Akinetic-rigid Parkinson's Disease Research Articles

P.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

Genetics of Parkinson's disease heterogeneity: A genome-wide association study of clinical subtypes

IntroductionSubstantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes. MethodsA total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data. ResultsWe identified one genome-wide significant association (P < 5 × 10−8), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 × 10−8). Suggestive associations (P < 1 × 10−6) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 × 10−7), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 × 10−7), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 × 10−7), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 × 10−7), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 × 10−7). ConclusionOur findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation.

Introversion and Neuroticism in Akinetic-Rigid Parkinson's Disease: Association With Frontal-Executive Dysfunction.

Personality changes have often been reported among people with Parkinson's disease (PD); however, no studies have investigated the associations between personality traits, cognitive function, and specific motor symptoms. In this study, the investigators assessed whether particular personality traits were associated with specific motor subtypes of PD (e.g., tremor-dominant and akinetic-rigid phenotypes) and whether frontal-executive functions were associated with personality traits among patients with a specific motor phenotype. Forty-one people with PD and 40 healthy control participants were enrolled in the study. All participants underwent assessments of cognitive and psychological function and personality traits. The study was conducted in Italy. Tremor-dominant symptoms occurred among 20 (48.8%) people with PD, whereas 21 (51.2%) patients exhibited akinetic-rigid symptoms. Multivariate analyses of variance revealed that participants with akinetic-rigid PD demonstrated significantly poorer performance on frontal-executive tests compared with those with tremor-dominant PD. Moreover, those with akinetic-rigid PD exhibited more psychopathological symptoms and higher neuroticism and introversion compared with those with tremor-dominant PD. Correlations revealed that among participants with akinetic-rigid PD, psychopathological symptoms and neuroticism and introversion personality traits were associated with frontal-executive dysfunction, whereas among those with tremor-dominant PD, no significant associations were found between personality traits and cognitive abilities. These findings suggest that specific personality and frontal-executive profiles are associated with the akinetic-rigid motor subtype of PD, thus helping to refine the different clinical manifestations of PD. A better understanding of the psychological, personality, and cognitive mechanisms in PD could also help to develop more targeted treatments.

Unilateral pallidothalamic tractotomy for akinetic-rigid Parkinson's disease: a prospective open-label study.

Neurosurgical ablation is an effective treatment for medically refractory motor symptoms of Parkinson's disease (PD). A limited number of studies have reported the effect of ablation of the pallidothalamic tract for PD. In this study, the authors evaluated the safety and efficacy of unilateral pallidothalamic tractotomy for akinetic-rigid (AR)-PD. Fourteen AR-PD patients, who were enrolled in this prospective open-label study, underwent unilateral pallidothalamic tractotomy. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III and Part IV (dyskinesia and dystonia) scores and levodopa equivalent daily dose (LEDD) were evaluated at baseline and at 3 and 12 months postoperatively. Of the 14 patients enrolled in the study, 4 were lost to follow-up and 10 were analyzed. The total MDS-UPDRS Part III score significantly improved from 45 ± 4.6 at baseline to 32.9 ± 4.8 at 12 months postoperatively (p = 0.005). Contralateral side rigidity and bradykinesia significantly improved from 4.4 ± 0.5 and 10.4 ± 1.5 at baseline to 1.7 ± 0.4 (p = 0.005) and 5.2 ± 1.4 (p = 0.011) at 12 months, respectively. While posture significantly improved with a 20% reduction in scores (p = 0.038), no significant improvement was found in gait (p = 0.066). Dyskinesia and dystonia were improved with a 79.2% (p = 0.0012) and 91.7% (p = 0.041) reduction in scores, respectively. No significant change was found in the LEDD. Hypophonia was noted in 2 patients, eyelid apraxia was noted in 1 patient, and a reduced response to levodopa, which resulted in an increase in the daily dose of levodopa, was noted in 3 patients. No serious permanent neurological deficits were observed. Unilateral pallidothalamic tractotomy improved contralateral side rigidity and bradykinesia, dyskinesia, and dystonia in patients with AR-PD. Clinical trial registration no.: UMIN000031138 (umin.ac.jp).

