Progression of putaminal degeneration in multiple system atrophy: A serial diffusion MR study

Loss of nigrosome-1 on 3T and 7T magnetic resonance imaging (MRI) is a recently explored imaging biomarker in the diagnosis of neurodegenerative parkinsonism. This study was undertaken to evaluate the utility of imaging of nigrosome in the diagnosis of neurodegenerative parkinsonism on 3T MRI. An institution-based prospective case-control study was conducted at a tertiary care center in North India. 3T venous blood oxygen level-dependent (VenoBOLD) and high-resolution susceptibility-weighted imaging (SWI) imaging sequences in MRI were performed in 100 patients with parkinsonism (56 with idiopathic Parkinson's disease [IPD], 30 with young onset Parkinson's disease [YOPD], 12 with progressive supranuclear palsy, and 2 patients with multiple system atrophy) and 15 controls. Grading of nigrosome was done in both the sequences. Each patient underwent 18F-DOPA positron emission tomography (PET), detailed neurological examination including Hoen and Yahr (H&Y) staging and Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scoring. The diagnostic sensitivity and specificity of the detection of loss of nigrosome-1 on VenoBOLD and SWI sequence at 3T MR imaging were 90% and 66.7% and 94% and 80%, respectively. A weak negative correlation was found between the grading of the nigrosome and clinical parameters (H&Y and UPDRS III). There was no correlation between the side of nigrosome loss and clinical asymmetry. However, nigrosome imaging was not able to differentiate between Parkinson's disease and atypical parkinsonism. The loss of nigrosome-1 on 3T MRI on SWI and VenoBOLD sequences may serve as a potential imaging marker in the diagnosis of degenerative parkinsonian syndromes. However, it cannot differentiate between idiopathic Parkinson's disease and atypical parkinsonian syndromes.

To evaluate the specificity of motor cortical excitability changes in parkinsonian syndromes and their relevance to the pathophysiology of cardinal parkinsonian features. Paired transcranial magnetic stimulation (TMS) was used to assess cortico-cortical inhibition (CCI) and facilitation (CCF) in the opponens pollicis muscle of patients with atypical, non-L-dopa- (LD) responsive parkinsonism. Compared with age-matched normal control subjects, CCI (interstimulus interval [ISI], 3 ms) was significantly reduced in 10 patients with predominantly parkinsonian multiple system atrophy (MSA-P) and in seven with vascular parkinsonism (VP), but not in four with predominantly cerebellar MSA. No significant change of CCF (ISI, 12 ms) was observed. No correlation was found between the amount of CCI and clinical status as evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS). In 10 patients (5 MSA-P, 5 VP), CCI was significantly increased by LD acute administration without concurrent clinical changes. Abnormalities of CCI are not peculiar to idiopathic Parkinson's disease and seem unlikely to underlie any specific parkinsonian feature, but rather possibly reflect a nonspecific imbalance of inhibitory and facilitatory motor cortical circuits.

The aim of this study was to investigate the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in patients with a subtype of multiple system atrophy (MSA) in which levodopa-unresponsive MSA parkinsonism (MSA-P) is predominant. After a local anesthetic was administered, electrodes were stereotactically implanted bilaterally into the STN in four patients with MSA-P and predominantly akinetorigid symptoms. Unified Parkinson's Disease Rating Scale (UPDRS) scores were evaluated preoperatively, at 1 month, and at long-term follow up. At 1 month the median decrease in the UPDRS III motor score was 22 on the 56-point scale (decreases of 16, 13, 29, and 15 points compared with baseline for Cases 1, 2, 3, and 4, respectively). This was mainly due to an improvement in rigidity and akinesia. The median decrease in the UPDRS II score was 11 on the 52-point scale (respective decreases of 5, 7, 13, and 9 points). At 2 years (mean follow up 27 months) there was a median decrease in the UPDRS III score of 12 (respective decreases of 18, 13, 21, and 9 points), and in the UPDRS II score of 5 (with respective decreases of 2, 2, 17, and 2), both compared with the stimulation off state. At long-term follow up there was an increase in the individual Schwab and England scores of 10 to 15% in the stimulation on compared with the stimulation off condition. There was a beneficial effect of STN HFS in these four patients on both a short-term and a long-term basis. A larger prospective study is justified.

