Keith A. Hawkins

The Parkinson Progression Marker Initiative (PPMI)

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis

Nearly twice as many participants are represented in the current literature than were available at the time of the last major meta-analytic neurocognitive examination of apolipoprotein E (ApoE) epsilon allele combinations [Small, B.J., Rosnick, C.B., Fratiglioni, L., Backman, L., 2004. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol. Aging 19, 592-600]. The meta-analysis in the current study sought to specifically examine (1) small effects and (2) possible moderating variables associated with ApoE allele combinations that may have been undiscoverable in previous examinations of smaller data sets. A total of 77 studies, representing 40,942 cognitively healthy adults were identified for inclusion in the current meta-analysis (random effects design). Results were congruent with the previous meta-analytic findings indicating that carriers of ApoE allele 4 (ɛ4) perform significantly worse on measures of episodic memory, executive functioning, and overall global cognitive ability. In addition, the current analysis revealed a small effect suggesting that ApoE allele 4 adversely impacts perceptual speed. In contrast to earlier studies, the results also indicate that increases in age result in significantly larger differences between ApoE ɛ4 carriers and ApoE non-ɛ4 carriers on measures of episodic memory and global cognitive ability. ApoE ɛ4 exerts broad, but specific, adverse small effects on a range of neurocognitive functions in cognitively healthy adults.

Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample.

BACKGROUND Auditory hallucinations are often resistant to treatment and can produce significant distress and behavioral difficulties. A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal repetitive transcranial magnetic stimulation (rTMS) compared to sham stimulation. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. METHODS Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. RESULTS Hallucination Change Score was more improved for rTMS relative to sham stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008). There was no evidence of neurocognitive impairment associated with rTMS. CONCLUSIONS Left temporoparietal 1-hertz rTMS warrants further study as an intervention for auditory hallucinations. Data suggest that this intervention selectively alters neurobiological factors determining frequency of these hallucinations.

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome

BACKGROUND The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. METHODS This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. RESULTS In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.

Neuropsychological status of subjects at high risk for a first episode of psychosis

Thirty-six subjects aged 16 years or older judged at risk for a first episode of psychosis within a North American multi-site study of the schizophrenia prodrome [McGlashan et al., Schizophr. Res. (2003); Miller et al., Schizophr. Res. (2003)] performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Conversely, the finding that they do not show the levels of impairment commonly observed in schizophrenia, including within the first episode, suggests that prodromal interventions might conceivably prevent, delay, or lessen the severity of declines associated with first psychotic episodes.

Endophenotypes in schizophrenia: A selective review

BACKGROUND Given the wealth of data in the literature on schizophrenia endophenotypes, it is useful to have one source to reference their frequency data. We reviewed the literature on disease-liability associated variants in structural and functional magnetic resonance images (MRI), sensory processing measures, neuromotor abilities, neuropsychological measures, and physical characteristics in schizophrenia patients (SCZ), their first-degree relatives (REL), and healthy controls (HC). The purpose of this review was to provide a summary of the existing data on the most extensively published endophenotypes for schizophrenia. METHODS We searched PubMed and MedLine for all studies on schizophrenia endophenotypes comparing SCZ to HC and/or REL to HC groups. Percent abnormal values, generally defined as >2 SD from the mean (in the direction of abnormality) and/or associated effect sizes (Cohens d) were calculated for each study. RESULTS Combined, the articles reported an average 39.4% (SD=20.7%; range=2.2-100%) of abnormal values in SCZ, 28.1% (SD=16.6%; range=1.6-67.0%) abnormal values in REL, and 10.2% (SD=6.7%; range=0.0-34.6%) in HC groups. CONCLUSIONS These findings are reviewed in the context of emerging hypotheses on schizophrenia endophenotypes, as well as a discussion of clustering trends among the various intermediate phenotypes. In addition, programs for future research are discussed, as instantiated in a few recent large-scale studies on multiple endophenotypes across patients, relatives, and healthy controls.

A randomized clinical trial of a manual-guided risk reduction intervention for HIV-positive injection drug users.

This study randomized 90 HIV-seropositive, methadone-maintained injection drug users (IDUs) to an HIV Harm Reduction Program (HHRP+) or to an active control that included harm reduction components recommended by the National AIDS Demonstration Research Project. The treatment phase lasted 6 months, with follow-ups at 6 and 9 months after treatment entry. Patients in both treatments showed reductions in risk behaviors. However, patients assigned to HHRP+ were less likely to use illicit opiates and were more likely to adhere to antiretroviral medications during treatment; at follow-up, they had lower addiction severity scores and were less likely to have engaged in high risk behavior. Findings suggest that enhancing methadone maintenance with an intervention targeting HIV-seropositive IDUs increases both harm reduction and health promotion behaviors.

Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study.

OBJECTIVE Most previous studies of the incidence of tardive dyskinesia with atypical antipsychotics compared with conventional antipsychotics have not had tardive dyskinesia as their primary focus. The current study aimed to compare the incidence of tardive dyskinesia with atypical vs conventional antipsychotics using methods similar to those from a previous prospective cohort study at our site in the 1980s. METHOD Three hundred fifty-two initially tardive dyskinesia-free psychiatric outpatients (diagnosed at baseline using the Structured Clinical Interview for DSM-IV) were examined for a new diagnosis of tardive dyskinesia (using the Abnormal Involuntary Movement Scale and Glazer-Morgenstern criteria) every 6 months for up to 4 years at a community mental health center. At baseline, subjects were receiving conventional antipsychotics only (23%), atypicals only (64%), or both (14%). Only 26 subjects had never received conventional antipsychotics. Baseline evaluations were conducted from November 2000 through May 2003. Follow-ups were conducted through February 2005. RESULTS Compared with subjects treated with conventional antipsychotics alone since the previous visit, the adjusted tardive dyskinesia incidence rate-ratio for subjects treated with atypical antipsychotics alone was 0.68 (95% CI, 0.29-1.64). The incidence and prevalence of tardive dyskinesia was similar to previous findings at this site in the 1980s. CONCLUSIONS The incidence of tardive dyskinesia with recent exposure to atypical antipsychotics alone was more similar to that for conventional antipsychotics than in most previous studies. Despite high penetration of atypical antipsychotics into clinical practice, the incidence and prevalence of tardive dyskinesia appeared relatively unchanged since the 1980s. Clinicians should continue to monitor for tardive dyskinesia, and researchers should continue to pursue efforts to treat or prevent it.

Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study.

To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At‐Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40‐item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty‐six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration.

Continuation of high-risk behavior by HIV-positive drug users: Treatment implications

Drug users who are positive for the human immunodeficiency virus (HIV) represent a major vector of HIV transmission, yet relatively little is known about their continued drug- and sex-related HIV-risk behavior, which may impede the development of effective risk-reduction interventions. In this study, 50 HIV-seropositive injection drug users entering methadone maintenance treatment completed a comprehensive risk assessment battery, including self-report of HIV-risk behavior since learning HIV serostatus, and measures of risk-reduction information, motivation, and behavioral skills. We found that a disconcertingly high proportion of patients (66%) reported having engaged in HIV-risk behavior since learning their HIV-seropositive status. Level of HIV-related knowledge did not predict high-risk behavior. Drug-related risk behavior was predicted by psychiatric severity and poor behavioral skills. Sex-related risk was predicted by low levels of motivation and poor behavioral skills. Implications of these findings for treatment are discussed.