GBA mutations in Parkinson disease: earlier death but similar neuropathological features.

BACKGROUND AND PURPOSE: Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. METHODS: Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. RESULTS: Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi-quantitative scores for Lewy-type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. CONCLUSIONS: In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.

Differential spectral quantitative electroencephalography patterns between control and Parkinson's disease cohorts.

BACKGROUND AND PURPOSE: It is believed that progressive Lewy-type synucleinopathy (LTS) is primarily responsible for the worsening of motor and non-motor Parkinson's disease (PD) signs and symptoms. Characterization of quantitative electroencephalography (QEEG) abnormalities across the spectrum of LTS to PD dementia (PD-D) may provide insight into the pathophysiology of PD cortical dysfunction. Here our enlarged EEG database was leveraged to characterize spectral QEEG abnormalities in asymptomatic autopsy-defined groups of control participants and incidental Lewy body disease (ILBD) and three clinically defined groups of participants with PD (cognitively normal PD, mild cognitive impairment PD, and PD-D). METHODS: The PD cohort was studied as part of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). AZSAND utilizes its Brain and Body Donation Program to perform prospective, standardized, regular longitudinal pre-mortem assessments until death. Resting EEG from subjects was analyzed for spectral domain QEEG measures of background rhythm frequency and global relative power in delta, theta, alpha and beta bands. RESULTS: The various spectral QEEG measures showed differential changes specific to the groups compared. Important findings were background rhythm frequency showing the most pairwise differences across the groups, and this also was the only significant difference between control and ILBD. An increase in delta bandpower was characteristic of worsening cognitive deficits. CONCLUSIONS: Different patterns of change amongst QEEG measures across LTS and PD cognitive states suggest that they correlate with heterogeneous pathophysiologies of cortical dysfunction within the PD clinical spectrum. In addition, the biomarker application of a specific spectral QEEG measure needs to be selectively suited to its study purpose.

Quantitative EEG as a predictive biomarker for Parkinson disease dementia.

OBJECTIVE: We evaluated quantitative EEG (QEEG) measures as predictive biomarkers for the development of dementia in Parkinson disease (PD). Preliminary work shows that QEEG measures correlate with current PD cognitive state. A reliable predictive QEEG biomarker for PD dementia (PD-D) incidence would be valuable for studying PD-D, including treatment trials aimed at preventing cognitive decline in PD. METHODS: A cohort of subjects with PD in our brain donation program utilizes annual premortem longitudinal movement and cognitive evaluation. These subjects also undergo biennial EEG recording. EEG from subjects with PD without dementia with follow-up cognitive evaluation was analyzed for QEEG measures of background rhythm frequency and relative power in δ, , α, and ß bands. The relationship between the time to onset of dementia and QEEG and other possible predictors was assessed by using Cox regression. RESULTS: The hazard of developing dementia was 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency (p < 0.001). Hazard ratios (HRs) were also significant for > median bandpower (HR = 3.0; p = 0.004) compared to below, and for certain neuropsychological measures. The HRs for δ, α, and ß bandpower as well as baseline demographic and clinical characteristics were not significant. CONCLUSION: The QEEG measures of background rhythm frequency and relative power in the band are potential predictive biomarkers for dementia incidence in PD. These QEEG biomarkers may be useful in complementing neuropsychological testing for studying PD-D incidence.

Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson's disease.

OBJECTIVE: To compare the medication dose reduction between deep brain stimulation (DBS) of the globus pallidus interna (GPi) vs subthalamic nucleus (STN) in matched patients with Parkinson's disease (PD). MATERIALS AND METHODS: Records of 12 patients with PD who underwent GPi-DBS at our institution from 2002 to 2008 were matched by pre-operative PD medication doses and pre-operative motor Unified Parkinson's Disease Rating Scale (UPDRS) scores to 12 cases of STN-DBS. PD medication doses were converted to levodopa equivalent doses (LEDs). RESULTS: GPi and STN groups had similar mean pre-operative LEDs and motor UPDRS scores. At 6 months post-DBS, there was no significant difference in percent reduction in LEDs between the GPi (47.95%) and STN (37.47%) groups (P = 0.52). The mean post-operative 'medication off/stimulation on' motor UPDRS scores did not differ significantly between GPi (15.33) and STN (16.25) groups (P = 0.74). The mean percent reduction in motor UPDRS scores was also similar between GPi (58.44%) and STN (58.98%) patients (P = 0.94). CONCLUSIONS: We conclude that in disease-matched patients with PD undergoing DBS, both GPi and STN may result in similar reduction in PD medication doses.

