Katie Kompoliti

Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results

We present a clinimetric assessment of the Movement Disorder Society (MDS)‐sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS). The MDS‐UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS‐UPDRS has four parts, namely, I: Non‐motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item‐specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS‐UPDRS (65 items) to 877 English speaking (78% non‐Latino Caucasian) patients with Parkinsons disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS‐UPDRS showed high internal consistency (Cronbachs alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS‐UPDRS across‐part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.

Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra

Nuclear receptor‐related factor 1 (Nurr1), a member of the nuclear receptor superfamily, is associated with the induction of dopaminergic (DA) phenotypes in developing and mature midbrain neurons. It is well established that dopaminergic nigrostriatal function decreases with age. Whether age‐related deficits in DA phenotypic markers are associated with alterations in Nurr1 expression is unknown. The present study found that virtually all of tyrosine hydroxylase‐immunoreactive (TH‐ir) neurons within the young adult human substantia nigra were Nurr1‐immunoreactive (Nurr1‐ir) positive. Stereologic counts revealed a significant reduction in the number of Nurr1‐ir nigral neurons in middle‐aged (23.13%) and aged (46.33%) individuals relative to young subjects. The loss of Nurr1‐ir neurons was associated with a similar decline in TH‐ir neuron number. In this regard, TH‐ir neuronal number was decreased in middle‐aged (11.10%) and in aged (45.97%) subjects, and this loss of TH‐ir neurons was highly correlated (r = 0.92) with the loss of Nurr1‐ir neurons. In contrast, the number of melanin‐containing nigral neuron number was generally stable across age groups, indicating that changes in Nurr1 and TH reflect phenotypic age‐related changes and not frank neuronal degeneration. In support of this concept, confocal microscopic analyses of Nurr1‐ir and TH‐ir fluorescence intensity revealed parallel decreases in Nurr1‐ and TH‐immunofluorescence as a function of age. These data demonstrate that age‐related decline of DA phenotypic markers is associated with down‐regulation of Nurr1 expression in the SN. J. Comp. Neurol. 450:203–214, 2002.

Nurr1 in Parkinson's disease and related disorders

In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organisms lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinsons disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimers disease (AD) or age‐matched‐matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing α‐synuclein‐immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1‐ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1‐ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies. J. Comp. Neurol. 494:495–514, 2006.

Sialorrhea in Parkinson's disease: A review

A significant number of patients with Parkinsons disease (PD) experience sialorrhea. This problem can cause social embarrassment, and because saliva pools in the mouth, may lead to aspiration pneumonia. Sialorrhea in PD is thought to be caused by impaired or infrequent swallowing, rather than hypersecretion. Oral medications, botulinum toxin injections, surgical interventions, radiotherapy, speech therapy, and trials of devices may be used to treat sialorrhea in PD, but few controlled trials have been published. This article reviews current knowledge regarding the frequency, etiology, assessment, and treatment of sialorrhea in PD.

'On' freezing in Parkinson's disease: Resistance to visual cue walking devices

To measure “on” freezing during unassisted walking (UW) and test if two devices, a modified inverted stick (MIS) and a visual laser beam stick (LBS) improved walking speed and number of “on” freezing episodes in patients with Parkinsons disease (PD).

Effects of central dopaminergic stimulation by apomorphine on speech in Parkinson’s disease

Objective: To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD. Background: Most patients with PD have a speech disorder. Of those, 89% have involvement of laryngeal function, and 45% have additional articulatory dysfunction. The effect of dopaminergic medications on these two dimensions of speech impairment in PD has not been selectively studied. Methods: In a randomized, double-blind, placebo-controlled crossover design, patients with PD and speech impairment, Hoehn and Yahr stages 2 to 4 “off,” and without severe dyskinesias were given placebo or apomorphine injections 0.05 mg/kg subcutaneously during two consecutive outpatient visits. They were pretreated with domperidone for 48 hours and were tested off their parkinsonian medications for 12 hours. Laryngeal function was assessed by maximum sustained vowel phonations and comfortable vowel phonations. Articulatory function was evaluated by speech intelligibility score, speaking rate, and efficiency ratio. Results: Ten patients, mean age 73.4 years (SD = 6.6), disease duration 8.7 years (SD = 6.3), were tested. The baseline motor score on the Unified Parkinson’s Disease Rating Scale (UPDRSm) and all experimental speech variables were equivalent on both placebo and apomorphine days. At a dose of apomorphine that provoked improvement in UPDRSm (p = 0.0078), no index of either laryngeal or articulatory function improved significantly after apomorphine administration. Conclusion: Laryngeal and articulatory speech components are not under prominent dopaminergic control in PD. Treatment regimens should focus on nondopaminergic pharmacology and other therapies.

