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1.  Psychiatrists’ views of the genetic bases of mental disorders and behavioral traits and their utilization of genetic tests 
We examined how 372 psychiatrists view genetic aspects of mental disorders and behaviors, and use genetic tests (GTs). Most thought the genetic contribution was moderate/high for several disorders (e.g. bipolar, schizophrenia, depression, Alzheimer’s, intelligence, creativity, anxiety, suicidality). In the past 6 months, 14.1% ordered GTs, 18.3% discussed prenatal testing with patients, 36.0% initiated discussions about other GTs, 41.6% had patients ask about GTs, and 5.3% excluded GT results from patient records. Many thought that GTs were available for schizophrenia (24.3%) and major depression (19.6%). Women were more likely to report that patients asked about GTs; and were less certain about the degree of genetic contribution to several disorders. Psychiatrists perceive strong genetic bases for numerous disorders and traits; and many have discussed and ordered tests for GTs; but have relatively little knowledge about available tests. These data suggest possible gender differences in psychiatrist’s beliefs about genetic contributions to disorders; and have implications for future research, education, policy, and care.
doi:10.1097/NMD.0000000000000154
PMCID: PMC4298352  PMID: 24933415
Genomics; epigenetics; genetic testing; decision making; etiology
2.  COMBINING ISOTONIC REGRESSION AND EM ALGORITHM TO PREDICT GENETIC RISK UNDER MONOTONICITY CONSTRAINT 
The annals of applied statistics  2014;8(2):1182-1208.
In certain genetic studies, clinicians and genetic counselors are interested in estimating the cumulative risk of a disease for individuals with and without a rare deleterious mutation. Estimating the cumulative risk is difficult, however, when the estimates are based on family history data. Often, the genetic mutation status in many family members is unknown; instead, only estimated probabilities of a patient having a certain mutation status are available. Also, ages of disease-onset are subject to right censoring. Existing methods to estimate the cumulative risk using such family-based data only provide estimation at individual time points, and are not guaranteed to be monotonic, nor non-negative. In this paper, we develop a novel method that combines Expectation-Maximization and isotonic regression to estimate the cumulative risk across the entire support. Our estimator is monotonic, satisfies self-consistent estimating equations, and has high power in detecting differences between the cumulative risks of different populations. Application of our estimator to a Parkinson’s disease (PD) study provides the age-at-onset distribution of PD in PARK2 mutation carriers and non-carriers, and reveals a significant difference between the distribution in compound heterozygous carriers compared to non-carriers, but not between heterozygous carriers and non-carriers.
doi:10.1214/14-AOAS730
PMCID: PMC4231830  PMID: 25404955
Binomial likelihood; Parkinson’s disease; Pool adjacent violation algorithm; Self-consistency estimating equations
3.  Parkinson Disease Phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations 
Background
The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking.
Objective
To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation.
Methods
We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants.
Results
LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status.
Conclusion
PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
doi:10.1002/mds.25647
PMCID: PMC3859844  PMID: 24243757
Parkinson; Genetics; LRRK2; PIGD
4.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
doi:10.1093/hmg/ddu334
PMCID: PMC4222357  PMID: 24973356
5.  Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker? 
Objective
Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease (PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated.
Methods
We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers.
Results
Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: −3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (−12.8, −9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers.
Interpretation
Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction.
doi:10.1002/acn3.95
PMCID: PMC4241794  PMID: 25493281
6.  Lessons from Epidemiologic Research about Risk Factors, Modifiers, and Progression of Late Onset Alzheimer’s Disease in New York City at Columbia University Medical Center 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S447-S455.
This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer’s disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer’s disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer’s disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer’s disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer’s disease.
doi:10.3233/JAD-2012-129041
PMCID: PMC4149254  PMID: 22836187
Alzheimer’s disease; conversion; diet; cognitive reserve; epidemiology; genes; mild cognitive impairment; predictors; progression; risk factors
7.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human Molecular Genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
doi:10.1093/hmg/ddu334
PMCID: PMC4222357  PMID: 24973356
8.  Relationship Of Mediterranean Diet And Caloric Intake To Phenoconversion In Huntington Disease 
JAMA neurology  2013;70(11):1382-1388.
Importance
Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer's and Parkinson's disease. Whether adherence to MeDi affects time to phenoconversion in Huntington’s Disease (HD), a highly penetrant, single gene disorder, is unknown.