Reader Response: Deep Brain Stimulation in Early-Stage Parkinson Disease: Five-Year Outcomes.

We have followed with great interest the pilot trial on subthalamic nucleus deep brain stimulation (DBS) for early-stage Parkinson disease (PD). The 5-year outcomes of this trial were just published by Hacker et al.1 The authors argue that DBS reduces the risk of disease progression based on a reduced rest tremor when these patients are compared with patients who were randomized to only optimized drug therapy (ODT). Barring rest tremor, this follow-up study did not show significant difference between the ODT and DBS + ODT groups for on-therapy motor scores and measures of disability and quality of life. Although tremor can be bothersome to patients with early-stage PD, bradykinesia is clearly the disabling feature.2 Interestingly, the DBS + ODT group performance in the timed tests at 5 years1 and off-therapy bradykinesia at 2 years3 were worse, although not significant. Besides, progressive neurodegeneration may lead to gradual abatement of tremor, and tremor-dominant PD often transforms to akinetic-rigid PD.4 We certainly agree that early DBS can reduce the need of medications and possibly abolish the risk of developing dyskinesias or hallucinations in the long term. Nonetheless, we would recommend caution when stating a “Class II evidence that DBS implanted in early-stage Parkinson disease decreases the risk of disease progression”. Although similar between-group adverse event profiles were reported, 2 of the 15 DBS + ODT patients had potentially disabling adverse events: a perioperative stroke and an intracranial infection.5 In our opinion, with several variables to factor in, it is premature—and possibly dangerous—to conclude that DBS in early-stage PD reduces the risk of disease progression.

Clinical features associated with drooling in Parkinson's disease.

Drooling is characterized by an excessive pooling of saliva in the oral cavity. The exact pathophysiological mechanism of drooling in Parkinson's disease (PD) is not yet fully understood. To identify the relationship between drooling and other clinical features in people diagnosed with PD. Research on the topic was carried out on the PubMed and ScienceDirect electronic databases. Articles published between March 2015 and March 2020 were selected. Search terms and inclusion and exclusion criteria were previously defined. The articles included met those requirements. Sixteen articles were included for analysis. The prevalence of drooling varies between 9.26 and 70% and can occur at any stage of the disease. Higher prevalence of drooling is related to disease duration, disease severity, older age, male, levodopa equivalent dose, hypomimia, dysphagia, dysarthria, cognition, sleep, non-dominant tremor, motor fluctuations, bradykinesia, more symmetric pattern, gastrointestinal and urinary problems, sexual dysfunction, obstipation, and orthostatic hypotension. However, it is not related to hallucinations, rapid eye movement sleep behavior disorder, akinetic-rigid PD, mixed, nor dyskinesias. Drooling is not caused by a single factor; it is influenced and related to several clinical features. Some clinical factors participate in the onset of drooling while others are concomitant.

Different functional connectivity modes of the right fronto-insular cortex in akinetic-rigid and tremor-dominant Parkinson's disease.

Patients with akinetic-rigid Parkinson's disease (AR-PD) are more prone to cognitive decline and depressive symptoms than tremor-dominant PD (TD-PD) patients. The right fronto-insular cortex (rFIC), as a key node of salience network, plays a critical role in the switching between central executive network and default mode network. In this study, we explored the functional connectivity mode of rFIC with triple-brain networks, namely default mode network, salience network, and central executive network, in two motor subtypes of PD. We recruited 44 PD patients (including the TD-PD group and AR-PD group) and 18 age-matched healthy controls (HCs). We performed functional connectivity (FC) analysis of resting-state functional MRI. Compared with TD-PD, decreased FC were found in the right insular cortex and bilateral anterior cingulate gyrus in AR-PD. Compared with HCs, decreased FC in the bilateral insula, the anterior cingulate gyrus, the precentral gyrus, and the right medial frontal gyrus were found; therein, the FC value of rFIC-precentral gyrus was positively correlated with the Unified Parkinson's Disease Rating Scale-II score in AR-PD (p = 0.0482, r = 0.4162). While TD-PD showed decreased FC in the left insula as well as bilateral anterior cingulate gyrus when compared with HCs, and the FC value of the rFIC-left insula was positively correlated with its Hamilton Depression Rating Scale score (p = 0.02, r = 0.50). The functional connectivity mode of rFIC in AR-PD differed from that in TD-PD. The decreased rFIC FC with the other nodes of salience network might be a potential indicator for AR-PD patients prone to develop cognitive decline and depressive symptoms.

