Biomedical subjects

Mark Guttman

Publications and source records attributed to Mark Guttman.

13 recordsLinked to original sources

PubMed2006

Preclinical Huntington's disease: compensatory brain responses during learning.

Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.

Adult↗

PubMed2005

Identification of motor and nonmotor wearing-off in Parkinson's disease: comparison of a patient questionnaire versus a clinician assessment.

This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of <5 years duration were evaluated; the mean subject age was 72 +/- 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearing-off was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature.

Activities of Daily Living↗

PubMed2005

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Aged↗

PubMed2004

Brain dopamine-stimulated adenylyl cyclase activity in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

The dopamine D(1) receptor is considered to participate in levodopa's antiparkinsonian action and levodopa-induced dyskinesias. We examined the functional status of the D(1) receptor in brain of patients with Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Dopamine-stimulated adenylyl cyclase activity was significantly increased in putamen (+43%) and frontal cortex (+52%) in PD, normal in PSP, but decreased by 47% in putamen in MSA. The supersensitive dopamine D(1) receptors in both striatum and cerebral cortex in PD might compensate for dopamine deficiency, but could also contribute to long-term complications of levodopa therapy.

Adenylyl Cyclases↗

PubMed2004

Parkinsonism in Ontario: comorbidity associated with hospitalization in a large cohort.

To study comorbidity in patients with Parkinsonism (PKM), relative hospitalization rates from 1994 to 1999 for 15,304 cases were compared with 30,608 controls. After correction for differential survival, the rates were higher for cases compared to controls for aspiration pneumonia (6.34; 95% confidence interval [CI], 5.23, 7.93), affective psychosis (2.71; 95% CI, 2.13, 3.32), hip fractures (2.56; 95% CI, 2.35, 2.76), other urinary tract disorders including infections (2.5; 95% CI, 2.17, 2.86), septicemia (2.39; 95% CI, 2.02, 2.85) and fluid and electrolyte disorders (2.27; 95% CI, 1.93,2.66). The rates for cardiac, cerebrovascular, and peripheral vascular disease were similar. Preventive measures and aggressive management of these conditions as outpatients may reduce the rates of hospitalization and improve the morbidity and mortality of PKM.

Adult↗

PubMed2004

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Antiparkinson Agents↗

PubMed2003

Current concepts in the diagnosis and management of Parkinson's disease.

Parkinson's disease is a progressive neurological disorder characterized by rest tremor, bradykinesia, rigidity and postural instability. The cause is unknown, but growing evidence suggests that it may be due to a combination of environmental and genetic factors. Treatment during the early stage of Parkinson's disease has evolved, and evidence suggests that dopamine agonist monotherapy may prevent the response fluctuations that are associated with disease progression. L-dopa therapy, however, remains the most efficacious treatment. Treatment during the advanced stage focuses on improving control of a number of specific clinical problems. Successful management of motor response fluctuations (e.g., "wearing off," on-off fluctuations, nighttime deterioration, early morning deterioration and dyskinesias) and of psychiatric problems is often possible with specific treatment strategies. Surgical treatment is an option for a defined patient population.

Age Distribution↗

PubMed2003

Burden of parkinsonism: a population-based study.

Parkinson's disease (PD) is associated with a significant burden of illness and cost to society, which has been difficult to quantify. Our objective was to use linked administrative databases from the population of Ontario, Canada, to assess the prevalence of parkinsonism, physician- and drug-related costs, and hospital utilization for parkinsonian patients compared with age/sex matched controls. An inception cohort of parkinsonian cases from 1993/1994 was age and sex matched (1:2) to controls and followed for 6 years. Patients were identified by the diagnostic code for PD, the use of specific PD drugs, or a combination. The parkinsonian case cohort (15,304) was matched to (30,608) controls that did not have parkinsonism. The age-adjusted prevalence rates were 3.63 for men and for 3.24 women per 1,000 (increased by 5.4% for men and 9.8% for women). Physician costs were 1.4 times more, there were 1.44 times more hospital admissions, admissions were on average 1.19 times longer, and drug costs were 3.0 times more for parkinsonian cases. We conclude that the substantially higher physician and drug costs as well as hospitalization rates compared with controls clearly suggest that parkinsonism is associated with large direct costs to society.

Adult↗

PubMed2003

Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease.

The consistent findings of decreased levels of the major antioxidant glutathione in substantia nigra of patients with idiopathic Parkinson's disease (PD) has provided most of the basis for the oxidative stress hypothesis of the etiology of PD. To establish whether a nigral glutathione deficiency is unique to PD, as is generally assumed, or is present in other Parkinsonian conditions associated with nigral damage, we compared levels of reduced glutathione (GSH) in postmortem brain of patients with PD to those with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). As compared with the controls, nigral GSH levels were decreased in the PD and PSP patient groups (P < 0.05 for PD [-30%], PSP [-21%]), whereas a similar decrease in the MSA patient group did not reach statistical significance (P = 0.078, MSA [-20%]). GSH levels were normal in all examined normal and degenerating extra-nigral brain areas in PSP and MSA. A trend for decreased levels of uric acid (antioxidant and product of purine catabolism) also was observed in nigra of all patient groups (-19 to -30%). These data suggest that glutathione depletion, possibly consequent to overutilisation in oxidative stress reactions, could play a causal role in nigral degeneration in all nigrostriatal dopamine deficiency disorders, and that antioxidant therapeutic approaches should not be restricted to PD.

Aged↗

PubMed2003

VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET.

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

Adolescent↗

PubMed2003

The value of positron emission tomography in the clinical evaluation of dementia.

Positron emission tomography (PET) has been promoted as a means of improving the diagnosis of Alzheimer's disease (AD), but the evidence to support its incremental value is unclear. To assess the evidence regarding the use of PET in the clinical evaluation of AD, a systematic review of the English-language literature indexed in MEDLINE (1975-January 2001), the Cochrane Library (issue 4, 2000), and health technology assessment (HTA) reports was conducted. Articles identified by this review process were graded for methodological and reporting quality using a standardized grading scheme. Sixteen original articles and seven HTA reports were identified. In general, the articles addressed: using PET to differentiate AD from normal aging or non-Alzheimer's dementias, PET imaging compared with single positron emission computed tomography imaging, using PET to predict the progression of dementia, and agreement and reliability in the interpretation of PET images. Serious problems with study design and methodology in all articles were identified. Previous HTA reports have generally recommended that PET not be used in the clinical evaluation of dementia. In conclusion, there is little evidence to support the addition of PET to the routine clinical evaluation of patients with suspected or established dementia. Suggestions for future research in this area are offered.

Aged↗

PubMed2002

PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study.

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

Adult↗

PubMed2002

Brain proteasomal function in sporadic Parkinson's disease and related disorders.

Because genetic defects relating to the ubiquitin-proteasome system were reported in familial parkinsonism, we evaluated proteasomal function in autopsied brains with sporadic Parkinson's disease. We found that proteasome peptidase activities in a fraction specific to the proteasome were preserved in five brain areas (including the striatum) of Parkinson's disease where neuronal loss is not observed. Striatal protein levels of two proteasome subunits were normal in Parkinson's disease but reduced mildly in disease controls (multiple system atrophy). Our brain data suggest that a systemic, global disturbance in the catalytic activity and degradation ability of the proteasome itself is unlikely to explain the cause of Parkinson's disease.

Aged↗