-2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99-2.24), which was nearly significant. Pesticide exposure may increase the risk of dementia and Alzheimer disease in late life.

• Non-steroidal anti-inflammatory drugs and Alzheimer's disease: the epidemiological evidence.

  Authors: C A Szekely, P P Zandi

  CNS & neurological disorders drug targets. 03/2010; 9(2):132-9.

  Alzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or moreAlzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or more ideally, prevent the disease. Epidemiologic evidence has suggested that non-steroidal anti-inflammatory drugs (or NSAIDs) may be neuro-protective. However, this evidence is controversial. Observational studies in humans have found that the use of NSAIDs is associated with a lower risk of developing Alzheimer's disease. By contrast, randomized trials have reported that NSAIDs are not effective in treating patients with clinically established disease nor in preventing the onset of dementia among those who are cognitively normal or have mild cognitive impairment. In this article, we review the existing epidemiologic evidence on the relationship between NSAIDs and Alzheimer's disease and discuss several hypotheses to explain the divergent findings.

• Sex-specific association of the reelin gene with bipolar disorder.

  Authors: F S Goes, V L Willour, P P Zandi, P L Belmonte, D F MacKinnon, F M Mondimore, B Schweizer, J R DePaulo, E S Gershon, F J McMahon, J B Potash

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 09/2009;

  The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patientsThe Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support. (c) 2009 Wiley-Liss, Inc.

• Genome-wide association study of bipolar disorder in European American and African American individuals.

  Authors: E N Smith, C S Bloss, J A Badner, T Barrett, P L Belmonte, W Berrettini, W Byerley, W Coryell, D Craig, H J Edenberg [......] J B Potash, J Rice, T G Schulze, W Scheftner, C Panganiban, N Zaitlen, P P Zandi, S Zöllner, N J Schork, J R Kelsoe

  Molecular psychiatry. 07/2009;

  To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases;To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.Molecular Psychiatry advance online publication, 2 June 2009; doi:10.1038/mp.2009.43.

• Singleton deletions throughout the genome increase risk of bipolar disorder.

  Authors: D Zhang, L Cheng, Y Qian, N Alliey-Rodriguez, J R Kelsoe, T Greenwood, C Nievergelt, T B Barrett, R McKinney, N Schork [......] P L Belmonte, P P Zandi, M G McInnis, S Zöllner, D Craig, S Szelinger, D Koller, S L Christian, C Liu, E S Gershon

  Molecular psychiatry. 01/2009;

  An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, weAn overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania </=18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.Molecular Psychiatry advance online publication, 30 December 2008; doi:10.1038/mp.2008.144.

• No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.

  Authors: C A Szekely, R C Green, J.C. S. Breitner, T Østbye, A S Beiser, M M Corrada, H H Dodge, M Ganguli, C H Kawas, L H Kuller, B M Psaty, S M Resnick, P A Wolf, A B Zonderman, K A Welsh-Bohmer, P P Zandi

  Neurology. 07/2008; 70(24):2291-8.

  INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs knownINTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

• Knee height and arm span: a reflection of early life environment and risk of dementia.

  Authors: T L Huang, M C Carlson, A L Fitzpatrick, L H Kuller, L P Fried, P P Zandi

  Neurology. 06/2008; 70(19 Pt 2):1818-26.

  OBJECTIVES: To determine if anthropometric measures, as markers of early life environment, are associated with risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A totalOBJECTIVES: To determine if anthropometric measures, as markers of early life environment, are associated with risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A total of 2,798 subjects were followed as part of the Cardiovascular Health Cognition Study for an average of 5.4 years; 480 developed dementia. Knee height was measured 3 years prior to and arm span 4 years after the study's baseline. Cox proportional hazard models were used to examine their association with subsequent risk of dementia, AD, and VaD. RESULTS: Among women, greater knee height and arm span were associated with lower risks of dementia (knee height: HR per 1-inch increase 0.84; 95% CI 0.74-0.96; arm span: HR per 1-inch increase 0.93; 95% CI 0.88-0.98) and AD (knee height: HR per 1-inch increase 0.78; 95% CI 0.65-0.93; arm span: HR per 1-inch increase 0.90; 95% CI 0.85-0.96). Women in the lowest quartile of arm span had approximately 1.5 times greater risk of dementia (HR 1.45; 95% CI 1.03-2.05) and AD (HR 1.70; 95% CI 1.10-2.62) than other women. Among men, only arm span was associated with lower risks of dementia (HR per 1-inch increase 0.94; 95% CI 0.89-1.00) and AD (HR per 1-inch increase 0.92; 95% CI 0.84-1.00). For each gender, knee height was not associated with VaD, while arm span was associated with a nonsignificant lower risk of VaD. CONCLUSIONS: Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk.

• NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.

  Authors: C A Szekely, J.C. S. Breitner, A L Fitzpatrick, T D Rea, B M Psaty, L H Kuller, P P Zandi

  Neurology. 02/2008; 70(1):17-24.

  BACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between useBACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD. METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant A beta(42). RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42). CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.

• Prevention of Alzheimer's disease.

  Authors: C A Szekely, J.C. S. Breitner, P P Zandi

  International review of psychiatry (Abingdon, England). 01/2008; 19(6):693-706.