Plasma catecholamine levels in the early stages of treatment-naïve Parkinson’s disease

Rationale: Parkinson's disease (PD) is a neurodegenerative disorder with predominant involvement of catecholamine-producing neurons of the central and peripheral nervous system. Taking into account the relative availability and low costs of plasma catecholamine measurements, it is worthwhile to study these parameters as biomarkers of the early stages of PD.Aim: To determinate whether plasma levels of dopamine (DA), norepinephrine (NE), L-3,4-dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) in patients with early stages of PD are related with akinetic-rigid and tremor-dominant variants and to compare the results to healthy volunteers.Materials and methods: This was an observational cross-sectional cohort study performed from 2012 to 2015. The main study group included unselected outpatients who attended the Republican Consultative and Diagnostic Center of Movement Disorders and Botulinotherapy (Kazan, Russia) with newly diagnosed early PD (Hoehn and Yahr stages I and II, 1967), of various ages and both genders, who had not been given any specific antiparkinsonian treatment. The control group included healthy volunteers with no clinical signs of PD (they could have other chronic diseases of the non-extrapyramidal origin). Plasma catecholamine levels were measured by gas liquid chromatography.Results: One hundred and thirty (130) treatment-naïve patients with newly diagnosed PD (mean age 59.34 ± 8.42 years, male gender 45.38%) were enrolled into the main study group. The control group included 56 healthy volunteers matched for age and gender. The distribution of various PD forms and stages was as follows: PD tremor-dominant variant 56.9%, PD akinetic-rigid variant 43.1%; PD stage I 76.9%, PD stage II 23.1%. Irrespective of the variant and stage, the PD patients demonstrated decreased NE levels, compared to the controls (95% confidence intervals 124–216 and 248–428 pg/mL, respectively, р &lt; 0.026). DOPA plasma level was reduced only in the patients with akinetic-rigid PD variant (р = 0.017), while DOPAC level in the patients with PD stage II (р = 0.008). The average DA:NE:DOPA:DOPAC ratio was 1:32:105:64 in the control group, 1:62:238:88 in the patients with PD tremor-dominant variant (the difference is significant for NE and DOPA, р &lt; 0.05), and 1:29:96:32 in those with PD akinetic-rigid variant (p &gt; 0.05). In the healthy controls the changes in DOPA levels account for 84% of the DA and NE variability; no correlation between DOPAC and other catecholamines was found. On the contrary, in the PD patients regardless of the stage and the disease variant, DOPAC levels directly correlated with DA (p &lt; 0.04). The PD tremor-dominant variant patients demonstrated a direct correlation between plasma NE and DOPA levels (p &lt; 0.05).Conclusion: The results obtained on absolute and relative parameters catecholamine turnover in the patients with early PD stages support the hypothesis on different pathophysiology of the tremor-dominant and akinetic-rigid variants of PD.

Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population.

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n= 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

Association of grey matter changes with stability and flexibility of prediction in akinetic-rigid Parkinson's disease.

