Apathy in patients with Parkinson’s disease

Apathy is a common feature of basal ganglia disorders such as Parkinson's disease (PD), yet it is often 'invisible' to the clinician, patient and family. Factors responsible for the lack of recognition of apathy include confusion between the presence of depression and apathy and the overlap of symptoms of apathy with the phenomenology of PD. Raising awareness of apathy in PD is important because apathy contributes to PD-related disability and has an important impact on quality of life. The neurotransmitter dopamine is central to normal motivational behavior. Therefore, PD, a disorder of primary dopamine deficiency, is an ideal model for the study of apathy and its management.     

Heatstroke in patients with Parkinson’s disease

We present two Parkinson's disease (PD) patients, who experienced heatstroke. Both patients manifested central nervous system dysfunction with elevated core temperature. Despite adequate lowering of the body temperature, multiorgan-dysfunction syndrome including encephalopathy, rhabdomyolysis, acute renal failure, acute respiratory failure, and disseminated intravascular coagulopathy was noted in one patient, leading to permanent neurologic damage. Because the ensuing multiorgan dysfunction could determine the functional prognosis in heatstroke patients, it is important to provide information about the prevention of heatstroke to patients, who are isolated or are severely disabled in the advanced stages of PD.     

Development of Parkinson’s disease in patients with Narcolepsy

Although amphetamine drugs can damage dopaminergic axons, it is unknown whether chronic treatment with amphetamine increases the risk of developing Parkinson's disease (PD). Of 1,152 consecutive PD patients, 3 had a prior diagnosis of narcolepsy. This rate is five times higher than expected (p = 0.02). These patients had typical onset of narcolepsy and underwent treatment with amphetamine. Although preliminary, this observation raises the possibility that some factors intrinsic to narcolepsy or its treatment may be a risk factor for PD.     

Mechanisms of unilateral STN-DBS in patients with Parkinson’s disease

Bilateral symptoms and signs of Parkinson’s disease (PD) are often improved by unilateral subthalamic nucleus deep brain stimulation (STN-DBS). However, the mechanism for such bilateral effects is unknown. This study was intended to examine effects of unilateral STN-DBS using positron emission computed tomography (PET) and to elucidate mechanisms for bilateral improvement achieved by unilateral stimulation. We conducted ¹⁸F-fluorodeoxyglucose (¹⁸FDG) and ¹⁸F-fluorodopa (¹⁸F-DOPA ) PET scans in PD patients whose bilateral limb symptoms and axial symptoms were improved by unilateral DBS. Two scans were performed in each PET study: when DBS was on and off. We compared those images using statistic parametric mapping (SPM) 99. The significant clinical improvement obtained by unilateral DBS was shown as improvements in bilateral motor limb, axial, and gait subscores of the Unified PD Rating Scale (UPDRS). Moreover, ¹⁸FDG PET revealed significant metabolic increases in the ipsilateral ventrolateral thalamic areas and metabolic decrease at the contralateral globus pallidus interna (GPi). In contrast, ¹⁸F-DOPA PET showed no significant differences between DBS on and off. Ipsilateral thalamic activation might induce ipsilateral motor cortical activation, which explains the improvement of contralateral limb symptoms. Furthermore, deactivation of the contralateral GPi might disinhibit the thalamus and contralateral motor cortex, which explains reduction of ipsilateral limb symptoms. These results suggest the mechanisms for bilateral improvement achieved by unilateral DBS.     

Pain perception in patients with Parkinson’s disease

Abnormalities in pain perception are a part of the clinical picture in Parkinson’s disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group [EG]) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS [ncVAS] and a color VAS [cVAS]) immediately after the stimulus (EG – ncVAS 1 and cVAS 1; CG – ncVAS 3 and cVAS 3) and 24 hours later (EG – ncVAS 2 and cVAS 2; CG – ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS (p < 0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients.     