  The already considerable public health burden of Alzheimer's disease will likely worsen as populations around the world age. As a result, there is considerable motivation to develop effectiveThe already considerable public health burden of Alzheimer's disease will likely worsen as populations around the world age. As a result, there is considerable motivation to develop effective strategies for preventing the disease. A wide variety of such strategies are under investigation and include pharmaceuticals, nutriceuticals, diet, physical activity and cognitive activity. We review here the most promising candidates and the epidemiologic evidence for their efficacy. Although none of these have yet to be definitively shown to prevent Alzheimer's disease, further research should help to clarify what role they may play in reducing the burden of this disease.

• Family-based association of FKBP5 in bipolar disorder.

  Authors: V L Willour, H Chen, J Toolan, P Belmonte, D J Cutler, F S Goes, P P Zandi, R S Lee, D F MacKinnon, F M Mondimore, B Schweizer, J R DePaulo, E S Gershon, F J McMahon, J B Potash

  Molecular psychiatry. 01/2008;

  The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence ofThe FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.Molecular Psychiatry advance online publication, 8 January 2008; doi:10.1038/sj.mp.4002141.

• Does NSAID use modify cognitive trajectories in the elderly? The Cache County study.

  Authors: K M Hayden, P P Zandi, A S Khachaturian, C A Szekely, M Fotuhi, M. C. Norton, J T Tschanz, C F Pieper, C Corcoran, C G Lyketsos, J.C. S. Breitner, K A Welsh-Bohmer

  Neurology. 08/2007; 69(3):275-82.

  BACKGROUND: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have notBACKGROUND: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. METHODS: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. RESULTS: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE epsilon4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more epsilon4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more epsilon4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an epsilon4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year; p = 0.02). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE epsilon4 alleles.

• Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates.

  Authors: P P Zandi, J A Badner, J Steele, V L Willour, K Miao, D F MacKinnon, F M Mondimore, B Schweizer, M G McInnis, J R DePaulo, E Gershon, F J McMahon, J B Potash

  Molecular psychiatry. 08/2007; 12(7):630-9.

  Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the geneticDespite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a non-parametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

• How migraines impact cognitive function: findings from the Baltimore ECA.

  Authors: A Kalaydjian, P P Zandi, K L Swartz, W W Eaton, C Lyketsos

  Neurology. 04/2007; 68(17):1417-24.

  OBJECTIVE: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. METHODS: The data were from Waves III (1993 through 1996) and IV (2004OBJECTIVE: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. METHODS: The data were from Waves III (1993 through 1996) and IV (2004 through 2005) of the Baltimore Epidemiologic Catchment Area Study. Migraine headaches were diagnosed according to modified criteria of the International Headache Society. Scores on the immediate and delayed recall tests and the Mini-Mental State Examination (MMSE) were compared for migraineurs (n = 204) vs nonmigraineurs (n = 1,244). The longitudinal association between migraine and cognitive changes was assessed by generalized estimating equations. RESULTS: Migraineurs scored lower on tests of immediate and delayed memory at baseline, but declined by less over time than nonmigraineurs. These associations were specific to migraineurs with aura, who declined by 1.26 (p < 0.01) and 1.47 (p < 0.01) words less on the immediate and delayed recall tests over the 12 years of follow-up. The effects of migraine, specifically with aura, on the MMSE were restricted to those older than 50 years. Among those younger than 50 years, migraineurs with aura declined at the same rate on the MMSE as nonmigraineurs. However, among those older than 50 years, migraineurs with aura declined by 0.99 points (p < 0.01) less over the follow-up. CONCLUSIONS: Migraineurs, specifically those with aura, exhibited less decline on cognitive tests over time vs nonmigraineurs. For the Mini-Mental State Examination, these effects were only apparent among those who were older than 50 years.

• Conversion to dementia from mild cognitive disorder: the Cache County Study.

  Authors: J T Tschanz, K A Welsh-Bohmer, C G Lyketsos, C Corcoran, R C Green, K. Hayden, M. C. Norton, P P Zandi, L. Toone, N A West, J.C. S. Breitner

  Neurology. 08/2006; 67(2):229-34.

  OBJECTIVE: To examine 3-year rates of conversion to dementia, and risk factors for such conversion, in a population-based sample with diverse types of cognitive impairment. METHODS: All elderly (agedOBJECTIVE: To examine 3-year rates of conversion to dementia, and risk factors for such conversion, in a population-based sample with diverse types of cognitive impairment. METHODS: All elderly (aged 65 or older) residents of Cache County, UT, were invited to undergo two waves of dementia screening and assessment. Three-year follow-up data were available for 120 participants who had some form of mild cognitive impairment at baseline. Of these, 51 had been classified at baseline with prodromal Alzheimer disease (proAD), and 69 with other cognitive syndromes (CS). RESULTS: Three-year rates of conversion to dementia were 46% among those with cognitive impairment at baseline. By comparison, 3.3% without impairment converted to dementia in the interval. Among converters, AD was the most common type of dementia. In individuals with at least one APOE epsilon4 allele, those with proAD or CS exhibited a 22- to 25-fold higher risk of dementia than cognitively unimpaired individuals (vs 5- to 10-fold higher risk in those without epsilon4). CONCLUSIONS: Individuals with all types of mild cognitive impairment have an elevated risk of dementia over 3 years, more so in those with an APOE epsilon4 allele. These results suggest value in dementia surveillance for broad groups of cognitively impaired individuals beyond any specific category, and utility of APOE genotyping as a prognostic method.