The importance of educational and psychological factors in Parkinson's disease quality of life

Objective:  To define the factors correlated with quality of life (QoL) in patients with idiopathic Parkinsons disease (PD).

Chronic ischemic stroke model in cynomolgus monkeys: behavioral, neuroimaging and anatomical study.

Abstract Previous nonhuman primate stroke models have employed temporary occlusion of arteries, had limited behavioral testing and imaging, and focused on the short-term outcome. Our goals were 1. to develop a stable model of chronic stroke in the nonhuman primate, 2. to study in vivo the long-term biochemical changes in the area adjacent to the infarct, using proton magnetic resonance spectroscopy (1H MRS), and 3. evaluate these changes in relation to the histopathological effects of stroke. Four adult cynomologous monkeys had an occlusion of the M1 segment of the right MCA. Behavioral tests included a clinical rating scale, motor planning task, fine motor task, and activity monitoring. Eight months afterwards, MRI and 1H MRS were performed. Following the imaging studies the monkeys were perfused transcardially, their brains extracted and processed. Nissl staining and immunohistochemistry for neuronal markers (NeuN) were performed and used to measure the lesion volume and neuronal optical density (OD). All animals developed a left hemiparesis and were unable to perform a fine motor task with the left hand. There was a significant (31%) decline in the motor planning ability with the nonparetic extremity. Monkeys displayed a stooped posture, episodes of rotation to the side of the lesion, partial left hemianopsia, and transient changes in activity. The clinical signs improved over the first 6–8 weeks but the deficits remained stable for the remaining six months of follow up. MRI demonstrated a subcortical and cortical infarction in the right MCA distribution. 1H MRS data detected a significant decrease in the N-acetyl-aspartate (NAA)/creatine (Cr) ratio in the area adjacent to the infarction (VOI-St) compared to a mirror area in the contralateral hemisphere (VOI-Co). Histopathological measurements revealed a significant decline in neuronal crosssectional area and neuronal optical density in the region of the VOI-St. We established a stable and reproducible model of chronic stroke in the MCA distribution, in the macaque monkey. Our data indicate that NAA detected by 1H MRS can be used to measure neuronal loss in vivo and help target this area for intervention. Our model may be particularly suitable for studies testing the effects of therapeutic strategies involving neural or stem cell transplantation, trophic factors or gene therapy.

Application of the Unified Parkinson's Disease Rating Scale in progressive supranuclear palsy: factor analysis of the motor scale.

An important criterion in scale validation is the demonstration of a stable factor structure. The Unified Parkinsons Disease Rating Scale (UPDRS) is widely used to assess Parkinsons disease (PD). The reliability and applicability of the motor subscale of the UPDRS (UPDRSm) when applied to patients diagnosed with progressive supranuclear palsy (PSP) is unknown. In a sample of 175 patients with PSP, factor analysis revealed five clinically distinct factors: two independent bradykinesia factors (axial/gait and extremities), one rigidity factor, and two independent tremor factors (rest and action). Two items (posture and rest head tremor) did not reach criteria for factor loadings. There was a high degree of internal consistency. These results suggest that UPDRSm is a reliable and applicable scale for assessing most aspects of PSP function as well as severity measures of five clinical disability domains.

Effects of estrogen replacement therapy on cholinergic basal forebrain neurons and cortical cholinergic innervation in young and aged ovariectomized rhesus monkeys

Estrogen modulates the function of cholinergic basal forebrain neurons in aged female rats. The present study tested the hypothesis that estrogen enhances the phenotype of cholinergic basal forebrain neurons and their cortical cholinergic innervation in young adult and aged ovariectomized rhesus monkeys. Sixteen monkeys (9 young and 7 aged) received two injections of estradiol cypionate or vehicle separated by 3 weeks. All monkeys were killed 1 day after the last injection. Quantitative immunofluorescence in the vertical limb of the diagonal band (VLDB) revealed enhanced optical density for choline acetyltransferase (ChAT) in both young and aged monkeys treated with estrogen. In contrast, optical density for low‐affinity p75 neurotrophin receptor immunoreactivity in the VLDB did not change after estrogen treatment in either aged or young animals. Quantitative immunofluorescence for either ChAT or the low‐affinity p75 neurotrophin receptor in the nucleus basalis Meynert failed to reveal differences between vehicle and estrogen treatment in either age group. Quantitative estimates of acetylcholinesterase (AChE) fiber density revealed that estrogen‐treated aged monkeys but not their younger counterparts had decreased numbers of AChE‐positive fibers in layer II of frontal, insular, and cingulate cortices. These data indicate that estrogen administered in a manner simulating natural hormonal cyclicity produces modest age‐specific chemical phenotypic and regional changes in select neuronal subfields of the cholinergic basal forebrain and their cortical projection sites in nonhuman primates. J. Comp. Neurol. 472:193–207, 2004.