There is neuropathologic evidence that, in early stages of the Parkinson variant of multiple system atrophy (MSA-P), the putamen shows a distinct topographical pathology affecting predominantly the dorsolateral and caudal regions while leaving the rostral to midparts almost intact. We investigated the topographic profile of putaminal degeneration in MSA-P patients in vivo by means of diffusion-weighted imaging (DWI), which has been shown to reveal abnormalities in the basal ganglia of patients with MSA-P compared to patients with PD and healthy controls. For this purpose, regional trace of the diffusion tensor (rTrace(D)) values were determined in the entire, anterior, and posterior putamen in 15 patients with probable MSA-P, in 20 patients with PD, and in 11 healthy volunteers matched for age and disease duration. MSA-P patients had significantly higher rTrace(D) values in entire, anterior, and posterior putamen compared to both controls and PD patients. Trace(D) values were significantly higher in the posterior compared to the anterior putamen in the MSA-P group. There were no significant differences between posterior and anterior putamen in both the control and PD group. Our study demonstrates prominent involvement of the posterior putamen in early disease stages of MSA-P in vivo by assessing putaminal diffusivity with the help of DWI.

BackgroundPutaminal diffusivity in brain magnetic resonance diffusion-weighted imaging (DWI) is increased in patients with the parkinsonian variant of multiple system atrophy (MSA-P) compared to Parkinson disease (PD) patients.PurposeWe performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of DWI to distinguish MSA-P from PD.MethodsStudies on DWI were identified through a systematic PubMed and Clarivate Analytics® Web of Science® Core Collection search. Papers were selected based on stringent inclusion criteria; minimum requirement was the inclusion of MSA-P and PD patients and documented true positive, true negative, false positive and false negative rates or overall sample size and reported sensitivity and specificity. Meta-analysis was performed using the hierarchical summary receiver operating characteristics curve approach.ResultsThe database search yielded 1678 results of which 9 studies were deemed relevant. Diagnostic accuracy of putaminal diffusivity measurements were reported in all of these 9 studies, whereas results of other regions of interest were only reported irregularly. Therefore, a meta-analysis could only be performed for putaminal diffusivity measurements: 127 patients with MSA-P, 262 patients with PD and 70 healthy controls were included in the quantitative synthesis. The meta-analysis showed an overall sensitivity of 90% (95% confidence interval (CI): 76.7%-95.8%) and an overall specificity of 93% (95% CI: 80.0%-97.7%) to distinguish MSA-P from PD based on putaminal diffusivity.ConclusionPutaminal diffusivity yields high sensitivity and specificity to distinguish clinically diagnosed patients with MSA-P from PD. The confidence intervals indicate substantial variability. Further multicenter studies with harmonized protocols are warranted particularly in early disease stages when clinical diagnosis is less certain.

Providing high-quality care for patients with Parkinson's disease (PD) involves addressing both motor and nonmotor features. We describe the implementation and evaluation of a 2-day, interdisciplinary Comprehensive Care Clinic (CCC) for patients with PD. Patients who attended the CCC between January 2010 and July 2013 were matched by sex and age with patients who were evaluated in specialist care during the same time frame. Provider documentation of the American Academy of Neurology (AAN) quality measures for PD and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were compared between specialist and CCC visits at baseline and at 12 months. Ninety-five patients participated in the CCC (60% men; 75% white; mean age, 68 years; age range, 38-97 years). Of these, 29 patients were matched to specialist care patients based on the availability of 12-month follow-up data. Both groups were similar with respect to race, marital status, years with PD, and baseline UPDRS motor scores. On average, patients who received CCC care met 10 of 10 AAN quality measures, whereas those who received specialist care met only 5 of 10 quality measures (P < 0.001) over 12 months. At 12-months, there were no significant differences in UPDRS motor scores between the groups (P = 0.5). According to the AAN quality measures, the CCC provided higher quality care than the gold standard of specialty care. A randomized controlled trial of the CCC model is warranted to determine its impact on patient-centered outcomes and to assess whether the standard model of care should be altered.