Parkinson's disease (PD), which is caused by degeneration of dopaminergic neurons in the midbrain, results in a heterogeneous clinical picture including cognitive decline. Since the phasic signal of dopamine neurons is proposed to guide learning by signifying mismatches between subjects' expectations and external events, we here investigated whether akinetic-rigid PD patients without mild cognitive impairment exhibit difficulties in dealing with either relevant (requiring flexibility) or irrelevant (requiring stability) prediction errors. Following our previous study on flexibility and stability in prediction (Trempler et al. J Cogn Neurosci 29(2):298-309, 2017), we then assessed whether deficits would correspond with specific structural alterations in dopaminergic regions as well as in inferior frontal cortex, medial prefrontal cortex, and the hippocampus. Twenty-one healthy controls and twenty-one akinetic-rigid PD patients on and off medication performed a task which required to serially predict upcoming items. Switches between predictable sequences had to be indicated via button press, whereas sequence omissions had to be ignored. Independent of the disease, midbrain volume was related to a general response bias to unexpected events, whereas right putamen volume correlated with the ability to discriminate between relevant and irrelevant prediction errors. However, patients compared with healthy participants showed deficits in stabilisation against irrelevant prediction errors, associated with thickness of right inferior frontal gyrus and left medial prefrontal cortex. Flexible updating due to relevant prediction errors was also affected in patients compared with controls and associated with right hippocampus volume. Dopaminergic medication influenced behavioural performance across, but not within the patients. Our exploratory study warrants further research on deficient prediction error processing and its structural correlates as a core of cognitive symptoms occurring already in early stages of the disease.

Effects of progressive resistance exercise in akinetic-rigid Parkinson's disease patients: a randomized controlled trial.

Progressive resistance exercise (PRE) can have a positive effect in individuals with Parkinson's disease (PD). However, the effect of PRE may vary with the clinical subtype of PD. To date, no study has assessed the effects of PRE in the different subtypes of PD. The aim of the present study was to assess the effects of PRE in PD patients with akinesia and rigidity (AR-subtype). A randomized controlled trial was conducted. Outpatients clinics of the Bierzo Parkinson Association (Ponferrada, Spain) and the Asturias Parkinson Association (Oviedo, Spain). Twenty-eight patients with AR-subtype PD were randomized into an Experimental Group (EG, N.=13) and Control Group (CG, N.=15). Static posturography (Centre of Pressure -CoP- parameters), gait (the Ten-Meter Walk Test [TMWT]), freezing of gait (the Freezing of Gait Questionnaire [FOG-Q]), the motor portion of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and patient-perceived quality of life (the 39-item Parkinson's disease Questionnaire [PDQ39]), were assessed at pre-test, post-test, and re-test. Ratings of perceived exertion (RPE) (Borg >6-20 Scale) were recorded at the end of each PRE training session. The EG displayed significant ameliorations in Length (CoP parameters) from pre- to post-test (P=0.048), in speed of fast rhythm walking (TMWT) from pre- to post-test (P=0.000), and from pre- to re-test (P=0.027), and in the PDQ39 Score from pre- to post-test (P=0.024). No significant differences were detected in Area or Speed (CoP parameters), speed of preferred rhythm walking (TMWT), FOG-Q scores, or the motor portion of the MDS-UPDRS scores. The EG reported a mean RPE of 9.95 (between "very light" and "fairly light") for the whole training program. These findings provide support for the use of PRE training in the rehabilitation of individuals with AR-subtype PD, as it can improve static posturography, gait, and quality of life. Furthermore, RPE scores showed that individuals with AR-subtype PD consider that PRE training require only light efforts. The PRE training can be a helpful and fruitful rehabilitation tool for AR-subtype PD patients.

Speech changes induced by deep brain stimulation of the subthalamic nucleus in Parkinson disease: involvement of the dentatorubrothalamic tract