Pathologic findings in prospectively ascertained essential tremor subjects.

OBJECTIVE: To assess pathologic changes in prospectively characterized subjects with essential tremor (ET). METHODS: Subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program were examined annually by a movement disorders neurologist, and semiannually by a behavioral neurologist and neuropsychologist. Twenty-four subjects without a prior diagnosis of dementia or other major movement disorder met clinical criteria for ET and came to autopsy. Subjects with mild cognitive impairment (n = 3) were included. These subjects were compared with 21 controls. Brains were examined postmortem according to standardized protocols for assessment of age-related changes and specific pathologic conditions (e.g., Parkinson disease, Alzheimer disease). RESULTS: Subjects had a mean age of 86.2 years and a mean duration of tremor of 11.1 years. Seven subjects had evidence for cerebellar pathology (Purkinje cell loss, cerebellar cortical sclerosis, and proliferation of Bergmann glia). Pigmented neurons were qualitatively depleted in the locus ceruleus in eight subjects and in the substantia nigra in five subjects. Of these, three had Lewy bodies, one subject had brainstem predominant disease, and two had limbic stage. Three subjects had a nonspecific cerebral tauopathy and another met pathologic criteria for progressive supranuclear palsy. However, when compared with controls, only changes in the locus ceruleus and gliosis of the cerebellum remained significant findings. CONCLUSIONS: This study supports previous findings of heterogenous pathology in essential tremor (ET). There is an increased frequency of cerebellar gliosis and locus ceruleus depletion. We did not find an increased incidence of Lewy bodies in subjects with ET.

Functional ability correlates with cognitive impairment in Parkinson's disease and Alzheimer's disease.

BACKGROUND/AIMS: Previously we have shown that functional declines in Parkinson's disease (PD) and Alzheimer's disease (AD) correlate to global measures of cognitive decline. We now determine if the correlation between cognitive impairment and functional ability in PD is similar to that in AD using individual cognitive measures. METHODS: 93 PD subjects and 124 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and a neuropsychological battery. RESULTS: In PD subjects, the FAST and GDS correlated significantly with Rey Auditory Verbal Learning Test (AVLT), Controlled Oral Word Association (COWA), Animal Fluency, and Stroop but not with Clock Draw or Judgment Line Orientation (JLO). In AD/MCI subjects, FAST and GDS correlated with all neuropsychological components except Stroop. In the AD/MCI group, the UPDRS significantly correlated with the FAST, GDS, MMSE, and all neuropsychological parameters except the Stroop. In the PD group, the motor UPDRS significantly correlated significantly with FAST, GDS, MMSE and all neuropsychological parameters except Digit Span, Stroop, Clock Draw and JLO. CONCLUSIONS: Similar to AD, functional decline in PD correlates with multiple measures of cognitive impairment. Some differences between PD and AD may be explained by the influence of motor disability and declines in visuospatial function in PD.

Both early and late cognitive dysfunction affects the electroencephalogram in Parkinson's disease.

We sought to define quantitative electroencephalographic (EEG) measures as biomarkers of both early and late cognitive decline in Parkinson's disease (PD). PD subjects classified as cognitively normal (PD-CogNL), mild cognitive impairment (PD-MCI), and dementia (PD-D) were studied. Cognitive status and neuropsychological testing was correlated with background rhythm and frequency band EEG power across five frequency bands. We conclude that global EEG measures have potential use as biomarkers in the study of both early and late cognitive deterioration in PD, including for evaluating its treatment. PD-MCI has mean quantitative EEG characteristics that represent an intermediate electrophysiological state between PD-CogNL and PD-D.

Nonvasculitic autoimmune inflammatory meningoencephalitis imitating Creutzfeldt-Jakob disease.