Objective
To determine if MeDi modifies the time to clinical onset of HD ('phenoconversion') in premanifest carriers participating in Prospective Huntington At Risk Observational Study (PHAROS), and to examine the effects of BMI and caloric intake on time to phenoconversion.
Design
A prospective cohort study.
Setting
41 Huntington Study Group sites in the US and Canada.
Participants
1001 participants were enrolled in PHAROS between July 1999 and January 2004, and were followed every 9 months until 2010. A total of 211 participants aged 26–57 with an expanded CAG repeat (≥37) were included in the current study.
Exposure
A semi-quantitative food frequency questionnaire (FFQ) was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty-acids, and alcohol, and constructed MeDi scores (0–9); higher scores indicate higher adherence. Demographics, medical history, BMI, and Unified Huntington's Disease Rating Scale (UHDRS) were collected.
Main Outcome Measure
Cox proportional hazards models to determine the association of MeDi and phenoconversion.
Results
Age, caloric intake, gender, education, and UHDRS motor scores did not differ among MeDi tertiles (0–3, 4–5, 6–9). The highest BMI was associated with lowest adherence to MeDi. 31 participants phenoconverted. In a model adjusted for age, CAG, and caloric intake, MeDi was not associated with phenoconversion (p for trend=0.14 for tertile of MeDi, and p=0.22 for continuous MeDi). When individual diet components of MeDi were analyzed, higher dairy consumption (hazard ratio 2.36; 1.0–5.57; p=0.051) and higher caloric intake (p=0.035) were associated with risk of phenoconversion.
Conclusion and Relevance
MeDi was not associated with phenoconversion, however higher consumption of dairy products had a two-fold increased risk, and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HD may provide data for interventions to modify specific components of diet that may delay the onset of HD.
doi:10.1001/jamaneurol.2013.3487
PMCID: PMC4040231  PMID: 24000094
Huntington disease; nutritional; cohort
9.  Attitudes and Practices Among Internists Concerning Genetic Testing 
Journal of genetic counseling  2012;22(1):90-100.
Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8%), followed by Breast/Ovarian Cancer (15.0%). In the past 6 months, 65% had counseled patients on genetic issues, 44% had ordered genetic tests, 38.5% had referred patients to a genetic counselor or geneticist, and 27.5% had received ads from commercial labs for genetic testing. Only 4.5% had tried to hide or disguise genetic information, and <2% have had patients report genetic discrimination. Only 53.4% knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7%) and guidelines for genetic testing (87.1%). Most felt needs for more training on when to order tests (79%), and how to counsel patients (82%), interpret results (77.3%), and maintain privacy (80.6%). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p<.001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p<.002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p<.019), counseled patients about genetics, larger practices (p<.032), fewer African-American patients (p<.027), and patients who had reported genetic discrimination (p<.044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests., These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education.
doi:10.1007/s10897-012-9504-z
PMCID: PMC3433636  PMID: 22585186
genetic testing; medical education; doctor-patient communication; ethics; genetic discrimination; decision-making; genetic counseling
10.  Views of internists towards uses of PGD 
Reproductive biomedicine online  2012;26(2):142-147.
Preimplantation genetic diagnosis (PGD) is increasingly available, but how physicians view it is unclear. Internists are gatekeepers and sources of information, often treating disorders for which PGD is possible. This quantitative study surveyed 220 US internists, who were found to be divided. Many would recommend PGD for cystic fibrosis (CF; 33.7%), breast cancer (BRCA; 23.4%), familial adenomatous polyposis (FAP; 20.6%) and familial hypertrophic cardiomyopathy (19.9%), but few for social sex selection (5.2%); however, in each case, >50% were unsure. Of those surveyed, 4.9% have suggested PGD to patients. Only 7.1% felt qualified to answer patient questions about it. Internists who would refer for PGD had completed medical training less recently and, for CF, were more likely to have privately insured patients (P < 0.033) and patients who reported genetic discrimination (P < 0.013). Physicians more likely to refer for BRCA and FAP were less likely to have patients ask about genetic testing. This study suggests that internists often feel they have insufficient knowledge about it and may refer for it based on limited understanding. They view possible uses of PGD differently, partly reflecting varying ages of onset and disease treatability. These data have critical implications for training, research and practice.
doi:10.1016/j.rbmo.2012.11.006
PMCID: PMC3565017  PMID: 23276655
assisted reproductive technology; ethics; IVF
11.  Lack of Association Between Cancer History and PARKIN Genotype: a Family Based Study in PARKIN/Parkinson’s Families 
Genes, chromosomes & cancer  2012;51(12):1109-1113.