Ropinirole, a non-ergoline dopamine agonist, has selective affinity for dopamine D2-like receptors and little or no affinity for non-dopaminergic brain receptors. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson's disease. It is also indicated, and recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson's disease. In the symptomatic treatment of early Parkinson's disease ropinirole monotherapy was significantly more effective than placebo in 2 multicentre, randomised, double-blind trials of 3 to 12 months duration as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and Clinical Global Impression/Clinical Global Evaluation Scales. In a similarly designed 3-year comparative study with bromocriptine, ropinirole recipients showed a significant improvement in UPDRS- activities of daily living (ADL) scores; however, motor scores were similar between the 2 groups. Ropinirole and levodopa treatments were similar in efficacy as measured by UPDRS ADL scores, although ropinirole recipients showed significantly less improvement on UPDRS motor scores at the 5-year study end-point in a multicentre, randomised double-blind trial. As an adjunct therapy to levodopa in patients with more advanced Parkinson's disease, ropinirole was reported to be as effective as bromocriptine and significantly more effective than placebo. In general in the comparisons with placebo ropinirole allowed a > or =20% reduction in the concomitant dose of levodopa without compromising efficacy in a significant proportion of patients and, in some trials decreased the amount of awake time spent in the 'off' state ('off' state is defined as a gradual return to parkinsonism despite adequate medication). Ropinirole was well tolerated either as monotherapy or as an adjunct to levodopa treatment. Nausea, dizziness and somnolence were the most commonly reported adverse events and were reported at a higher incidence by patients receiving ropinirole than by those receiving placebo. In patients with early Parkinson's disease, ropinirole generally showed a similar overall tolerability profile to bromocriptine although, over a 3-year period nausea was more commonly reported with ropinirole recipients. In a 5-year study, the incidence of dyskinesia was significantly lower with ropinirole than with levodopa regardless of levodopa supplementation. Prior to the addition of supplementary levodopa 5% of ropinirole recipients had experienced dyskinesia compared with 36% of those receiving levodopa. In patients with early Parkinson's disease, ropinirole monotherapy was more efficacious than bromocriptine with regard to improvement in activities of daily living, and need for supplemental levodopa. Ropinirole recipients had a higher requirement for levodopa supplementation than levodopa recipients in a 5-year study, but the incidence of dyskinesia was significantly lower with ropinirole than with levodopa (markedly so in the one third of ropinirole recipients who were able to remain on monotherapy with no levodopa supplementation). Thus available data suggest that ropinirole may provide a means of treating early Parkinson's disease while minimising the risk of dyskinesia and delaying the need for supplemental levodopa in some patients. In addition, ropinirole is also efficacious in the management of more advanced Parkinson's disease in patients who are experiencing motor complications after long term levodopa use.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

The motor examination section of the unified Parkinson's disease rating scale (UPDRS) is widely used in research but few studies have examined whether subscales exist that tap relatively distinct motor abnormalities. We analyzed data from 193 persons enrolled in a population-based study in Central California. Patients were examined after overnight PD medication washout (“OFF” state) and approximately one hour after taking medication (“ON” state). We performed confirmatory factor analysis of the UPDRS for OFF and ON state examinations; correlations, reliability, and relative validity of resulting subscales were evaluated. A model with five factors (gait/posture, tremor, rigidity, bradykinesia affecting the left extremities, bradykinesia affecting the right extremities) fit the data well, with similar results for OFF and ON states. Internal consistency reliability coefficients were 0.90 or higher for all subscales. The gait/posture subscale most strongly discriminated across levels of patient reported PD symptom severity and of how PD affects them on a daily basis. Compared to the right sided bradykinesia subscale, the left sided bradykinesia subscale had higher discrimination across levels of self-reported PD symptom severity and functional impairment. This supports motor UPDRS containing multiple subscales that can be analyzed separately and provide information distinct from the total score that may be useful in clinical studies.

