Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals.

BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease.

BACKGROUND: Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS: Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).

European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism.

OBJECTIVE: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies. METHODS: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins. RESULTS: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression. CONCLUSIONS: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society.

BACKGROUND: Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. OBJECTIVES: Convene an international panel of experienced investigators to review the definition and classification of tremor. METHODS: Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: "tremor", "tremor disorders", "essential tremor", "dystonic tremor", and "classification" limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. RESULTS: Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1-clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2-etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. CONCLUSIONS: This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society.

[The Competence Network Parkinson (CNP)]. / Das Kompetenznetz Parkinson (KNP).

The Competence Network Parkinson (CNP) is a research infrastructure for disease-oriented translational and clinical research in the field of Parkinson syndromes (PS). It was initiated in 1999 and funded until 2008 by the German Ministry for Education and Research (BMBF). The CNP created a highly frequented website with information on PS for the general public and for experts. The CNP designed and established one of the first electronic internet-based data entry systems (secuTrial®) - fulfilling the legal standards of data safety and security - a material bank for genetic research on Parkinson's disease (PD), implemented and investigated new methods for early diagnosis of PD and related atypical PS including in vivo dopamine transporter imaging (DAT SPECT), established the German Parkinson Study Group (GPS-Pharma) with 40 certified trial centres for pharmacotherapeutical trials and the German interdisciplinary Parkinson Study Group (neurology and neurosurgery) for deep brain stimulation (GPS-DBS), and carried out several pharmacoeconomic and health care studies on PD in Germany. Sustainability of the infrastructure CNP has in part been achieved in form of the GPS-Pharma and the GPS-DBS, as well as in the German Study Group on REM Sleep Behaviour Disorder (RBD), a prodromal phase of PD. Part of the CNP activities, such as genetic research and research on cohorts of PD patients, have been incorporated into the German Center for Neurodegenerative Disorders (DZNE). Furthermore, topics such as health care research are funded within projects of the EU research program. The article describes problems in setting up a competence network from scratch and contains recommendations how to avoid them in the future.

Validation and application of computer vision algorithms for video-based tremor analysis.

Tremor is one of the most common neurological symptoms. Its clinical and neurobiological complexity necessitates novel approaches for granular phenotyping. Instrumented neurophysiological analyses have proven useful, but are highly resource-intensive and lack broad accessibility. In contrast, bedside scores are simple to administer, but lack the granularity to capture subtle but relevant tremor features. We utilise the open-source computer vision pose tracking algorithm Mediapipe to track hands in clinical video recordings and use the resulting time series to compute canonical tremor features. This approach is compared to marker-based 3D motion capture, wrist-worn accelerometry, clinical scoring and a second, specifically trained tremor-specific algorithm in two independent clinical cohorts. These cohorts consisted of 66 patients diagnosed with essential tremor, assessed in different task conditions and states of deep brain stimulation therapy. We find that Mediapipe-derived tremor metrics exhibit high convergent clinical validity to scores (Spearman's ρ = 0.55-0.86, p≤ .01) as well as an accuracy of up to 2.60 mm (95% CI [-3.13, 8.23]) and ≤0.21 Hz (95% CI [-0.05, 0.46]) for tremor amplitude and frequency measurements, matching gold-standard equipment. Mediapipe, but not the disease-specific algorithm, was capable of analysing videos involving complex configurational changes of the hands. Moreover, it enabled the extraction of tremor features with diagnostic and prognostic relevance, a dimension which conventional tremor scores were unable to provide. Collectively, this demonstrates that current computer vision algorithms can be transformed into an accurate and highly accessible tool for video-based tremor analysis, yielding comparable results to gold standard tremor recordings.

Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor.

Background: Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited. Objectives: To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date. Methods: Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons. Results: The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation. Conclusions: In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

Subthalamic and pallidal deep brain stimulation for Parkinson's disease-meta-analysis of outcomes.

Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson's disease (PD), a recent meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson's Disease Rating Scale (UPDRS) III motor scores at baseline and 6-12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation.

Standard guidelines for publication of deep brain stimulation studies in Parkinson's disease (Guide4DBS-PD).

While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies due to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinson's disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders.

Interpretation of health-related quality of life outcomes in Parkinson's disease from the EARLYSTIM Study.

