Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS).

Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

Knowledge of the Genetic Information Nondiscrimination act among individuals affected by Huntington disease.

The Genetic Information Nondiscrimination Act (GINA) of 2008 was the first US legislation to address genetic discrimination. We sought to assess understanding of GINA among individuals affected by the autosomal dominant condition, Huntington disease (HD). We conducted a cross-sectional survey of individuals with varying risk of HD to assess their familiarity with GINA. As a control, individuals were surveyed about their familiarity with the Health Insurance Portability and Accountability Act (HIPAA). Those who reported familiarity with GINA were asked about their knowledge of specific provisions of the legislation. The survey was offered to 776 participants and completed by 410 (response rate 53%). Respondents across all groups were less familiar with GINA (41% slightly, somewhat, or very familiar) than with HIPAA (65%; p < 0.0001). Of individuals with or at risk for HD who reported some familiarity with GINA, less than half correctly identified GINA's protections, and less than 15% correctly identified its limitations. Thus, among individuals affected by HD, familiarity with and knowledge of GINA are low. The effectiveness of the legislation may be limited by this lack of knowledge.

Experimental therapeutics of neurodegenerative disorders: unmet needs.

Viewpoint The experimental therapeutics of neurodegenerative disorders is in its infancy, but neuroprotective strategies are already being applied in healthy persons at high risk of developing disease as well as in patients with manifest illness. Knowledge of etiology and pathogenesis, improved design of clinical trials, the development of biological markers, the advent of genetic animal models, the enhanced identification of susceptibility factors, and more effective drug delivery-such advances have improved the prospects for forestalling onset of illness and clinical decline in the growing numbers of people affected by neurodegenerative disorders.

Neural transplantation: a call for patience rather than patients.

KIE: Research into embryonic cell grafting in human subjects suffering from Parkinson's disease should not repeat the mistakes made by adrenal autograft investigators, who operated on far more humans than on nonhuman primates because of a single unconfirmed report of dramatic improvement in two Mexican patients. Citing extensive data from experimental transplants conducted as early as 1944, the authors argue that, until a sufficient number of animal studies have been performed to answer many crucial questions about human fetal tissue transplants, researchers should refrain from experimenting on human patients.^ieng

NMDA receptor losses in putamen from patients with Huntington's disease.

N-Methyl-D-aspartate (NMDA), phencyclidine (PCP), and quisqualate receptor binding were compared to benzodiazepine, gamma-aminobutyric acid (GABA), and muscarinic cholinergic receptor binding in the putamen and cerebral cortex of individuals with Huntington's disease (HD). NMDA receptor binding was reduced by 93 percent in putamen from HD brains compared to binding in normal brains. Quisqualate and PCP receptor binding were reduced by 67 percent, and the binding to other receptors was reduced by 55 percent or less. Binding to these receptors in the cerebral cortex was unchanged in HD brains. The results support the hypothesis that NMDA receptor-mediated neurotoxicity plays a role in the pathophysiology of Huntington's disease.

Alterations in L-glutamate binding in Alzheimer's and Huntington's diseases.

Brain sections from patients who had died with senile dementia of the Alzheimer's type (SDAT), Huntington's disease (HD), or no neurologic disease were studied by autoradiography to measure sodium-independent L-[3H]glutamate binding. In brain sections from SDAT patients, glutamate binding was normal in the caudate, putamen, and claustrum but was lower than normal in the cortex. The decreased cortical binding represented a reduction in numbers of binding sites, not a change in binding affinity, and appeared to be the result of a specific decrease in numbers of the low-affinity quisqualate binding site. No significant changes in cortical binding of other ligands were observed. In brains from Huntington's disease patients, glutamate binding was lower in the caudate and putamen than in the same regions of brains from control and SDAT patients but was normal in the cortex. It is possible that development of positron-emitting probes for glutamate receptors may permit diagnosis of SDAT in vivo by means of positron emission tomographic scanning.

Detection of Huntington's disease decades before diagnosis: the Predict-HD study.

OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms.