OBJECTIVE Patients with Parkinson disease (PD) who undergo subthalamic nucleus (STN) deep brain stimulation (DBS) often develop a deterioration in speech performance, but there is no clear consensus on the specific effects seen or the mechanism involved and little description of the impact of DBS on conversational speech. Furthermore, there has been no fiber tract connectivity analysis to identify the structures potentially modulated by DBS to cause such deficits. The main objective of this study was to quantify spontaneous speech performance and identify potential involvement of the dentatorubrothalamic tract (DRTt) in patients who underwent STN DBS, because this tract has been implicated in speech deterioration. METHODS Spontaneous speech samples were obtained with STN DBS in both on and off modes in 35 patients with PD and assessed across multiple domains. Diffusion tensor imaging tractography seeded from the therapeutic DBS contacts was performed to identify the fiber tracts involved and, specifically, the DRTt. The position of active electrode contacts was assessed relative to that of the STN. RESULTS Fifteen patients with akinetic-rigid (AR) PD and 20 with tremor-dominant (TD) PD subtypes were identified. In the AR-PD subgroup of patients, in whom there was DRTt involvement, 71% demonstrated much better overall speech and largely improved or unchanged fluency in the DBS-off condition. In patients with TD PD with DRTt involvement, 50% demonstrated better overall speech in the off condition, and equivocal results regarding improved or worsened fluency were found. When there was minimal DRTt involvement, 75% of patients with AR PD had better overall speech in the DBS-on condition and better or minimal fluency changes. Similarly, 83% of patients with TD PD with minimal DRTt involvement had better or minimal overall speech and fluency changes in the on condition. More medially placed left electrode contacts were associated with more DRTt involvement in 77% of patients (10 of 13). CONCLUSIONS To the authors' knowledge, this is the first study to have investigated a specific fiber tract involved in STN DBS in different subtypes of PD relative to its impact on spontaneous speech. At optimal therapeutic programming of STN DBS, overall spontaneous speech and fluency were affected more negatively in patients with AR PD than in those with TD PD when there was DRTt involvement. After fiber tract analysis and modeling, it was found that medially positioned left electrode contacts more often involved fibers of the DRTt. If possible, avoidance of the DRTt by using active electrode contacts that are positioned less medially, specifically in patients with AR PD, might result in less speech deterioration.

Subthalamic local field potentials in Parkinson's disease and isolated dystonia: An evaluation of potential biomarkers

Local field potentials (LFP) recorded from the subthalamic nucleus in patients with Parkinson's disease (PD) demonstrate prominent oscillations in the beta (13–30Hz) frequency range, and reduction of beta band spectral power by levodopa and deep brain stimulation (DBS) is correlated with motor symptom improvement. Several features of beta activity have been theorized to be specific biomarkers of the parkinsonian state, though these have rarely been studied in non-parkinsonian conditions. To compare resting state LFP features in PD and isolated dystonia and evaluate disease-specific biomarkers, we recorded subthalamic LFPs from 28 akinetic-rigid PD and 12 isolated dystonia patients during awake DBS implantation. Spectral power and phase-amplitude coupling characteristics were analyzed. In 26/28 PD and 11/12 isolated dystonia patients, the LFP power spectrum had a peak in the beta frequency range, with similar amplitudes between groups. Resting state power did not differ between groups in the theta (5–8Hz), alpha (8–12Hz), beta (13–30Hz), broadband gamma (50–200Hz), or high frequency oscillation (HFO, 250–350Hz) bands. Analysis of phase-amplitude coupling between low frequency phase and HFO amplitude revealed significant interactions in 19/28 PD and 6/12 dystonia recordings without significant differences in maximal coupling or preferred phase. Two features of subthalamic LFPs that have been proposed as specific parkinsonian biomarkers, beta power and coupling of beta phase to HFO amplitude, were also present in isolated dystonia, including focal dystonias. This casts doubt on the utility of these metrics as disease-specific diagnostic biomarkers.

Decreased interhemispheric functional connectivity in subtypes of Parkinson's disease.

Parkinson's disease (PD) can be classified into tremor-dominant (TD) subtype and akinetic-rigid (AR) subtype, which exhibit different clinical courses and prognoses. However, the neural mechanisms underlying different subtypes of PD are not well understood. Using voxel-mirrored homotopic connectivity (VMHC), we examined the homotopic resting-state functional connectivity patterns in akinetic-rigid PD (AR-PD) and tremor-dominant PD (TD-PD) to study the neural basis for these disparate manifestations of PD. Twenty-one TD-PD patients, 29 AR-PD patients and 26 normal control subjects participated in this study. Resting-state fMRI data were analyzed using VMHC. Correlations between VMHC values and each clinical characteristic were also calculated. Compared with normal control subjects and subjects with AR-PD, subjects with TD-PD exhibited significantly lower VMHC values in the posterior lobe of the cerebellum. Moreover, tremor scores and VMHC values for the cerebellum were found to be significantly negatively correlated in TD-PD patients. By contrast, subjects with AR-PD exhibited lower VMHC values in the precentral gyrus compared with normal control subjects. These findings suggest that functional coordination between homotopic brain regions is impaired in AR-PD and TD-PD patients. This study provides evidence of both cerebellum-related connectivity deficits in TD-PD. The finding that VMHC values and tremor scores were significantly correlated suggests that VMHC measurements may be of potential clinical relevance in TD-PD.

