Paul S. Fishman

The Clinically Important Difference on the Unified Parkinson's Disease Rating Scale

OBJECTIVE To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinsons Disease Rating Scale (UPDRS). DESIGN Cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution- and anchor-based approaches based on the following 3 external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey). SETTING University of Maryland Parkinson Disease and Movement Disorders Center, Patients Six hundred fifty-three patients with PD. RESULTS A minimal CID was 2.3 to 2.7 points on the UPDRS motor score and 4.1 to 4.5 on the UPDRS total score. A moderate CID was 4.5 to 6.7 points on the UPDRS motor score and 8.5 to 10.3 on the UPDRS total score. A large CID was 10.7 to 10.8 points on the UPDRS motor score and 16.4 to 17.8 on the UPDRS total score. CONCLUSIONS Concordance among multiple approaches of analysis based on subjective and objective data show that reasonable estimates for the CID on the UPDRS motor score are 2.5 points for minimal, 5.2 for moderate, and 10.8 for large CIDs. Estimates for the UPDRS total score are 4.3 points for minimal, 9.1 for moderate, and 17.1 for large CIDs. These estimates will assist in determining clinically meaningful changes in PD progression and response to therapeutic interventions.

Hematopoietic progenitors express neural genes

Bone marrow, or cells selected from bone marrow, were reported recently to give rise to cells with a neural phenotype after in vitro treatment with neural-inducing factors or after delivery into the brain. However, we showed previously that untreated bone marrow cells express products of the neural myelin basic protein gene, and we demonstrate here that a subset of ex vivo bone marrow cells expresses the neurogenic transcription factor Pax-6 as well as neuronal genes encoding neurofilament H, NeuN (neuronal nuclear protein), HuC/HuD (Hu-antigen C/Hu-antigen D), and GAD65 (glutamic acid decarboxylase 65), as well as the oligodendroglial gene encoding CNPase (2′,3′ cyclic nucleotide 3′-phosphohydrolase). In contrast, astroglial glial fibrillary acidic protein (GFAP) was not detected. These cells also were CD34+, a marker of hematopoietic stem cells. Cultures of these highly proliferative CD34+ cells, derived from adult mouse bone marrow, uniformly displayed a phenotype comparable with that of hematopoietic progenitor cells (CD45+, CD34+, Sca-1+, AA4.1+, cKit+, GATA-2+, and LMO-2+). The neuronal and oligodendroglial genes expressed in ex vivo bone marrow also were expressed in all cultured CD34+ cells, and GFAP was not observed. After CD34+ cell transplantation into adult brain, neuronal or oligodendroglial markers segregated into distinct nonoverlapping cell populations, whereas astroglial GFAP appeared, in the absence of other neural markers, in a separate set of implanted cells. Thus, neuronal and oligodendroglial gene products are present in a subset of bone marrow cells, and the expression of these genes can be regulated in brain. The fact that these CD34+ cells also express transcription factors (Rex-1 and Oct-4) that are found in early development elicits the hypothesis that they may be pluripotent embryonic-like stem cells.

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor

BACKGROUND Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

The evolution of disability in Parkinson disease

The objectives of this study are to assess the level of disease severity associated with disability in Parkinson disease (PD) and the sequence of loss of independence in basic and instrumental activities of daily living (ADLs and IADLs). Six hundred eighteen patients with PD were evaluated for disease severity with the Unified PD Rating Scale (UPDRS) and for disability with the Older Americans Resource and Services Disability Subscale (OARS). The association between patient‐reported disability on ADLs and IADLs and level of disease severity on the total UPDRS was examined cross‐sectionally. Disability, with loss of independent function is reported between total UPDRS scores 30 to 40, and HY stages II to III. Difficulty with daily activities, without loss of independent function is reported earlier, at UPDRS <20 and HY I to II. Difficulty with walking is initially reported, followed by problems with a number of gait‐dependent activities including housework, dressing, transferring in and out of bed, and traveling in the community. The transition from HY stage II to III marks a pivotal milestone in PD, when gait and balance impairment results in disability in many gait‐dependent activities. The onset of disability in PD can be identified by asking patients about their walking, housework, dressing, and traveling. While individual patients vary in progression, the benchmarks of disability in this study provide guidance when counseling patients about prognosis. Better understanding of the stages of disability may facilitate the development of novel outcome measures in clinical trials in PD.