BACKGROUND: Cognitive and behavioral adverse events (AEs) such as hallucinations, confusion, depression, somnolence and other sleep disorders commonly limit effective management of motor symptoms in PD. Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a novel, second-generation, selective, irreversible monoamine oxidase type B inhibitor, demonstrated in monotherapy and adjunctive trials to be effective for PD with excellent tolerability. METHODS: The occurrence of cognitive and behavioral AEs and the change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) part I mental subscores were reviewed in two multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with PD. The UPDRS is a multi-item rating scale specific to PD; part I rates the patient's intellectual impairment, thought disorders, depression and motivation/initiative. RESULTS: The TEMPO study evaluated rasagiline monotherapy in early PD patients (n=404). The PRESTO study evaluated rasagiline as adjunctive therapy in moderate-to-advanced PD patients with motor complications who were receiving optimized levodopa/carbidopa (n=472). In the analysis of adverse event reporting for both studies, no cognitive and behavioral AE in either the rasagiline 1 mg or placebo groups exceeded 10% of the study population and the frequency differences between rasagiline 1 mg and placebo never exceeded 3%. There was no adverse effect on the UPDRS mental subscore relative to placebo in either of the two studies. CONCLUSION: Rasagiline 1 mg once daily improves PD symptoms and motor fluctuations in early and moderate-to-advanced PD patients without causing significant cognitive and behavioral AE or adverse changes in mentation, behavior and mood.

Reversal of systemic manifestations of cryoglobulinemia. Treatment with melphalan and prednisone.

In a patient with essential cryoglobulinemia with systemic, cutaneous, and neurologic manifestations and a mixed IgG-IgM cryoprotein, elimination of systemic and cutaneous disease manifestations, as well as notable reversal of neurologic impairment, followed therapy with melphalan. Levels of circulating cryoprotein decreased, but protein structure was unchanged by chemotherapy. Experience to date with alkylating agents suggests that this mode of treatment is the most effective currently available.

Deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP). Parkinson Study Group.

DATATOP is a double-blind, multi-center, placebo-controlled clinical trial aimed at slowing the decline of patients who are in the early stages of Parkinson's disease (PD). The specific aim is to determine whether or not chronic administration of deprenyl 10 mg per day and/or tocopherol 2000 IU per day to early, otherwise untreated PD patients will prolong the time until levodopa therapy is required to treat emerging disability. Deprenyl and tocopherol exert antioxidative effects through separate but complementary mechanisms of action. A 2 X 2 factorial design allocates eligible subjects to one of four treatment groups: 1) deprenyl alone, 2) tocopherol alone, 3) deprenyl plus tocopherol, or 4) placebo. Eligible subjects include early PD patients (illness duration less than 5 years and in stages I and II), aged 30 to 79, who are not taking or requiring any anti-PD medications. The major response variable is the time period from randomization until the blinded investigator judges levodopa necessary to treat emerging parkinsonian disability. Randomization is stratified to ensure that treatment assignments are balanced for each blinded investigator. Cerebrospinal fluid is sampled just prior to randomization and one month after washout of experimental medications in order to help distinguish between symptomatic and protective effects of interventions. Based on pilot studies it is estimated that approximately 85% of untreated PD patients will require levodopa within two years and a total sample size of 800 subjects will provide a 95% likelihood for detecting a 10% "survival" difference between experimental medications and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Fenfluramine in man: hypophagia associated with diminished serotonin turnover.

A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent. The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.

Bromocriptine inhibits norepinephrine release.

Bromocriptine is a dopamine agonist that induces postural hypotension and can be used as an antihypertensive. The drug inhibits release of norepinephrine (NE) from an isolated artery by stimulating presynaptic receptors. In normotensive subjects it lowers both plasma and cerebrospinal fluid (CSF) levels of NE by 50% and lowers blood pressure moderately in standing subjects and slightly in recumbent subjects. Through central and peripheral mechanisms, bromocriptine inhibits sympathetic nervous discharge of NE.

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Psychiatric syndromes in Huntington's disease.