Parkinson's disease subtypes show a specific link between dopaminergic and glucose metabolism in the striatum.

BackgroundPrevious studies have shown different clinical and imaging pattern in tremordominant and akinetic-rigid Parkinson’s disease (PD) subtypes. The association between dopaminergic and glucose metabolism has in contrast not been investigated yet. Therefore, this study compared PD subtypes with respect to clinical and imaging findings with the aim of establishing a relationship between clinical subtypes, dopamine and glucose metabolism.MethodsTwo groups of a total of 64 idiopathic PD patients (42 male, 22 female, mean age 56±10.9 years) were analysed: akinetic-rigid (AR, n = 32) and tremor-dominant (TD, n = 32) patients. Both were compared with respect to differential involvement of local striatal dopamine and glucose metabolism using [18F]-fluoro-L-dopa (F-dopa) and [18F]-fluorodeoxyglucose (FDG)-PET.ResultsThe analysis of PD subgroups showed significant differences in the F-dopa uptake in the anterior putamen. Using the results of the local striatal dopamine difference as a volume of interest for the FDG-analysis, analysis of AR patients revealed a significantly lower normalised cerebral metabolic rate of glucose (nCMRGlc) within the ventral striatum.ConclusionsThe dual tracer study illlustrates clear differences between TD and AR subtypes in the ventral striatum. In accordance with previous FP-CIT-SPECT studies, it discloses congruent results for the presynaptic dopaminergic system and extends the knowledge about an additional involvement of local metabolic activity in the caudate and anterior putamen. The findings corroborate the specific role of distinct PD subtypes within the cerebello-thalamo-cortical-circuits. Multitracer PET imaging may thus enhance the knowledge about the clinical segregation into subtypes.

Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD

The underlying pathophysiology of tremor in Parkinson disease (PD) is unclear; however, it is known that tremor does not appear to be as responsive to dopaminergic medication as bradykinesia or rigidity. It is suggested that serotonergic dysfunction could have a role in tremor development. Using (11)C-DASB PET, a marker of serotonin transporter binding, and clinical observations, we have investigated function of serotonergic terminals in 12 patients with tremor-predominant and 12 with akinetic-rigid PD. Findings were compared with those of 12 healthy controls. Reductions of (11)C-DASB in caudate, putamen, and raphe nuclei significantly correlated with tremor severity on posture and action, but not with resting tremor. The tremor-predominant group also showed reductions of (11)C-DASB in other regions involved in motor circuitry, including the thalamus and Brodmann areas 4 and 10. Our findings support a role for serotonergic dysfunction in motor circuitries in the generation of postural tremor in PD.

Accuracy of subjective and objective handwriting assessment for differentiating Parkinson’s disease from tremulous subjects without evidence of dopaminergic deficits (SWEDDs): an FP-CIT-validated study

Handwriting examinations are commonly performed in the analysis of tremor and Parkinson's disease (PD). We analyzed the accuracy of subjective and objective assessment of handwriting samples for distinguishing 27 PD cases, 22 with tremulous PD, and five with akinetic-rigid PD, from 39 movement-disorder patients with normal presynaptic dopamine imaging (subjects without evidence of dopamine deficiency or SWEDDs; 31 with dystonic tremor (DT), six indeterminate tremor syndrome, one essential tremor, one vascular parkinsonism). All handwriting analysis was performed blind to clinical details. Subjective classification was made as: (1) micrographia, (2) normal, or (3) macrographia. In addition, a range of objective metrices were measured on standardized handwriting specimens. Subjective assessments found micrographia more frequently in PD than SWEDDs (p = 0.0352) and in akinetic-rigid than tremulous PD (p = 0.0259). Macrographia was predominantly seen in patients with dystonic tremor and not other diagnoses (p = 0.007). Micrographia had a mean sensitivity of 55 % and specificity of 84 % for distinguishing PD from SWEDDs and mean sensitivity of 90 % and specificity of 55 % for distinguishing akinetic-rigid PD from tremulous PD. Macrographia had a sensitivity of 26 % and specificity of 96 % for distinguishing DT from all other diagnoses. The best of the objective metrices increased sensitivity for the distinction of SWEDDs from PD with a reduction in specificity. We conclude that micrographia is more indicative of PD than SWEDDs and more characteristic of akinetic-rigid than tremulous PD. In addition, macrographia strongly suggests a diagnosis of dystonic tremor.