Functional synapses are formed between human NTera2 (NT2N, hNT) neurons grown on astrocytes

The formation of functional synapses is a late milestone of neuronal differentiation. The establishment of functional synapses can be used to assess neuronal characteristics of different cell lines. In the present study, we examined the in vitro conditions that influence the ability of human neurons derived from the NT2 cell line (NT2N neurons) to establish synapses. The morphologic, immunologic, and electrophysiologic characteristics of these synapses was examined. In the absence of astrocytes, NT2N neurons rarely formed synapses and their action potentials were weak and uncommon. In contrast, when plated on primary astrocytes, NT2N neurons were able to form both glutamatergic excitatory (71%) and GABAergic inhibitory (29%) functional synapses whose properties (kinetics, ion selectivity, pharmacology, and ultrastructure) were similar to those of synapses of neurons in primary cultures. In addition, coculture of NT2N neurons with astrocytes modified the morphology of the neurons and extended their in vitro viability to more than 1 year. Because astrocyte‐conditioned medium did not produce these effects, we infer that direct contact between NT2N neurons and astrocytes is required. These results suggest that NT2N neurons are similar to primary neurons in their synaptogenesis and their requirement for glial support for optimal survival and maturation. This system provides a model for further investigations into the neurobiology of synapses formed by human neurons. J. Comp. Neurol. 407:1–10, 1999.

Free-living daily energy expenditure in patients with Parkinson's disease.

Previous studies have suggested that elevated resting energy expenditure contributes to weight loss in patients with Parkinsons disease (PD).Body weight is, however, ultimately determined by variation in daily energy expenditure and not just resting energy expenditure. Therefore, we examined the hypothesis that PD patients are characterized by elevated daily energy expenditure. Sixteen patients with levodopa responsive PD and 46 healthy elderly controls were characterized for daily energy expenditure and its components (resting and physical activity energy expenditure) using a combination of the doubly labeled water technique (over 10 days) and resting indirect calorimetry. Fat-free mass and fat mass were measured by dual energy x-ray absorptiometry. Results showed that fat mass and fat-free mass did not differ between groups. Daily energy expenditure was 15% lower (2214 +/- 460 vs. 2590 +/- 497 kcal/d; p < 0.01) in PD patients compared to controls. This was primarily due to lower physical activity energy expenditure (339 +/- 366 vs. 769 +/- 412 kcal/d; P < 0.01) in PD patients as resting energy expenditure was not different between groups (1655 +/- 283 vs. 1561 +/- 219 kcal/d). These results show that daily energy expenditure is lower in PD patients compared to healthy elderly, primarily due to reduced physical activity energy expenditure. These results argue against the hypothesis that an abnormally elevated daily energy expenditure contributes to weight loss in PD. NEUROLOGY 1997;48: 88-91

Impact of psychogenic movement disorders versus Parkinson's on disability, quality of life, and psychopathology.

