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Background Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. Objective We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. Methods Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. Results 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p = 0.033-0.082). Smoking was associated with older AAO (p = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (p = 0.001 and p = 0.002, respectively). Conclusions Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.

Susceptibility to Parkinson’s disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD.

Aim: The present study aimed to investigate whether the response variability of infants to modified constraint-induced movement therapy and bimanual therapy are associated with different types of brain lesions. Method: Infants with unilateral cerebral palsy (N = 22) ages 8-15 months (mean = 10.95, standard deviation = 2.15 months) were grouped according to having either a periventricular brain lesion or a middle cerebral artery infarct lesion. Improvement in hand function was analyzed based on the mini–Assistive Hand Assessment results. Results: Infants with periventricular brain lesion displayed greater positive response to upper limb treatment compared to those with middle cerebral artery infarct ( P = .02). A significant difference in improvement according to type of treatment was found in the middle cerebral artery infarct group but not in the periventricular brain lesion. Conclusion: The present study showed an association between the type of brain lesion and the efficacy of upper limb treatment in infants. Infants with periventricular brain lesions displayed greater positive responses than those with middle cerebral artery infarct.

To identify variables that can predict proficiency in powered mobility use for children in young adults.Participants included 80 children and young adults (42 males, 38 females; mean age 10y 2mo, [SD 5y 1mo]; range: 2-22y) with cerebral palsy, neuromuscular disease, and spinal cord injury who participated in the ALYN Hospital Powered Mobility Lending Program from 2009 to 2016. Data were collected and compared before and after participation in the program and powered mobility levels were determined by the Israeli Ministry of Health (MOH) Powered Mobility Proficiency Test. Multivariate logistic regression analysis followed by a bootstrapping procedure that was based on 1000 samples were used to determine if the variables were predictive of success on the Israeli MOH Powered Mobility Proficiency Test.Significant variables for predicting success were identified: manual wheelchair propulsion, go-stop voluntarily upon request, and using a joystick. The model was able to correctly identify 80% of the children.Children and young adults with the ability to go-stop upon request, propel a manual wheelchair short distances, and use a joystick to activate the powered wheelchair had a higher chance of becoming proficient. In countries where wheelchair proficiency is a requirement for powered wheelchair procurement, these findings may support policy changes, as they did in Israel.Using powered wheelchairs offers children earlier and more natural practice to determine driving proficiency. Manual wheelchair propulsion, go-stop voluntarily upon request, and using a joystick were predictors of powered mobility proficiency. More than 80% of children use a joystick with their hand to activate a powered wheelchair.MODELO PREDICTIVO DE LA COMPETENCIA EN MOVILIDAD MOTORIZADA DE NIÑOS Y ADULTOS JÓVENES CON DEFICIENCIAS MOTORAS: OBJETIVO: Identificar variables que puedan predecir la capacidad de uso de la movilidad motorizada para niños en adultos jóvenes. MÉTODO: Fueron incluidos 80 niños y adultos jóvenes (42 varones, 38 mujeres; edad media 10a 2m, [SD 5a 1m]; rango: 2-22a) con parálisis cerebral, enfermedad neuromuscular y lesión de la médula espinal que participaron en el Programa de Movilidad Motorizada del ALYN Hospital del 2009 a 2016. Los datos se recopilaron y compararon antes y después de la participación en el programa y los niveles de movilidad impulsados ​​se determinaron mediante la Prueba de competencia de movilidad impulsada por el Ministerio de Salud de Israel. Se utilizó el análisis de regresión logística multivariable seguido de un procedimiento de arranque que se basó en 1000 muestras para determinar si las variables eran predictivas de éxito en la Prueba de Competencia de Movilidad Movida por MOH de Israel. RESULTADOS: Se identificaron variables significativas para predecir el éxito: propulsión manual en silla de ruedas, posibilidad de arranque y freno a la orden, y uso de un joystick. El modelo fue capaz de identificar correctamente al 80% de los niños. INTERPRETACIÓN: Los niños y adultos jóvenes que tienen la capacidad de detenerse cuando se lo requiere, que pueden impulsar una silla de ruedas manual a corta distancia y que pueden usar un joystick para activar la silla de ruedas motorizada tienen una mayor probabilidad de convertirse en expertos. En los países donde el dominio de las sillas de ruedas es un requisito para la adquisición de sillas de ruedas motorizadas, estos hallazgos pueden respaldar cambios en las políticas, como lo hicieron en Israel.MODELO PREDITIVO DE PROFICIÊNCIA NA MOBILIDADE MOTORIZADA DE CRIANÇAS E ADULTOS COM DEFICIÊNCIAS MOTORAS: OBJETIVO: Identificar variáveis que podem predizer proficiência no uso da mobilidade motorizada para crianças e adultos jovens. MÉTODO: Os participantes incluíram 80 crianças e jovens adultos (42 do sexo masculino, 38 do sexo feminino; média de idade 10a 2m, [DP 5a 1m]; variação: 2-22a) com paralisia cerebral, doença neuromuscular, e lesão da medula espinhal que participaram do Programa de Mobilidade Motorizada do Hospital ALYN de 2009 a 2016. Os dados foram coletados e comparados antes e após a participação no programa, e os níveis de mobilidade motorizada foram determinados pelo Teste de Proficiência em Mobilidade Motorizada do Ministério da Saúde (MS) Israelense. Análise de regressão logística multivariada seguida por procedimento e bootstrapping baseado em 1.000 amostras foi usada para determiner se as variáveis eram preditivas do sucesso no Teste de Proficiência em Mobilidade Motorizada do MS Israelense. RESULTADOS: Variáveis significativas na predição de sucesso foram identificadas: propulsão da cadeira manual, capacidade de iniciar e parar voluntariamente quando solicitado, e uso de controle do tipo joystick. O modelo foi capaz de identificar corretamente 80% das crianças. INTERPRETAÇÃO: Crianças e adultos jovens com a capacidade de iniciar e parar quando solicitados, de impulsionar uma cadeira de rodas manual por distâncias curtas, e usar um joystick para ativar a cadeira de rodas tiveram maior chance de se tornar proficientes. Em países em que a proficiência na cadeira é um requisite para solicitar a cadeira de rodas motorizada, estes achados podem dar suporte a mudanças nas políticas empregadas, como ocorreu em Israel.