A number of publications have attributed a tumor suppressive (TS) function to PARKIN, a gene associated with recessive familial early-onset Parkinson’s disease (EOPD). Discoveries of PARKIN deletions and point mutations in tumors, functional studies, and data from mouse models have been presented to support the hypothesis. We have asked whether PARKIN mutations are associated with history of cancer in humans. We interviewed 431 participants who were screened for PARKIN mutations, including 149 EOPD cases and their family members, who were unaware of mutation status. We found no significant difference in self-reported history of cancer among carriers of one or two PARKIN mutations and non-carriers, odds ratio 0.75 (95% confidence interval 0.27-1.83). In particular, no increase in cancer history was seen among homozygous and compound heterozygous mutation carriers compared to non-carriers. Therefore, we hypothesize that published studies attributing TS capability to PARKIN merit further exploration and we present a reevaluation of these data with respect to patterns of mutation frequencies in normal and cancer cells. We conclude that although Parkin may exert a suppressive effect in mice, further studies are required prior to assigning a TS function to PARKIN in humans.
doi:10.1002/gcc.21995
PMCID: PMC3465486  PMID: 22927236
Tumor suppressor; PARKIN - Early-onset Parkinson’s cohort; cancer risk
12.  A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies 
JAMA neurology  2013;70(6):10.1001/jamaneurol.2013.1925.
Importance
While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.
Objective
To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).
Design
We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.
Setting
Eleven centers from sites around the world performing genotyping.
Participants
Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.
Main Outcome Measures
Frequency of GBA1 mutations in cases and controls.
Results
We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78–14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53–15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P<.001), with higher disease severity scores.
Conclusions and Relevance
Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
doi:10.1001/jamaneurol.2013.1925
PMCID: PMC3841974  PMID: 23588557
13.  Lower cognitive performance in healthy G2019S LRRK2 mutation carriers 
Neurology  2012;79(10):1027-1032.
Objective:
To assess cognitive abilities of healthy first-degree relatives of Ashkenazi patients with Parkinson disease (PD), carriers of the G2019S mutation in the LRRK2 gene.
Methods:
In this observational study, 60 consecutive healthy first-degree relatives (aged 50.9 ± 6.2 years; 48% male; 30 G2019S carriers) were assessed using a computerized cognitive program, the Montreal Cognitive Assessment questionnaire, the Unified Parkinson's Disease Rating Scale Part III, and the Geriatric Depression Scale.
Results:
G2019S carriers scored significantly lower on the computerized executive function index (p = 0.04) and on specific executive function tasks (Stroop test, p = 0.007).
Conclusion:
Carrying the LRRK2 G2019S mutation was associated with lower executive performance in a population at risk for PD.
doi:10.1212/WNL.0b013e3182684646
PMCID: PMC3430708  PMID: 22914834
14.  Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson's disease among Ashkenazi Jews 
To date, only one genome-wide study has assessed the contribution of copy number variants (CNVs) to Parkinson's disease (PD). We conducted a genome-wide scan for CNVs in a case–control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high-confidence CNVs, we examined the global genome wide burden of large (≥100 kb) and rare (≤1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and ≥2× frequency) were found 1.4 times more often in cases than in controls (P = 0.019). The large CNVs (≥500 kb) were also significantly associated with PD (P = 0.046, 1.24-fold higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n = 7) but not in controls (P = 0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1, and MBD3 in the same disease pathway with known PD genes.
doi:10.1002/mgg3.18
PMCID: PMC3782064  PMID: 24073418
Ashkenazi Jews; candidate genes; case–control study; CNV; Parkinson's disease
15.  TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease 
Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3′ untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease.
doi:10.1016/j.bbrc.2012.06.120
PMCID: PMC3752397  PMID: 22771793
Huntington's disease (HD); Age at onset; GRIK2; Genetic modifier
16.  CCL3L1 gene copy number in individuals with and without HIV-associated neurocognitive disorder 
Current biomarker findings  2012;2012(2):1-6.