Background-Covid-19 pandemic has posed a great challenge for people with neurological disorders like Parkinson’s-disease to commute to treatment center due to risk of infection, unavailability of transport and most importantly to avail contact treatment commonly practiced in physiotherapy management of neurological patients. With the view of providing home-bound physiotherapy treatment for these patients, we speculated that safe balance intervention under expert supervision may prove beneficial improving their overall function. Thus, study was conducted in sitting using chair based Tele-rehabilitation. Aim: To study effect of chair-based Tele-rehabilitation on motor and functional components of unified Parkinson’s disease rating scale (UPDRS) in Parkinson’s patient. Objectives: To study effect of intervention on activities-of-daily-living and motor components. Methodology: A 70-year-old female patient complained of resting tremors in right hand and presented with difficulty in walking, imbalance and frequent episodes of fall. After multiple investigations including CT-brain, she has diagnosed with grade 3(Hoehn &amp;Yahr scale) Parkinson’s disease. With medical management, the patient received 30-45 minutes/day, 3 days a week, 12-weeks chair-based exercises using zoom as Tele-medium focusing on stretching, flexibility, strengthening and postural-stability exercises. Baseline offline assessment on (UPDRS)outcome measure was done in September-2021 and post training assessment was done after 12 weeks on 30thDecember-2021. Results: Motor and Functional improvement was noted on UPDRS scale which included hand mobility, tremors, co-ordination, improvement in balance and gait(walking)pattern and patient could perform all functional activities such as dressing, sit-to-stand, log-rolling independently and reported no fall-episodes. Conclusion: Present study concludes that chair-based exercises using tele-rehabilitation provides a safe and highly beneficial alternative mode of rehabilitation especially for patients with Parkinson’s who have difficulty in commuting to treatment center and can be effectively prescribed to Parkinson’s patients to prevent frequent episodes of fall and to gain functional independence. KEY WORDS: Chair-based exercises, Tele-rehabilitation, Parkinson’s disease.

Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed.

This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD). Four databases (Medline, Embase, Web of Science and CENTRAL) were searched from establishment of database to 23 March 2024, for articles studying robot-assisted DBS in patients diagnosed with PD. Meta-analyses of vector error, complication rate, levodopa-equivalent daily dose (LEDD), Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, and UPDRS IV were performed. A total of 15 studies were included in this meta-analysis, comprising 732 patients with PD who received robot-assisted DBS. The pooled results revealed that the vector error was measured at 1.09 mm (95% CI: 0.87 to 1.30) in patients with Parkinson's disease who received robot-assisted DBS. The complication rate was 0.12 (95% CI, 0.03 to 0.24). The reduction in LEDD was 422.31 mg (95% CI: 68.69 to 775.94). The improvement in UPDRS, UPDRS III, and UPDRS IV was 27.36 (95% CI: 8.57 to 46.15), 14.09 (95% CI: 4.67 to 23.52), and 3.54 (95% CI: -2.35 to 9.43), respectively. Robot-assisted DBS is a reliable and safe approach for treating PD. Robot-assisted DBS provides enhanced accuracy in contrast to conventional frame-based stereotactic techniques. Nevertheless, further investigation is necessary to validate the advantages of robot-assisted DBS in terms of enhancing motor function and decreasing the need for antiparkinsonian medications, in comparison to traditional frame-based stereotactic techniques.Clinical trial registration: PROSPERO(CRD42024529976).