BACKGROUND: Nonvasculitic autoimmune inflammatory meningoencephalitis and Creutzfeldt-Jakob disease can present as rapidly progressive encephalopathies with similar clinical features. Slowing of background rhythm is an electroencephalographic characteristic shown by both, but persistent periodic sharp waves are more specific for Creutzfeldt-Jakob disease and have not been reported in nonvasculitic autoimmune inflammatory meningoencephalitis or related autoimmune meningoencephalitides. OBJECTIVE: To describe a patient with clinical (rapidly progressive myoclonus, dementia, and Parkinsonism) and electroencephalographic findings (persistent periodic sharp waves) that diagnostically suggest Creutzfeldt-Jakob disease. DESIGN AND SETTING: A case report at the Mayo Clinic Arizona, Scottsdale. RESULTS: The patient made a dramatic recovery with resolution of the periodic sharp wave complexes after treatment with high-dose corticosteroids. Our case is the first reported case of a patient with probable nonvasculitic autoimmune inflammatory meningoencephalitis and electroencephalographic periodic complexes suggestive of Creutzfeldt-Jakob disease. CONCLUSION: Rapidly progressive encephalopathy with periodic sharp wave complexes can be associated with a reversible autoimmune syndrome.

Is the functional decline of Parkinson's disease similar to the functional decline of Alzheimer's disease?

Since many Parkinson's disease (PD) subjects develop dementia, we determined whether the correlation between functional and cognitive decline seen in Alzheimer's disease (AD) is seen in PD. Seventy-five PD subjects with and without dementia and 103 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), the UPDRS motor portion, and the MMSE. In AD/MCI subjects, changes in FAST and GDS scores correlated with MMSE (rho=-0.814, P<0.001; rho=-0.840, P<0.001, respectively). In PD subjects, the FAST and GDS also correlated with MMSE (rho=-0.675, P<0.001; rho=-0.647, P<0.001, respectively). The UPDRS correlated with the GDS and FAST more closely in PD than in AD. Similar to AD, functional declines in PD correlates with cognitive decline and may be influenced by motor disability in PD.

Ropinirole for restless legs syndrome: a placebo-controlled crossover trial.

The authors performed a double-blind, placebo-controlled, crossover study of ropinirole (0.5 to 6.0 mg/day) for restless legs syndrome (RLS). The RLS Rating Scale score improved (p < 0.001) from a mean (SD) of 25 (7) during placebo treatment to 13 (12) during ropinirole treatment. Eight of the 22 patients had complete resolution of symptoms on ropinirole. Adverse events included nausea and dizziness. Ropinirole was effective and well tolerated for treating the symptoms of RLS.

Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors.

Previous data suggest a relationship between the loss of response to levodopa in Parkinson's disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (+/-dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D(2) receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (+/-dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D(3) receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D(3) receptors. The alterations in D(3) receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D(2) receptor.

Motor unit number estimates in idiopathic Parkinson's disease.

We previously reported changes in motor unit morphology in patients with Parkinson's disease (PD) using subjective and computerized quantitative electromyography. Now, we present data on motor unit number estimates (MUNE) to address the hypothesis of motor neuron dropout in PD. Twenty patients with PD and 20 age-matched control subjects were screened by clinical criteria and nerve conduction studies to exclude those with neuropathy. Motor unit number estimates in the extensor digitorum brevis and hypothenar group were assessed by three different MUNE techniques. The MUNE technique types included (1) the statistical method developed by Daube, (2) a threshold method, and (3) an F-wave method. The overall multivariate comparison for the six MUNE measurements was significantly lower for the patients than the controls (P=0.02). The only significant difference in the individual measures was found in the threshold MUNE method of the hypothenar group (P<0.05). These results are consistent with those of our previous work, and both support the hypothesis that mild motor neuron dropout occurs in idiopathic PD. However, MUNE methods characteristically have large standard deviations which make it difficult to detect small changes. Progress in decreasing the variance of MUNEs will facilitate their use in detecting small motor unit number changes in neurodegenerative disease.

Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.

Persistent chorea triggered by hyperglycemic crisis in diabetics.