The EARLYSTIM Study compared deep brain stimulation (DBS) with best medical treatment (BMT) over 2-years, showing a between-group difference of 8.0 from baseline in favor of DBS in health-related quality of life (HRQoL), measured with the PDQ-39 SI (summary index). This study obtained complementary information about the importance of the change in HRQoL as measured by the PDQ-39, using anchor-based (Patient Global Impression of Change, PGIC) and distribution-based techniques (magnitude of change, effect size, thresholds, distribution of benefit) applied to the EARLYSTIM study data. Anchor-based techniques showed a difference follow-up-baseline for patients who reported "minimal improvement" of -5.8 [-9.9, -1.6] (mean [95%CI]) in the DBS group vs -2.9 [-9.0, 3.1] in the BMT group. As the vast majority (80.8%) of DBS patients reported "much or very much improvement", this difference was explored for the latter group and amounted to -8.7 for the DBS group and -6.5 in the BMT group. Distribution-based techniques that analyzed the relative change and treatment effect size showed a moderate benefit of the DBS on the HRQoL, whereas a slight worsening was observed in the BMT group. The change in the DBS group (-7.8) was higher than the MIC (Minimally Important Change) estimated value (-5.8 by the anchor; -6.3 by triangulation of thresholds), but not in the BMT (0.2 vs. -3.0 to -5.4, respectively). Almost 90% of the patients in the DBS group declared some improvement (58.3% and 56.7% beyond the estimated MIC), which was significantly different from the BMT group whose proportions were 32.0% and 30.3%, respectively. The number needed to treat to improve ≥1 MIC by DBS vs BMT was 3.8. Change in depression, disability and pain influenced the improvement of the DBS group. DBS improved HRQoL in a high proportion of patients to a significant and moderate degree, at 2 years follow-up.

Evolution of hippocampal CA-1 diffusion lesions in transient global amnesia.

OBJECTIVE: Selective focal MR-Signal (diffusion-) changes in the CA-1 sector of the hippocampus have been described in transient global amnesia (TGA), but the pathophysiological substrate of these lesions is largely unknown. As several imaging and epidemiological findings point to a vascular origin an analysis of the temporal evolution of the hippocampal apparent diffusion coefficient (ADC) changes may offer new understanding of the pathomechanisms of TGA. METHODS: The time course of the ADC of hippocampal DWI lesions in TGA patients was studied using serial 3 T high-resolution MR-imaging within 1-10 days as well as 4-6 months after TGA. ADC values from 76 MR-studies were analyzed and expressed as ratio ADC (rADC) in reference to the unaffected hemisphere. RESULTS: Twenty-nine patients with TGA showed 34 DWI lesions with corresponding T2 lesions in the CA-1 sector of the hippocampal cornu ammonis within a time window of 24-72 h after onset. Ratio ADC decreased below 1.0 (0.66 +/- 0.08) 24 h after the acute TGA episode and did show a further significant decrease to 0.57 +/- 0.1 after 3 days (p < 0.05). After 72 h, rADC increased and normalized around day 10 with rADC values of 1.0 (p < 0.05). INTERPRETATION: The temporal evolution of the rADC in hippocampal signal changes in TGA shows a time course previously described for ischemic lesions in human stroke patients. This might imply a vascular origin of diffusion changes leading to a transient perturbation of memory relevant circuits in the hippocampus.

Rating Scales for Pain in Parkinson's Disease: Critique and Recommendations.

BACKGROUND: We aimed at critically appraising the clinimetric properties of existing pain scales or questionnaires and to give recommendations for their use in Parkinson's disease (PD). METHODS: Clinimetric properties of pain scales used in PD were systematically evaluated. A scale was classified as 'recommended' if was used in PD, showed adequate clinimetric properties, and had been used by investigators other than the original developers; as 'suggested' if it was used in PD and fulfilled only one other criterion; and as 'listed' if it was used in PD but did not meet the other criteria. Only scales rating pain intensity or for syndromic classification were assessed. RESULTS: Eleven of the 34 scales initially considered fulfilled inclusion criteria. Among the scales rating pain intensity, the "Brief Pain Inventory short form," "McGill Pain Questionnaire short and long forms," "Neuropathic Pain Symptoms Inventory," "11-point Numeric Rating Scale," "10-cm Visual Analog Scale," and "Pain-O-Meter" were "recommended with caution" because of lack of clinimetric data in PD, whereas the "King's PD Pain Scale" was "recommended." Among scales for pain syndromic classification, the "DN4" was "recommended with caution" because of lack of clinimetric data in PD; the "Leeds Assessment of Neuropathic Symptoms and Signs," "Pain-DETECT," and the "King's PD Pain Scale" were "suggested." CONCLUSIONS: King's PD pain scale can be recommended for the assessment of pain intensity in PD. Syndromic classification of pain in PD may be achieved by the DN4, but clinimetric data in PD are needed for this scale.

