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.).

To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinson's 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 anchorbased 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).

Parkin, the most commonly mutated gene known to result in familial Parkinson's disease (PD), 1 encodes an E3 ubiquitin ligase (1). Several substrates for parkin have been identified including CDCrel-1, an o-glycosylated form of ␣-synuclein ␣Sp22, Pael-R (2), and synphilin-1 (3-5). These parkin substrates have little sequence or functional similarities; however, Pael-R and ␣-synuclein have a propensity to misfold and aggregate (2, 4). This common property of known parkin substrates suggests that parkin may play a general role in the degradation of misfolded proteins, which might otherwise overwhelm the ubiquitin-proteasome system (UPS).Parkin has been demonstrated to function in the endoplasmic reticulum-associated degradation (ERAD) of misfolded ER proteins (2, 6). Parkin is up-regulated during the unfolded protein response (6). Pael-R overexpression results in ER accumulation of the protein, causing ER stress-induced cell death; parkin overexpression ameliorates these effects (2). Proteasome function is also important for normal ERAD and proteasomal dysfunction can cause ER stress (7, 8). Whereas ERAD is an important pathway for eliminating misfolded proteins in the ER, there are many misfolded aggregation-prone proteins that are translated in the cytosol including most of the polyglutamine (poly(Q)) containing proteins. Accumulation of misfolded cytosolic and ER-translated proteins can ultimately inhibit proteasomal activity (9 -11).Whereas the cytotoxicity of expanded poly(Q) proteins may be because of a variety of mechanisms (12-16), expanded poly(Q) proteins impair proteasome function (9 -11). Proteasomal dysfunction has also been demonstrated in PD brain and may play a role in the accumulation of aberrant proteins and neuronal loss that characterize several of the adult neurodegenerative diseases (17). Accumulation of aberrant proteins is a hallmark of both PD and the poly(Q) expansion diseases, which include Huntington's disease (HD) and several spinocerebellar ataxias. Overexpression of aberrant proteins has been very useful for identifying genes and proteins capable of modifying their accumulation or toxicity. Molecular chaperones such as Hsp70 improve cell viability (18 -20) and facilitate the elimination of poly(Q) proteins in cellular models and ameliorate disease phenotype in transgenic Drosophila models (18,(21)(22)(23)(24)(25). Hsp70 also improves the phenotype in a Drosophila PD model in which human ␣-synuclein is overexpressed (26). Parkin appears to interact with Hsp70 along with the ubiquitinating factor CHIP (27). The N terminus of parkin contains a domain homologous to ubiquitin called the ubiquitin-like (Ubl) domain. A similar domain in the human homologue of the yeast DNA repair factor (hhRad23) has been shown to interact with expanded poly(Q) proteins (28) and bind the proteasome (29,30). Other Ubl domain containing proteins such as Dsk2 (31, 32) and Ubp6 (33) also bind the proteasome. These findings suggest that parkin may also bind expanded poly(Q) proteins and proteasomes via its Ubl ...

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.