Subtype-specific statistical causalities in parkinsonian tremor

Tremor is one of the cardinal symptoms of Parkinson's disease. Up to now, however, its pathophysiology remains poorly understood. Previously, oscillatory coupling at tremor frequency between the subthalamic nucleus und affected muscles was shown. In these studies, however, causality of coupling could not be demonstrated. Thus, we analyzed the statistical causality between intraoperatively recorded local field potentials in the subthalamic area and affected arm muscles during tremor episodes, using squared partial directed coherence, a recently developed causality measure. The analysis identified differential statistical causality patterns for Parkinson's disease patients of the akinetic-rigid subtype during tremor episodes (n=6) versus patients of the tremor-dominant subtype (n=8): for the akinetic-rigid Parkinson's disease patients significantly more cases of the subthalamic region were found to be statistically causal for electromyographic-tremor activity, a result in accordance with the standard basal ganglia model. In contrast, for the tremor-dominant patients, significantly more instances of electromyographic tremor activity turned out to be causal for activity of the subthalamic region. Furthermore, the clinical effective stimulation site coincided with the location of most input causalities from the periphery in seven out of eight tremor-dominant patients. The data suggest that, although tremor activity in tremor-dominant and akinetic-rigid Parkinson's disease patients was clinically similar, statistical causality between tremor electromyogram (EMG) and the subthalamic nucleus was fundamentally different. Therefore, we hypothesize different pathophysiological mechanisms to underlie the generation of tremor in the two subtypes of Parkinson's disease.

117 Diagnostic FP-CIT SPECT and clinical progression in Parkinson's disease

BackgroundFunctional imaging of striatal dopamine transporters (DaT) is abnormal at presentation in Parkinson's disease (PD). While there is a cross-sectional relationship between the severity of bradykinesia and rigidity, and the...

Quantitative Bewegungsanalyse der Rumpfmotorik von Parkinsonpatienten mittels dreidimensionaler Kinematik und Oberflächenelektromyografie

Hintergrund Im Krankheitsverlauf der Parkinsonerkrankung (PD) werden axiale Defizite als Ausdruck einer reduzierten Rumpfmotorik prominent. Obwohl die Rumpfmotorikstörung progressiv verläuft und die tägliche Aktivität der Patienten beeinträchtigt wird, ist die quantitative Beurteilung noch nicht standardisiert und üblich. Methode Wir verglichen die Rumpfmotorik im 3-dimensionalen Raum mit synchroner Oberflächenelektromyografie (oEMG) von 19 PD-Patienten vom akinetisch-rigiden Subtyp (Hoehn & Yahr: 2–3, UPDRS motor score: 25,5 ± 10,7 in „on” Phase) mit einer altersgemachten Kontrollgruppe. Ergebnisse Die Rumpfbeweglichkeit (Range of Motion) war in frontaler, sagittaler und transversaler Ebene in der PD-Gruppe signifikant reduziert (Mittelwerte für alle Bewegungsrichtungen p < 0,001) mit jeweils signifikant erhöhter Bewegungsvariabilität (p < 0,001) bei reduzierter muskulärer Aktivität (oEMG). Die kinematischen Daten korrelierten nicht mit der täglichen L-Dopa-Dosis in mg. Schlussfolgerung Die 3-dimensionale Rumpfkinematik und die analoge Oberflächenelektromyografie ermöglichen den Klinikern und Therapeuten eine quantitative und objektive Beurteilung der Rumpfmotorik bei PD-Patienten. Der fehlende Einfluss von L-Dopa auf die Rumpfkinematik zeigt die unabhängige Kontrolle des axialen Tonus gegenüber des Extremitätentonus.