Five female patients developed chorea concurrent with, or shortly after a hyperglycemic episode (admission glucose values 500-1,000 mg/dL). In four of these five patients, there was no prior history of diabetes mellitus. The chorea continued despite correction of blood glucose and persisted to the time of last follow-up, 6 months to 5 years later. The chorea developed subacutely over 2 days to 1 month and was generalized in one, unilateral in three, and involved right > left lower extremity in the other; the severity initially reached ballistic proportions in two. Associated clinical features were nil in four of these patients, but cognitive impairment and personality change occurred in one. The histories and laboratory studies identified no predisposing factors other than the hyperglycemia. The chorea was sufficiently troublesome to require administration of neuroleptic medication in all five cases. Four of the five cases had high signal intensity within basal ganglia on T1-weighted magnetic resonance (MR) imaging, as has previously been described; however, this was not seen in one case (who had the most severe clinical condition). Most previously described cases have involved a reversible clinical syndrome, in contrast to our patients. The pathogenic mechanisms remain uncertain.

Serum leptin concentrations and satiety in Parkinson's disease patients with and without weight loss.

We compared serum leptin and satiety measures in 18 Parkinson's disease (PD) patients with unintended weight loss (WL) and 18 PD patients whose weight was stable (WS). Mean serum leptin concentrations tended to be lower in WL than WS patients, but this did not reach statistical significance. Body mass index correlated with serum leptin concentrations. Ratings of hunger, satiety, fullness, and thirst did not differ between groups. However, the mean sensation of fullness before meals correlated with serum leptin in the entire cohort of patients, particularly in the WL group. The results indicate that unintended weight loss in PD patients is unlikely to be due to abnormal serum leptin concentrations.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Effect of NASA light-emitting diode irradiation on wound healing.

OBJECTIVE: The purpose of this study was to assess the effects of hyperbaric oxygen (HBO) and near-infrared light therapy on wound healing. BACKGROUND DATA: Light-emitting diodes (LED), originally developed for NASA plant growth experiments in space show promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. In this paper, we review and present our new data of LED treatment on cells grown in culture, on ischemic and diabetic wounds in rat models, and on acute and chronic wounds in humans. MATERIALS AND METHODS: In vitro and in vivo (animal and human) studies utilized a variety of LED wavelength, power intensity, and energy density parameters to begin to identify conditions for each biological tissue that are optimal for biostimulation. RESULTS: LED produced in vitro increases of cell growth of 140-200% in mouse-derived fibroblasts, rat-derived osteoblasts, and rat-derived skeletal muscle cells, and increases in growth of 155-171% of normal human epithelial cells. Wound size decreased up to 36% in conjunction with HBO in ischemic rat models. LED produced improvement of greater than 40% in musculoskeletal training injuries in Navy SEAL team members, and decreased wound healing time in crew members aboard a U.S. Naval submarine. LED produced a 47% reduction in pain of children suffering from oral mucositis. CONCLUSION: We believe that the use of NASA LED for light therapy alone, and in conjunction with hyperbaric oxygen, will greatly enhance the natural wound healing process, and more quickly return the patient to a preinjury/illness level of activity. This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program.

The effect of temperature on hand function in patients with tremor.

Hand therapists may notice a patient's tremor when treating another diagnostic problem, such as arthritis or a fracture. In these instances, the tremor may become apparent as the patient attempts to don or doff a splint or to practice a home exercise program, or it may be reported in terms of difficulty with dressing or eating. The authors hypothesized that limb cooling would temporarily improve hand function among patients with essential tremor (ET) and that limb warming would temporarily improve hand function among patients with resting tremor secondary to Parkinson disease (PD). Twenty patients with ET and 20 patients with PD completed this single-blind randomized crossover study. Scores following exposure to cold water were compared with scores following exposure to warm water. For patients with ET, subtest scores for the Archimedes spiral, simulated feeding, and checkers were, statistically, significantly lower (i.e., improved) following exposure to cold water than following exposure to warm water; scores for Archimedes spiral card turning, simulated feeding, and checkers were significantly lower following exposure to cold water than at baseline. Scores for Archimedes spiral and card turning were also significantly lower following exposure to warm water than at baseline. For patients with PD, no statistically significant differences were noted between treatments or from baseline except the score for small common objects, which was lower (improved) following exposure to warm water than at baseline. The significant findings from this study support the therapeutic use of cooling to temporarily decrease tremor, thereby improving hand function among patients with ET.