Deep brain stimulation in late stage Parkinson's disease: a retrospective cost analysis in Germany.

During the last few years, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as a promising therapy, alleviating major motor symptoms of Parkinson's disease (PD). However, in times of growing budgetary limitations, medical decisions are no longer merely based on clinical efficacy, but also on cost-effectiveness. Here we assess treatment costs (i. e. costs for conservative pharmacological treatment and all in-patient admissions) of 46 PD patients for one year before and two years after STN-DBS. The present data show that total treatment costs were increased by 32% for the first year and decreased by 54% for the second year of STN-DBS in comparison with preoperative values while the Unified Parkinson's Disease Rating Scale (UPDRS III) was significantly improved. The increase for the first year after surgery was mainly due to the implantation of the STN electrodes and the stimulation device. Taken together, STNDBS pays off from the second year of stimulation while motor symptoms are significantly improved. The present study provides first data of an important number of patients on clinical effectiveness and expenses in relation to STNDBS.

ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia.

OBJECTIVE: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia. METHODS: A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used. RESULTS: Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene. CONCLUSIONS: We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype.

Tremor syndromes.

PURPOSE OF REVIEW: The purpose of this review is to explain a practical clinical approach to the diagnosis and management of tremor. RECENT FINDINGS: A number of rare but important causes of tremor have been delineated, which means that attention to detail in clinical assessment of patients with tremor is even more important. SUMMARY: Tremors are best divided into those occurring mainly at rest, mainly on posture, and mainly during action. This basic division leads directly to differential diagnosis and effective treatment.

Comparison of causality analysis on simultaneously measured fMRI and NIRS signals during motor tasks.

Brain activity can be measured using different modalities. Since most of the modalities tend to complement each other, it seems promising to measure them simultaneously. In to be presented research, the data recorded from Functional Magnetic Resonance Imaging (fMRI) and Near Infrared Spectroscopy (NIRS), simultaneously, are subjected to causality analysis using time-resolved partial directed coherence (tPDC). Time-resolved partial directed coherence uses the principle of state space modelling to estimate Multivariate Autoregressive (MVAR) coefficients. This method is useful to visualize both frequency and time dynamics of causality between the time series. Afterwards, causality results from different modalities are compared by estimating the Spearman correlation. In to be presented study, we used directionality vectors to analyze correlation, rather than actual signal vectors. Results show that causality analysis of the fMRI correlates more closely to causality results of oxy-NIRS as compared to deoxy-NIRS in case of a finger sequencing task. However, in case of simple finger tapping, no clear difference between oxy-fMRI and deoxy-fMRI correlation is identified.

Changing the research criteria for the diagnosis of Parkinson's disease: obstacles and opportunities.

Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.

Axonal integrity of corticospinal projections to the upper limbs in patients with pure hereditary spastic paraplegia.

OBJECTIVE: Patients with hereditary spastic paraplegia (HSP) show pathological findings when transcranial magnetic stimulation (TMS) is used to test corticospinal projections to the lower limbs. However, TMS studies on the pathways to the upper limbs revealed inconsistent results. Standard clinical TMS procedures are not well suited for testing axonal integrity, which is thought to be affected in HSP. More appropriate measures can be achieved by testing corticospinal projections with the triple stimulation technique (TST). METHODS: TST was used to test axonal integrity of corticospinal projections to the upper limbs in 15 patients with pure HSP (13 of whom were tested positive for SPG 4) and 15 healthy control subjects. RESULTS: TST measurements revealed normal values for corticospinal transmission in all 15 patients with pure HSP, as well as in all healthy control subjects. No differences between groups could be found. CONCLUSIONS: Axonal integrity of projections to the upper limbs is unimpaired in patients with pure HSP. The pathological mechanisms leading to spasticity and motor disability seem to be restricted to those fibres of the corticospinal pathways projecting to the lower limbs. SIGNIFICANCE: Abnormal corticospinal function to the upper limbs seems to be incompatible with pure HSP.