Thirty patients with Huntington's disease, a genetically transmitted neuropsychiatric disorder that can be diagnosed reliably, were evaluated systematically for psychopathology, followed for extended periods, and treated with psychopharmacological medications when necessary. DSM-III criteria were used for establishing syndromic diagnoses. Twenty-four individuals demonstrated substantial behavioral abnormalities, including affective and schizophrenic syndromes, changes of personality, and disorders that could not be classified adequately. Pharmacotherapy was modestly beneficial in some cases. Consideration of the array of behavioral disturbances encountered in this pathogenetically unified disorder suggests that a dimensional approach to symptom classification might prove more useful heuristically than present typological methods.

Severe compression neuropathy following sudden onset of parkinsonian immobility.

Prolonged immobility with adoption of unusual fixed body postures may lead to compression neuropathy. Although parkinsonism has not been considered to predispose to nerve compression, we report three patients with Parkinson's disease and on-off motor fluctuations who developed severe compression neuropathy following a sudden onset off period. The stereotyped posture assumed by parkinsonian patients during an off period appears to make them especially prone to injury of the radial nerve in the upper arm and the brachial plexus.

Coexistent Meige's syndrome and myasthenia gravis. A relationship between blinking and extraocular muscle fatigue?

We studied five patients with a combination of Meige's syndrome (blepharospasm-oromandibular dystonia) and myasthenia gravis. The coexistence of two disorders impairing eyelid opening led to diagnostic confusion and delayed appropriate therapy. Detailed oculographic monitoring of one patient indicated that eye position drifting due to myasthenic oculomotor fatigue was corrected by eye blinks, and that blinks tended to occur with slower saccades. Our observations suggest that fatigue of extraocular muscles may lead to synkinetic blinking and perhaps eventually to autonomous blepharospasm.

A controlled neuropsychological comparison of Huntington's disease and multiple sclerosis.

This study compared the intellectual deficits of patients who had the earliest stages of Huntington's disease (HD) with those of mildly or moderately affected patients suffering from multiple sclerosis; both groups were matched for age, education, and ability to function. Twenty-one HD patients, 30 multiple sclerosis subjects, and 15 matched controls were evaluated neuropsychologically; all were free of psychoactive medications. The two patient groups showed similar overall patterns of impairment, though the HD group had greater verbal and nonverbal memory deficits. The HD patients also demonstrated significant dyscalculia and showed indications of developing problems in language usage and copying. These results are discussed in light of each disorder's neuropathologic substrate.

Severity of Tourette's syndrome in one large kindred. Implication for determination of disease prevalence rate.

An accurate prevalence rate for Tourette's syndrome (TS) has not been established. To assess severity of illness, a potential source of bias in determining prevalence rate, we administered standardized questionnaires and examinations to 159 members of a large Mennonite kindred showing apparent autosomal dominant transmission of motor and vocal tics (TS) or chronic motor tics (CMTs). Fifty-four family members were diagnosed as having definite or probable TS or CMTs. For these 54 subjects, 30% (n = 16) were unaware of tics noted by the examiners and only 18.5% (n = 10) had sought medical care. Our findings suggest that most cases of TS and CMTs are mild and do not come to medical attention. These tic disorders are probably much more prevalent than generally appreciated.

Cerebrospinal fluid correlates of depression in Huntington's disease.

Patients with Huntington's disease (HD) commonly have concomitant depressive disorders. Prompted by reports of elevated corticotropin releasing factor (CRF) and reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in lumbar cerebrospinal fluid (CSF) of patients with major depression, these CSF constituents were examined in 56 nonmedicated patients who were in the early stages of HD. Elevated CRF concentrations were found in patients with HD in comparison with a control group of 21 subjects without neurologic illness. The CSF 5-HIAA concentrations in patients with HD did not differ from that in four normal volunteers. Patients with HD who had depressive disorders (major depression or dysthymia) did not differ from those without depression with respect to CSF 5-HIAA or CRF concentration. However, a positive correlation was observed between severity of major depression and CRF concentration. These findings suggest that the depression associated with HD may differ neurochemically from that seen in other major depressive disorders, and support the notion that clinically significant depressive symptoms reflect heterogeneous pathophysiologic conditions with different neurochemical correlates.