Automatic and objective assessment of alternating tapping performance in Parkinson’s disease

This paper presents the development and evaluation of a method for enabling quantitative and automatic scoring of alternating tapping performance of patients with Parkinson’s disease (PD). Ten healthy elderly subjects and 95 patients in different clinical stages of PD have utilized a touch-pad handheld computer to perform alternate tapping tests in their home environments. First, a neurologist used a web-based system to visually assess impairments in four tapping dimensions (‘speed’, ‘accuracy’, ‘fatigue’ and ‘arrhythmia’) and a global tapping severity (GTS). Second, tapping signals were processed with time series analysis and statistical methods to derive 24 quantitative parameters. Third, principal component analysis was used to reduce the dimensions of these parameters and to obtain scores for the four dimensions. Finally, a logistic regression classifier was trained using a 10-fold stratified cross-validation to map the reduced parameters to the corresponding visually assessed GTS scores. Results showed that the computed scores correlated well to visually assessed scores and were significantly different across Unified Parkinson’s Disease Rating Scale scores of upper limb motor performance. In addition, they had good internal consistency, had good ability to discriminate between healthy elderly and patients in different disease stages, had good sensitivity to treatment interventions and could reflect the natural disease progression over time. In conclusion, the automatic method can be useful to objectively assess the tapping performance of PD patients and can be included in telemedicine tools for remote monitoring of tapping.

Long duration exercise program in individuals with parkinson´s disease: effects on functional capacity

The aim of this study was to investigate the effects of long duration exercise program on physical fitness components of functional capacity in individuals with Parkinson disease (PD) and to evaluate ongoing effects of exercise after 8 to 10-week follow-up without exercise. Twenty-four individuals with PD were randomly assigned to two groups: generalized exercise program and stretching exercise program (control group). The generalized exercise program provided training in physical fitness components of functional capacity. The stretching exercise program was characterized by low intensity and volume, mainly with static exercises. Both groups were evaluated before (BI) and after the 4-month (AI) exercise program. In addition, the individuals of generalized exercise program were also evaluated after 8-month exercise program and after 8 to 10- week follow-up without exercise. The generalized exercise program improved flexibility (BI - 38.50±12.42 cm; AI - 44.00±12.74 cm) and agility (BI - 30.59±7.54 s; AI - 28.56±8.20 s) while the stretching exercise program worsened coordination (BI - 23.27±6.58 s; AI - 28.06±7.37 s) and aerobic resistance (BI- 13.64±3.76 min; AI - 17.27±5.15 min) and improved balance (BI - 44.00±7.79 pts; AI - 46.57±6.53 pts). Lower-limb strength and UPDRS-motor scale scores were better at 8 months (14.75±2.92 rep and 26.25±13.97 pts, respectively) compared to baseline (13.13±2.59 rep and 31.63±12.82 pts, respectively) and 4 months (13.50±1.93 rep and 30.38±14.52 pts, respectively) for generalized exercise program. However, the benefits of 8 months of exercise were lost after 8 to 10-week follow-up without exercise (lower-limb strength - 12.43±3.15 rep and UPDRS-motor scale - 32.57±14.05 pts). In conclusion, generalized exercise program improved the functional capacity in individuals with PD, differently of stretching exercise program. In addition, a long duration exercise program promoted benefits for functional capacity and disease progression in individuals with PD. However, benefits were lost after a short period without exercise.

Classification of handwriting patterns in patients with Parkinson´s disease, using a biometric sensor

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Visual conditions and postural directions affect postural sway variability in patients with Parkinson’s disease

Postural sway variability was evaluated in Parkinson’s disease (PD) patients at different stages of disease. Twenty PD patients were grouped into two groups (unilateral, 14; bilateral, 6) according to disease severity. The results showed no significant differences in postural sway variability between the groups (p ≥ 0.05). Postural sway variability was higher in the antero-posterior direction and with the eyes closed. Significant differences between the unilateral and bilateral groups were observed in clinical tests (UPDRS, Berg Balance Scale, and retropulsion test; p ≤ 0.05, all). Postural sway variability was unaffected by disease severity, indicating that neurological mechanisms for postural control still function at advanced stages of disease. Postural sway instability appears to occur in the antero-posterior direction to compensate for the stooped posture. The eyes-closed condition during upright stance appears to be challenging for PD patients because of the associated sensory integration deficit. Finally, objective measures such as postural sway variability may be more reliable than clinical tests to evaluate changes in balance control in PD patients.