The deficit in ability to attribute mental states such as thoughts, beliefs, and intentions of another person is a key component in the functional impairment of social cognition in schizophrenia. In the current study, we compared the ability of persons with first episode schizophrenia (FE-SZ) and individuals with schizophrenia displaying symptomatic remission (SZ-CR) to decode the mental state of others with healthy individuals and schizoaffective patients. In addition, we analyzed the effect of dopamine-related genes polymorphism on the ability to decode the mental state of another, and searched for different genetic signatures. Our results show that overall, individuals with schizophrenia performed worse in the “Reading the Mind in the Eyes” (eyes) test, a simple well-defined task to infer the mental state of others than healthy individuals. Within the schizophrenia group, schizoaffective scored significantly higher than FE-SZ, SZ-CR, and healthy individuals. No difference was observed in performance between FE-SZ and SZ-CR subjects. Interestingly, FE-SZ and SZ-CR, but not schizoaffective individuals, performed worse in decoding negative and neutral emotional valance than the healthy control group. At the genetic level, we observed a significant effect of the DAT genotype, but not D4R genotype, on the eyes test performance. Our data suggest that understanding the mental state of another person is a trait marker of the illness, and might serve as an intermediate phenotype in the diagnostic process of schizophrenia disorders, and raise the possibility that DA-related DAT gene might have a role in decoding the mental state of another person.

Background From the moment a child is diagnosed as having cerebral palsy, families have to cope on a daily basis with the multifaceted challenges of life-long disability management. Family-centred service is embraced as a ‘best practice’ model because of accumulating evidence supporting its positive influence on parents and children's outcomes. Nevertheless, research comparing parent and provider perspectives on family-centred practices of educational service providers in education settings is scarce. The aims of this study were to compare the extent to which parents and conductors experience the service delivery in Tsad Kadima, the Association for Conductive Education in Israel, as being family-centred, as well as comparing parents’ perception of different educational settings as being family-centred. Methods Measurements of family-centeredness, the Israeli Measure of Processes of Care for families (MPOC-20) and for service providers (MPOC-SP), were administrated to 38 teacher conductors and 83 families of children with cerebral palsy (aged 1–14), from different conductive educational settings. Results Parents and conductors perceive Conductive Education service as being highly family centred in most domains, rating respectful and supportive care the highest and providing general information the lowest, thus indicating an area where improvements should be made. Parents perceived the service they receive to be more family-centred than conductor's perception about their own activities. In addition, educational setting (day care, pre-school and school) was found to be associated with parent's scores. Conclusions The current study, which is the first to examine family-centred service provision in a conductive special education setting, from the perspectives of both parents and conductors, provides significant evidence for high-quality services in these settings.

Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation.This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment.Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial.The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

Sensory modulation disorder (SMD) and attention deficit hyperactivity disorder (ADHD) can co-occur and have overlapping symptoms, thus challenging practitioners. This study aimed to phenotypically explore parent–child associations in SMD, and the interplay between SMD- and ADHD-related symptoms in children with SMD and their parents. A cross-sectional study examined 70 parents (n = 35 mothers; n = 35 fathers) and their 35 children with and without SMD, aged 4–6 years. Parents completed care-giver reports: The Short Sensory Profile (SSP) and the ADHD Rating Scale, and self-reports: The Sensory Responsiveness Questionnaire (SRQ) and the ADHD Self-Report Scale (ASRS). In the entire sample, we found a mother–offspring correlation between SSP and SRQ-Aversive scores (rs = −0.68; p

Development of specific treatments for vascular dementia requires appropriate animal models. Bilateral carotid artery stenosis (BCAS) employs metal coils wrapped around both common carotid arteries to induce cerebral hypoperfusion, white matter lesions and memory impairment in mice. We focused on the relationship of memory impairment induced by BCAS to white matter lesions demonstrated by ex vivo magnetic resonance imaging (MRI). We found a significant effect of BCAS on perceptual learning in the novel object recognition test and on number of errors and latency to platform in the radial arm water maze. MRI analysis revealed a significant effect of BCAS on diffusion tensor imaging (DTI) parameters in white matter areas. After correction for multiple testing, significantly lower fractional anisotropy (FA) values were found in the corpus callosum and anterior commissure and significantly higher mean diffusivity values in the internal capsule. Focusing on the corpus callosum, we found that correlations between FA and number of errors on the RAWM test were significant after controlling for treatment. We further found that the effects of BCAS on cognition were partly mediated by its effects on white matter integrity. Immunofluorescence studies demonstrated significantly higher microglia cell density and soma size in the corpus callosum of BCAS mice compared to controls, and these parameters were correlated with the imaging data. The results of this study indicate that cognitive deficits induced by cerebral hypoperfusion due to BCAS result in part from microglia activation and disruption of white matter integrity, supporting the face and construct validity of this unique model of vascular dementia.

Objectives Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1 Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. Patients and methods An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n = 9) or combined with HF PFC rDTMS (M1-PFC, n = 10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. Results For the M1 + PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p = 0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p = 0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. Conclusion rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

Background The role of nuclear imaging in predicting Parkinson's disease (PD) progression is unclear. This study investigated whether the degree of reduced striatal dopamine transporter binding at diagnosis of PD predicts later motor complications and time to disease progression. Methods We retrospectively studied 41 patients with early PD who underwent 123I-FP-CIT SPECT and were followed thereafter with a mean disease duration of 9.51 ± 3.18 years. The association of quantitatively analyzed 123I-FP-CIT binding in striatal subregions with the development of motor fluctuations, dyskinesias, freezing of gait (FOG) and falls as well as the time to Hoehn and Yahr (HY OR = 0.01, p = 0.04; respectively) but not falls. Cox proportional hazard analysis did not reveal significant relationship between 123I-FP-CIT binding and motor fluctuations, dyskinesias, or H&Y stage 3. Conclusions Our results suggest that a more severe depletion of presynaptic dopamine in early PD is a bad prognostic sign in terms of FOG development. These findings, if replicated, may point to dopaminergic transmission as part of the mechanism underlying FOG in PD.