Although the Unified Parkinson's Disease Rating Scale (UPDRS) is the most common performance measure for people with Parkinson disease (PD), the Berg Balance Scale (BBS), Forward Functional Reach Test (FFR), Backward Functional Reach Test (BFR), Timed "Up & Go" Test (TUG), and gait speed may be used to quantify some aspects of functional performance not measured by the UPDRS. The purpose of this study was to describe the relationship among a set of tests of balance, walking performance, and mobility in people with PD. Twenty-five community-dwelling adults (11 female, 14 male) with a diagnosis of PD were recruited from PD support groups in southeastern Wisconsin and consented to participate in the study. The mean age of the participants was 76 years (SD=7). The average Hoehn and Yahr Stage Scale score was 2. Functional abilities of each subject were assessed with the UPDRS, BBS, FFR, BFR, TUG, and gait speed. Spearman and Pearson correlations were performed. The UPDRS total score was correlated with the BBS (r=-.64, P<.001), FFR (r=-.52, P<.05), and TUG (r=.50, P<.05) measurements. The BBS is the only test of functional performance where scores correlate with all other functional tests and the UPDRS. The UPDRS total score may not reflect a comprehensive measure of mobility in people with PD. Because the BBS scores correlate both with UPDRS scores and with scores of all other tests of functional performance, the BBS appears to be a good overall measure of function in this population.

Item response theory (IRT) has been recently adopted to successfully characterize the progression of Parkinson's disease using serial Unified Parkinson's Disease Rating Scale (UPDRS) measurements. However, it has yet to be applied in predicting the longitudinal changes of levodopa dose requirements in the real‐world setting. Here we use IRT to extract two latent variables that represent tremor and non‐tremor‐related symptoms from baseline assessments of UPDRS Part III scores. We show that relative magnitudes of the two latent variables are strong predictors of the progressive increase of levodopa equivalent dose (LED). Retrospectively collected item‐level UPDRS Part III scores and longitudinal records of prescribed medication doses of 128 patients with de novo PD extracted from the electronic medical records were used for model building. Supplementary analysis based on a subset of 36 patients with at least three serial assessments of UPDRS Part III scores suggested that the two latent variables progress at significantly different rates. A web application was developed to facilitate the use of our model in making individualized predictions of future LED and disease progression.

To quantitatively evaluate motor activity, its fluctuations, and drug effects in patients with Parkinson's disease (PD), the Lifecorder, a new monitoring device, was attached to a group of patients for several weeks. This enabled the continuous recording of motor activity in ten scaled magnitudes at two-minute intervals for 6 weeks. Thirteen patients with PD who required dopamine receptor agonist therapy were monitored with Lifecorder, and seven healthy subjects served as the control group. The data obtained with this device correlated well with the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr grading. The dose of cabergoline, a D2-receptor agonist, was increased every 2 weeks, until optimum improvement was achieved. By adding cabergoline, the mean UPDRS improved from 40.5 to 28.4, which was significant. In parallel, the mean daily walking count (WC) also increased from 2,459 to 3,315 steps (p < 0.01) and movement-related calorie consumption (MCC) increased from 56 to 74 kcal (p < 0.05). UPDRS thus correlated well with WC and MCC (p < 0.05) obtained with this device. The improvement ratio of WC and MCC of each individual patient was compared with that of UPDRS. WC, and MCC shifted in parallel with UPDRS with one exception. The daily time-dependent fluctuation of motor activity was clearly shown by the Excel-generated graphs to improve with D-agonist therapy. In contrast to enhanced daytime activities, nocturnal restfulness was also clearly documented with this device. The unique properties of Lifecorder make this device a useful adjunct to the UPDRS for the objective evaluation of Parkinsonian motor activity. The device has a significant advantage over conventional clinical scales, as daytime as well as nocturnal motor activity can be objectively evaluated over long time periods ranging from one hour to one month, and the magnitude of motor activity is quantifiable in relation to the time-course.