Multimodal (EEG-fMRI) functional connectivity study of levodopa effect in Parkinson’s disease

Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa.

Motor control system in Parkinson’s disease: a modeling approach

Parkinson’s disease is a neurodegenerative disorder due to the death of the dopaminergic neurons of the substantia nigra of the basal ganglia. The process that leads to these neural alterations is still unknown. Parkinson’s disease affects most of all the motor sphere, with a wide array of impairment such as bradykinesia, akinesia, tremor, postural instability and singular phenomena such as freezing of gait. Moreover, in the last few years the fact that the degeneration in the basal ganglia circuitry induces not only motor but also cognitive alterations, not necessarily implicating dementia, and that dopamine loss induces also further implications due to dopamine-driven synaptic plasticity got more attention. At the present moment, no neuroprotective treatment is available, and even if dopamine-replacement therapies as well as electrical deep brain stimulation are able to improve the life conditions of the patients, they often present side effects on the long term, and cannot recover the neural loss, which instead continues to advance. In the present thesis both motor and cognitive aspects of Parkinson’s disease and basal ganglia circuitry were investigated, at first focusing on Parkinson’s disease sensory and balance issues by means of a new instrumented method based on inertial sensor to provide further information about postural control and postural strategies used to attain balance, then applying this newly developed approach to assess balance control in mild and severe patients, both ON and OFF levodopa replacement. Given the inability of levodopa to recover balance issues and the new physiological findings than underline the importance in Parkinson’s disease of non-dopaminergic neurotransmitters, it was therefore developed an original computational model focusing on acetylcholine, the most promising neurotransmitter according to physiology, and its role in synaptic plasticity. The rationale of this thesis is that a multidisciplinary approach could gain insight into Parkinson’s disease features still unresolved.

Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study

BACKGROUND Inflammatory bowel diseases (IBD) are systemic conditions that commonly display extraintestinal manifestations. Inflammatory articular disease (IAD: axial or peripheral) is the most common extraintestinal manifestation. The aim of this study was to evaluate the prevalence and the clinical characteristics associated with IAD in patients with IBD. METHODS We analyzed patients enrolled in the Swiss IBD cohort study. IAD was defined as persistent or recurrent joint pain with an inflammatory pattern (night pain, progressive relief during the day, morning stiffness lasting at least 30 minutes) or the presence of arthritis as diagnosed by the physicians. A multivariate logistic regression was performed to analyze which disease characteristics were independently associated with the presence of IAD. RESULTS A total of 2353 patients with IBD, 1359 with Crohn's disease, and 994 with ulcerative colitis (UC) were included. Forty-four percent of patients fulfilled the criteria for IAD, whereas 14.5% presented with other extraintestinal manifestations. IAD was associated with Crohn's disease, with female sex, with older age, and generally in patients with more active intestinal disease. Only in UC, IAD was further associated with tobacco smoking and with increasing body mass index. CONCLUSIONS This population of patients with IBD displays a high prevalence of IAD. IAD was more strongly associated with Crohn's disease than UC. Other risk factors for IAD were female sex, advanced age, active digestive disease, and tobacco consumption in patients with UC, which is interesting given the established association between smoking and other inflammatory arthritides.