Patients with psychogenic movement disorders (PMD) often report severe impairment, yet the impact of PMD on disability and quality of life has not been examined. We compared 66 patients with PMD and 704 patients with Parkinsons disease (PD) on measures of disability (Older Americans Resources and Services Scale, OARS); quality of life (QOL; SF‐12v2 Health Survey) and psychiatric symptomatology (Brief Symptom Inventory 18, BSI‐18). On the total OARS, PMD and PD patients reported similar levels of disability (17.6 ± 6.6, 19.8 ± 10.9, P = 0.490 at “best” function and 24.1 ± 11.2, 26.2 ± 14.3, P = 0.497 at their “worst” function). PMD patients reported similar Physical Health QOL to PD patients (38.9 ± 14.5, 39.8 ± 11.6, P = 0.652) but worse mental health QOL (41.6 ± 13.4 vs. 48.9 ± 11.0, P < 0.001). On the BSI‐18, PMD patients reported higher levels of distress on the Global Symptom Index (62.03 ± 9.6 vs. 53.7 ± 9.9, P < 0.001) and on Anxiety, Depression and Somatization subscales (PMD vs. PD scores: Anxiety 58.9 ± 12.0 vs. 52.3 ± 10.1, P < 0.001; Depression 58.8 ± 11.9 vs. 51.3 ± 10.3, P < 0.001; Somatization 60.5 ± 11.0 vs. 54.7 ± 8.7, P < 0.001). Thus, severity of disability reported by the PMD group was equal to that seen in a progressive neurodegenerative condition. Quality of life and mental health implications of PMD were also evident. PMD impacts several aspects of patient function and daily life.

Retrograde transneuronal transfer of the C-fragment of tetanus toxin

The transport of the C-fragment of tetanus toxin after intramuscular injection was studied with immunohistochemical techniques. Brainstems and spinal cords of mice were examined after injections of C-fragment into the tongue or forearm. Labelled motorneurons were observed within 6 h. By two days after injection, the bulk of detectable C-fragment had passed out of motorneurons into the surrounding neuropil. C-fragment, like native tetanus toxin, appears to be transferred from motorneurons to presynaptic structures to an extent not observed with other proteins. It is useful in the study of retrograde transneuronal transfer since it lacks the toxicity of tetanus toxin.

Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system

Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The effects of BoNT serotype A (BoNT/A) can last several months, whereas the effects of BoNT serotype E (BoNT/E), which shares the same synaptic target, synaptosomal-associated protein 25 (SNAP25), last only several weeks. The long-lasting effects or persistence of BoNT/A, although desirable for therapeutic applications, presents a challenge for medical treatment of BoNT intoxication. Although the mechanisms for BoNT toxicity are well known, little is known about the mechanisms that govern the persistence of the toxins. We show that the recombinant catalytic light chain (LC) of BoNT/E is ubiquitylated and rapidly degraded in cells. In contrast, BoNT/A LC is considerably more stable. Differential susceptibility of the catalytic LCs to ubiquitin-dependent proteolysis therefore might explain the differential persistence of BoNT serotypes. In this regard we show that TRAF2, a RING finger protein implicated in ubiquitylation, selectively associates with BoNT/E LC and promotes its proteasomal degradation. Given these data, we asked whether BoNT/A LC could be targeted for rapid proteasomal degradation by redirecting it to characterized ubiquitin ligase domains. We describe chimeric SNAP25-based ubiquitin ligases that target BoNT/A LC for degradation, reducing its duration in a cellular model for toxin persistence.

Optical coherence tomography in the diagnosis and treatment of neurological disorders

Optical contrast is often the limiting factor in the imaging of live biological tissue. Studies were conducted in postmortem human brain to identify clinical applications where the structures of interest possess high intrinsic optical contrast and where the real-time, high-resolution imaging capabilities of optical coherence tomography (OCT) may be critical. Myelinated fiber tracts and blood vessels are two structures with high optical contrast. The ability to image these two structures in real time may improve the efficacy and safety of a neurosurgical procedure to treat Parkinsons disease called deep brain stimulation (DBS). OCT was evaluated as a potential optical guidance system for DBS in 25 human brains. The results suggest that catheter-based OCT has the resolution and contrast necessary for DBS targeting. The results also demonstrate the ability of OCT to detect blood vessels with high sensitivity, suggesting a possible means to avoid their laceration during DBS. Other microscopic structures in the human brain with high optical contrast are pathological vacuoles associated with transmissible spongiform encephalopathy (TSE). TSE include diseases such as Mad Cow disease and Creutzfeldt-Jakob disease (CJD) in humans. OCT performed on the brain from a woman who died of CJD was able to detect clearly the pathological vacuoles.