OBJECTIVE Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific member of the protein tyrosine phosphatase (PTP) family that has been implicated in learning and memory. In this study, we examined the association of the protein tyrosine phosphatase non-receptor 5 (PTPN5) gene, which encodes for STEP, with both schizophrenia and cognitive functioning in the Israeli Jewish population. METHODS A schizophrenia (SZ) case-control study of 868 participants was carried out (286 patients and 582 controls). Eleven PTPN5 tagging single-nucleotide polymorphisms (SNPs) were selected and single markers and haplotype association analyses were carried out. A cognitive variability study included 437 healthy women who completed a computerized cognitive battery. We performed univariate associations between the SNPs and cognitive performance. The possible functional role of these variants was examined by studying their association with gene expression levels in the brain. RESULTS In the SZ study, we found a nominal association in the whole sample between rs4075664 and SZ. Male patients with SZ showed a more significant association for three SNPs (rs4075664, rs2278732, and rs4757710). Haplotypes of the studied SNPs were associated with SZ both in the overall sample and within the male subsample. Expression analysis provided some support for the effects of the associated SNPs on PTPN5 expression level. The cognitive variability study showed positive associations between PTPN5 SNPs and different cognitive subtests. Principal component analysis showed an 'attention index' neurocognitive component that was associated with two SNP pairs (rs10832983 × rs10766504 and rs7932938 × rs4757718). CONCLUSION The results imply a model in which PTPN5 may play a role in normal cognitive functioning and contribute to aspects of the neuropathology of SZ.

Parkinson's disease (PD) exacts a physical and emotional toll on both patients and family. The aim of this study was to compare patient and caregiver perceptions of the social consequences of basic symptoms of PD and levodopa-induced dyskinesias. Forty patients with PD and dyskinesias and 35 of their caregivers completed a self-report questionnaire on the impact of PD and dyskinesias on their feelings of security and embarrassment and participation in family/social events, and indicated their preference for the "on" (with dyskinesias) or the "off" (without dyskinesias) state. The patients scored significantly higher than the caregivers did on the negative social impact of the disease in general (p = 0.002) and of the dyskinesias in particular (p = 0.03). Nevertheless, the patients expressed a significantly greater preference for the "on" state (83 %) than the caregivers (59 %) (p = 0.03). Preferences turned to be reverse in direction among spouse-caregivers who significantly preferred the "off" state (54 %) than the patients (25 %) (p = 0.04). Although patients have a worse perception of the effects of PD than their caregivers do, they prefer the more independent "on" state, whereas their caregivers prefer the "off" state.

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻⁵ in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

In prior studies we found that young, female smokers manifest poorer performance than non-smokers on attention-related tasks and that these findings can be moderated by variation in nicotinic acetylcholine receptor (nAChR) genes. We predicted that under controlled conditions (1) nicotine would improve functioning on attentional tasks in smokers who previously manifested relatively poor performance, and that (2) smokers who carry genetic variations associated with poorer attention performance would derive greater benefit from nicotine. To test these hypotheses, 31 young female smokers, who participated in our previous study, performed the Matching Familiar Figures Test (MFFT), Tower of London Test and Continuous Performance Task (CPT) in a double-blind, within-between subject design, placebo or nicotine (4 mg as gum) serving as the within factor and genetic profile as the between factor. Repeated measures ANCOVA controlling for attention deficit symptomatology, substance abuse and nicotine dependence showed better performance under nicotine among participants with higher levels of attention deficit symptoms (MFFT errors: P=0.04; CPT commissions: P=0.01) and nicotine dependence (CPT stability of response: P=0.04) and greater consumption of caffeine (CPT stability of response: P=0.04). An interactive effect of genetic profile was demonstrated for SNP rs2337980 in CHRNA7. These findings suggest that nicotine may have stronger short-term facilitating effects on attention in women who have more attention deficit symptoms and consume more nicotine and caffeine. This effect may be modified by a specific genetic make-up. Such individuals may be at increased risk for nicotine addiction and for greater difficulties in smoking cessation.

Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of neuroleptic treatment. Interindividual heterogeneity in AIP development and severity is associated with risk factors such as antipsychotic drug type, old age, and female gender. There is evidence for genetic predisposition to develop AIP but the variants that confer susceptibility or protection are mostly unknown.To identify genes related to AIP susceptibility, we performed a pharmacogenomic genome-wide association study (GWAS) for AIP severity.Three hundred ninety-seven American schizophrenia patients who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-GWAS project were included in our analysis. Patients had been randomized to treatment with antipsychotic monotherapy for periods ranging from 2 weeks to 18 months during phase 1 of the CATIE trial. They were regularly assessed for AIP severity using the modified Simpson-Angus Scale (SAS). For statistical analysis, patients were dichotomized as cases (average SAS mean global score0.3 during CATIE phase 1, N = 199) or controls (average SAS mean global score 0, N = 198).Using logistic regression and controlling for population stratification, age, gender, SAS score at baseline, and concomitant use of anticholinergic drugs, we identified several single-nucleotide polymorphisms associated with AIP severity. Although none reached the GWAS significance level of P4.2 x 10(-7), some promising candidate genes for further research on genetic predisposition to AIP were identified including EPF1, NOVA1, and FIGN.Our finding may contribute to understanding of the pathophysiology of AIP as well as to a priori identification of patients vulnerable for development of AIP.

Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS) and extensive Nigro-Striatal degeneration, manifested by reduced uptake of [123I]FP-CIT is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small "proof of concept" study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

Association with schizophrenia of the Abelson Helper Integration Site 1 (AHI1) gene on chromosome 6q23 and the adjacent primate-specific gene, C6orf217, was demonstrated in an inbred, Arab Israeli family sample and replicated in an Icelandic case control sample. Further support was provided by a second replication in a large European sample and a meta-analysis that supported association with schizophrenia of all seven alleles overtransmitted to affected subjects in the original study. We examined constitutive expression of AHI1 and C6orf217 in immortalized lymphoblasts of patients from the Arab Israeli family sample in which the association with schizophrenia was originally discovered and population-matched normal controls, and in post-mortem brain of patients with schizophrenia and bipolar (BP) disorder and control subjects from the Stanley Medical Research Institute Collection. We found a significant effect of diagnostic group in the lymphoblast sample (F=5.72; df=2,39; p=0.006). Patients with early age of onset had higher AHI1 expression than controls and later onset patients (p=0.002; 0.03 respectively). C6orf217 expression in lymphoblasts was too low to measure. We found no difference in brain expression of AHI1 in schizophrenia or BP patients compared to controls. However, there was a genotypic difference in AHI1 expression for SNP rs9321501, which was strongly associated with schizophrenia in the original study. Genotypes that included the undertransmitted C allele (CC/AC) showed lower expression than the homozygous AA genotype (F=4.73, df=2,83; p=0.028). There was no significant difference in brain expression of C6orf217 between patients and controls and no genotypic effect. This study provides further evidence for involvement of AHI1 in susceptibility to schizophrenia.

Background Timely administration/supplementation of a specific serotonin reuptake inhibitor with a second therapeutic agent could improve treatment outcome in patients with major depressive disorder (MDD). The purpose of this study was to identify the optimal time at which to implement supplementation so as to maximize the likelihood of remission by 8 weeks and minimize overtreatment. Method Data from patients with MDD treated with sertraline (n = 108) or citalopram (n = 107) in a randomized controlled trial were analyzed by multivariate logistic regression. The 21-item Hamilton Depression Scale scores at weeks 1, 2, 3, 4, and 6; sex; age; and baseline Hamilton Anxiety Scale score were used as predictors of remission by 8 weeks sustained for a further 4 weeks. Results Regression models for weeks 2, 3, 4, and 6 were significant (area under the curve values, 0.73-0.91). The models for weeks 3 to 6 yielded κ coefficients greater than 0.40 with the outcome variable. A Hamilton Depression Scale reduction score of 50% at week 4 as a criterion for supplementation would have resulted in overtreatment of 4% and 0% of patients in the sertraline and citalopram groups, respectively, and none if applied at week 6. The rates at which patients who should have received supplementation (destined to be nonremitters at 8 weeks) would have been missed would be 49%/54% for sertraline/citalopram at week 4 and 43%/50% at week 6. Limitations The study limitations are as follows: secondary analysis of data, relatively low sertraline dose, and relatively small sample sizes. Conclusions It may be possible to identify patients treated with specific serotonin reuptake inhibitors who will not achieve sustained remission by 8 weeks. If supplementation were implemented accordingly, the number of overtreated patients would be small. However, a substantial number of patients who should be supplemented would be missed, indicating a need for greater sensitivity of the prediction model. Further studies are needed.

Role of genetic variants in the CHRNA5–CHRNA3–CHRNB4 cluster in nicotine dependence risk: importance of gene–environment interplay

RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10–0.54, P=0.001) in the overall sample, and 0.20 (0.07–0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11–0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3′-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.