Effects of subthalamic nucleus stimulation on cognition and mood in Parkinson’s disease (PD)

Objective: To assess the neuropsychological outcome as a safety measure and quality control in patients with subthalamic nucleus (STN) stimulation for PD. Background: Deep brain stimulation (DBS) is considered a relatively safe treatment used in patients with movement disorders. However, neuropsychological alterations have been reported in patients with STN DBS for PD. Cognition and mood are important determinants of quality of life in PD patients and must be assessed for safety control. Methods: Seventeen consecutive patients (8 women) who underwent STN DBS for PD have been assessed before and 4 months after surgery. Besides motor symptoms (UPDRS-III), mood (Beck Depression Inventory, Hamilton Depression Rating Scale) and neuropsychological aspects, mainly executive functions, have been assessed (mini mental state examination, semantic and phonematic verbal fluency, go-no go test, stroop test, trail making test, tests of alertness and attention, digit span, wordlist learning, praxia, Boston naming test, figure drawing, visual perception). Paired t-tests were used for comparisons before and after surgery. Results: Patients were 61.6±7.8 years old at baseline assessment. All surgeries were performed without major adverse events. Motor symptoms ‘‘on’’ medication remained stable whereas they improved in the ‘‘off’’ condition (p<0.001). Mood was not depressed before surgery and remained unchanged at follow-up. All neuropsychological assessment outcome measures remained stable at follow-up with the exception of semantic verbal fluency and wordlist learning. Semantic verbal fluency decreased by 21±16% (p<0.001) and there was a trend to worse phonematic verbal fluency after surgery (p=0.06). Recall of a list of 10 words was worse after surgery only for the third attempt of recall (13%, p<0.005). Conclusions: Verbal fluency decreased in our patients after STN DBS, as previously reported. The procedure was otherwise safe and did not lead to deterioration of mood.

Co-morbidity burden in Parkinson’s disease : Comparison with controls and its influence on prognosis

Open Access funded by Parkinson's UK Financial support: This study was funded by Parkinson’s UK, the Scottish Chief Scientist Office, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The funders had no involvement in the study. We acknowledge funding for the PINE study from Parkinson’s UK (G-0502, G-0914 G-1302), the Scottish Chief Scientist Office (CAF/12/05), the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, NHS Grampian endowments and SPRING. We thank the patients and controls for their participation and the research staff who collected data and supported the study database.

Potential Benefit of Singing for People with Parkinson’s Disease : A Systematic Review

Acknowledgements including sources of support This study was not supported by any particular grant or funding source. The senior author MSB, an epidemiologist with research experience in PD, wishes to thank clinician authors JB, RAA and SMB for their invaluable contributions. JB is a retired health professional with long-standing experience in community health. RAA and SMB are qualified and practising speech and language therapists and RAA specialises in adult neurological disorders. Additionally, we thank Dr Katherine Deane of the University of East Anglia for expert input regarding the Threats to Validity quality tool, on which she was the lead developer.

α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson’s disease in rats

A recombinant adeno-associated virus (rAAV) vector capable of infecting cells and expressing rat glial cell line-derived neurotrophic factor (rGDNF), a putative central nervous system dopaminergic survival factor, under the control of a potent cytomegalovirus (CMV) immediate/early promoter (AAV-MD-rGDNF) was constructed. Two experiments were performed to evaluate the time course of expression of rAAV-mediated GDNF protein expression and to test the vector in an animal model of Parkinson’s disease. To evaluate the ability of rAAV-rGDNF to protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6-hydroxydopamine (6-OHDA) lesion model, rats received perinigral injections of either rAAV-rGDNF virus or rAAV-lacZ control virus 3 weeks prior to a striatal 6-OHDA lesion and were sacrificed 4 weeks after 6-OHDA. Cell counts of back-labeled fluorogold-positive neurons in the substantia nigra revealed that rAAV-MD-rGDNF protected a significant number of cells when compared with cell counts of rAAV-CMV-lacZ-injected rats (94% vs. 51%, respectively). In close agreement, 85% of tyrosine hydroxylase-positive cells remained in the nigral rAAV-MD-rGDNF group vs. only 49% in the lacZ group. A separate group of rats were given identical perinigral virus injections and were sacrificed at 3 and 10 weeks after surgery. Nigral GDNF protein expression remained relatively stable over the 10 weeks investigated. These data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson’s disease.