Background
CCL3L1 copy number variation has been implicated as a marker for susceptibility and immunity to human immunodeficiency virus (HIV)-1 infection and its pathogenic sequelae. Some of these findings have been confirmed in several, but not all, subsequent independent cohort studies. A three-fold risk for the development of HIV-associated dementia was reported in individuals possessing a CCL3L1 copy number below the ethnic group median combined with a detrimental CCR5 genotype. With the availability of antiretroviral therapy since 1996, there has been a significant decline in HIV-associated dementia, and milder forms of HIV-associated neurocognitive impairment (HAND) are now most prevalent. Moreover, patients are living longer with HIV-1 infection and it is recognized that aging may be a contributory factor to the development of cognitive disorder. Thus, the need for biomarkers that can be used in clinical practice to identify and provide optimal treatment for those at increased risk for HAND is great. HAND affects 20%–30% of HIV-infected individuals, and several genetic loci which have been shown to confer susceptibility to HIV infection may also modulate the development of neurocognitive disorder. The aim of this study was to determine whether CCL3L1 chemokine gene copy number in self-defined ethnic groups could differentiate HIV-infected individuals with and without HAND.
Methods
Genomic DNA was isolated from buccal swabs or peripheral blood mononuclear cells obtained from HIV-infected patients with or without a diagnoses of neurocognitive dysfunction in the Northeast AIDS Dementia Cohort and National NeuroAIDS Tissue Consortium. To maintain a uniform standard, a quantitative polymerase chain reaction design similar to previous studies using Taqman probes and fixed input DNA between 2 ng and 10 ng was used to determine a CCL3L1 copy number. Standard curves with two-fold dilutions from 25 ng to 1.56 ng were generated. CCL3L1 copy number was determined in triplicate in 262 subjects using quantitative polymerase chain reaction and the relative quantitation method. Data were analyzed using analysis of variance, with significance defined as P < 0.05 and Bonferroni post hoc tests.
Results
Significant differences as determined by analysis of variance in CCL3L1 copy number between African-Americans and Caucasians (P < 0.0001) were found, highlighting ethnic group differences in the copy number of this gene. However, there were no differences in CCL3L1 copy number across the neurocognitive groups within each ethnic group. The median CCL3L1 copy number in African-Americans of two and Caucasians of one in this study was significantly lower than the previously reported ethnic group means of two and four copies, respectively. A higher prevalence of abnormal cognition with a relative risk of four was seen in African-Americans versus Caucasians.
Conclusion
Based on this nested case-control study, CCL3L1 copy number alone may not be useful for distinguishing between individuals at risk for mild or severe neurocognitive disorder. Additional larger cohort studies are required to determine whether CCL3L1 copy number in combination with polymorphisms in other genes known to contribute to HIV risk will be useful in identifying those at increased risk for HAND.
doi:10.2147/CBF.S27685
PMCID: PMC3693394  PMID: 23814703
neurological; HIV-associated dementia; HAND; chemokine; copy number; African-American; Caucasian
17.  A 6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease 
Objective
In patients with Alzheimer’s disease (AD) with psychosis or agitation that respond to haloperidol treatment, to evaluate the risk of relapse following discontinuation.
Methods
In outpatients with AD with symptoms of psychosis or agitation, responders to 20 weeks of haloperidol (0.5 to 5 mg daily) were randomized to a 24-week, double-blind pilot trial of discontinuation on placebo versus continuation haloperidol. Phase A response criteria were minimum 50% reduction in 3 target symptoms, and improvement on the Clinical Global Impression-Change (CGI-C) score for psychosis/agitation. Phase B relapse criteria required 50% worsening in target symptoms and on the CGI-C. Alpha=0.1 was the significance criterion in this pilot study.
Results
Of 44 patients, 22 patients responded in Phase A. The sum score of target symptoms, and Brief Psychiatric Rating Scale psychosis and hostile suspiciousness factor scores, decreased in Phase A (p’s < .001). Extrapyramidal signs increased in Phase A (p < .01). Of 22 responders, 21 patients entered Phase B, and 20 had at least one follow-up visit. Four of 10 patients (40%) on continuation haloperidol relapsed compared to 8 of 10 patients on placebo (80%, χ2=3.3, p=0.07). In survival analyses, time to relapse was shorter on placebo than haloperidol (χ2=4.1, p=0.04).
Conclusions
Haloperidol open treatment was efficacious, and relapse was greater on placebo than with haloperidol continuation. In patients with AD who have psychosis or agitation and respond to antipsychotic medication, the increased risk of relapse after discontinuation needs to be weighed against the side effects associated with continuing the medication.
doi:10.1002/gps.2630
PMCID: PMC3685500  PMID: 21845596
Antipsychotic; discontinuation; Alzheimer’s disease
18.  Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset 
Neurogenetics  2013;14(3-4):173-179.
Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
doi:10.1007/s10048-013-0364-y
PMCID: PMC3825533  PMID: 23644918
Huntington’s disease; Glutamate receptors; Dopamine pathway; Genetic modifiers
19.  Clinical and pathological characteristics of LRRK2 G2019S patients with PD 
Journal of Molecular Neuroscience  2011;47(1):139-143.
Objective
To describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson’s disease (PD).
Methods
We cross referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients.
Results
All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy Body (LB) pathology, tau inclusions and amyloid pathology consistent with advanced Alzheimer’s disease; one had diffuse cortical LB and one had only brainstem predominant LB pathology.
Conclusions
Cognitive impairment may be a long term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.
doi:10.1007/s12031-011-9696-y
PMCID: PMC3335886  PMID: 22194196
Parkinson’s disease; Lewy Bodies; LRRK2 gene mutation; Dementia
20.  Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington’s Disease 
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington’s Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.
doi:10.1155/2012/375935
PMCID: PMC3589804  PMID: 23476655
21.  Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2 
Annals of Neurology  2012;71(3):370-384.
Objective
Genome-wide association (GWAS) methods have identified genes contributing to Parkinson disease (PD); we sought to identify additional genes associated with PD susceptibility.
Methods
A two stage design was used. First, individual level genotypic data from five recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 SNPs were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).
Results
Genome-wide significance was reached for SNPs in SNCA (rs356165, G: odds ratio (OR)=1.37; p=9.3 × 10−21), MAPT (rs242559, C: OR=0.78; p=1.5 × 10−10), GAK/DGKQ (rs11248051, T:OR=1.35; p=8.2 × 10−9/ rs11248060, T: OR=1.35; p=2.0×10−9), and the HLA region (rs3129882, A: OR=0.83; p=1.2 × 10−8), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K OR=1.71; p=5 × 10−8 Combined Sample) (N370 OR=3.08; p=7 × 10−5 Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5 × 10−5 Discovery Sample; p=1.52 × 10−7 Replication sample; p=2 × 10−10 Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.
Interpretation
We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than one risk allele within SNCA and GBA.
doi:10.1002/ana.22687
PMCID: PMC3354734  PMID: 22451204
22.  Familial Parkinson's disease iPSCs show cellular deficits in mitochondrial responses that can be pharmacologically rescued 
Science translational medicine  2012;4(141):141ra90.
Parkinson's disease (PD) is a common neurodegenerative disease caused by genetic and environmental factors. We analyzed induced pluripotent stem cell (iPSC)-derived neural cells from PD patients and presymptomatic individuals carrying mutations in the PINK1 and LRRK2 genes, and healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial function in iPSC-derived neural cells from PD patients and at-risk individuals could be rescued with coenzyme Q10, rapamycin or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insights into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in PD.
doi:10.1126/scitranslmed.3003985
PMCID: PMC3462009  PMID: 22764206
23.  Learning fast accurate movements requires intact frontostriatal circuits 
The basal ganglia are known to play a crucial role in movement execution, but their importance for motor skill learning remains unclear. Obstacles to our understanding include the lack of a universally accepted definition of motor skill learning (definition confound), and difficulties in distinguishing learning deficits from execution impairments (performance confound). We studied how healthy subjects and subjects with a basal ganglia disorder learn fast accurate reaching movements. We addressed the definition and performance confounds by: (1) focusing on an operationally defined core element of motor skill learning (speed-accuracy learning), and (2) using normal variation in initial performance to separate movement execution impairment from motor learning abnormalities. We measured motor skill learning as performance improvement in a reaching task with a speed-accuracy trade-off. We compared the performance of subjects with Huntington's disease (HD), a neurodegenerative basal ganglia disorder, to that of premanifest carriers of the HD mutation and of control subjects. The initial movements of HD subjects were less skilled (slower and/or less accurate) than those of control subjects. To factor out these differences in initial execution, we modeled the relationship between learning and baseline performance in control subjects. Subjects with HD exhibited a clear learning impairment that was not explained by differences in initial performance. These results support a role for the basal ganglia in both movement execution and motor skill learning.
doi:10.3389/fnhum.2013.00752
PMCID: PMC3826079  PMID: 24312037
motor skill; kinematics; reaching; striatum; basal ganglia; movement disorder; neurodegenerative; neurological
24.  Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research 
PLoS ONE  2012;7(8):e43099.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
doi:10.1371/journal.pone.0043099
PMCID: PMC3428297  PMID: 22952635
25.  Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset 
Human Genetics  2012;131(12):1833-1840.
Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation.
doi:10.1007/s00439-012-1205-z
PMCID: PMC3492689  PMID: 22825315

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