Cerebral microbleeds in patients with Parkinson’s disease

Cerebral microbleeds (CMBs) are known to be associated with cognitive impairments in the elderly and in patients with various diseases; however, the nature of this association has not yet been evaluated in Parkinson’s disease (PD). In the present study, we analyzed the incidence of CMBs in PD according to cognitive status, and the impact of CMBs on cognitive performance was also evaluated. The CMBs in PD with dementia (n = 36), mild cognitive impairment (MCI, n = 46), or cognitively normal (n = 41) were analyzed using conventional T2*-weighted gradient-recalled echo images. Additionally, the relationship between the presence of CMBs and cognitive performance on individual tests of cognitive subdomains was analyzed using a detailed neuropsychological test. CMBs occurred more frequently in PD patients with dementia (36.1 %) compared to those with MCI (15.2 %), those who are cognitively normal (14.6 %), and normal controls (12.2 %, p = 0.025). However, the significant association of CMBs with PD dementia disappeared after adjusting white matter hyperintensities (WMHs) as a covariate. The frequencies of deep, lobar, and infratentorial CMBs did not differ among the four groups. After adjusting for age, sex, years of education, and WMHs, PD patients with CMBs had poorer performance in attention domain compared with those without CMBs (34.9 vs 42.6, p = 0.018). The present data demonstrate that even though CMBs were inseparably associated with the presence of WMHs, CMBs occur more commonly in PD patients with dementia than in those without dementia. Additionally, the burden of CMBs may contribute to further cognitive impairment in PD.     

Selection of gait parameters for differential diagnostics of patients with de novo Parkinson’s disease

Background: Gait disturbances are an integral part of clinical manifestations of Parkinson’s disease (PD), even in the initial stages of the disease. Our goal was to identify the set of spatio-temporal gait parameters that bear the highest relevance for characterizing de novo PD patients.

Methods: Forty patients with de novo PD and forty healthy controls were recorded while walking over an electronic walkway in three different conditions: (1) base walking, (2) walking with an additional motor task, (3) walking with an additional mental task. Both groups were well balanced concerning age and gender. To select a smaller number of relevant parameters, affinity propagation clustering was applied on parameter pairwise correlation. The exemplars were then sorted by importance using the random forest algorithm. Classification accuracy of a support vector machine was tested using the selected parameters and compared to the accuracy of the model using a set of parameters derived from literature.

Results: Final selection of parameters included: stride length and stride length coefficient of variation (CV), stride time and stride time CV, swing time and swing time CV, step time asymmetry, and heel-to-heel base support CV. Classification performed using these parameters showed higher overall accuracy (85%) than classification using the common parameter set containing: stride time, stride length, swing time and double support time, along with their CVs (78%).

Conclusion: In early stages of PD, double support time and its CV appear to be weak indicators of the disease. We instead found step time asymmetry and support base CV to significantly contribute to classification accuracy.     

Motor learning of hands with auditory cue in patients with Parkinson’s disease

Summary. In the present research, changes in motor cortex function were observed in relation to repetitive, voluntary thumb movement (training) in patients with Parkinson’s disease (PD) and normal control subjects. Changes in the direction of thumb movement due to motor evoked potential (MEP) by transcranial magnetic stimulation (TMS), after motor training with and without rhythmic sound, were measured using a strain gauge for 12 patients with PD and 9 normal control subjects. PD patients who experienced the freezing phenomena showed poor change in direction of TMS-induced movement after self-paced movement; however, marked change in direction of TMS-induced movement was observed after training with auditory cue. PD patients who had not experienced the freezing phenomena showed positive effects with the auditory cue, producing similar results as the normal control subjects. Two routes for voluntary movement are available in the nervous system. The decreased function of basal ganglia due to PD impaired the route from the basal ganglia to the supplementary motor cortex. These data suggest that the route from sensory input to cerebellum to premotor cortex could compensate for the decreased function of the route via the basal ganglia to the premotor cortex. Once change in the motor cortex occurred, such change persisted even after the interruption of training. These phenomena suggest that motor memory can be stored in the motor cortex.     

The progression of pathology in longitudinally followed patients with Parkinson’s disease

The present study describes the pathological progression of longitudinally followed cases with levodopa-responsive Parkinson’s disease who came to autopsy during the Sydney Multicenter Study of Parkinson’s disease. Standardised clinical and neuropathological assessments over five epochs of time verified three different clinicopathological groups. A group of younger onset patients with a typical long duration clinical course of Parkinson’s disease. This group of cases had Lewy body distributions consistent with the Braak staging of disease. In this group, brainstem Lewy bodies dominate in those surviving to 5 years; by 13 years, 50% of cases have a limbic distribution of Lewy bodies; and by 18 years, all will have at least this pathological phenotype. Approximately 25% of cases had an early malignant, dementia-dominant syndrome and severe neocortical disease consistent with dementia with Lewy bodies. The last group had an older onset, shorter survival, and a more complex disease course with higher Lewy body loads and a higher proportion with additional neuropathologies. These cases with higher loads of Lewy bodies and shorter survivals suggest that widespread Lewy body pathology either occurs at the onset of clinical disease or rapidly infiltrates the brain. In these cases with shorter survivals, there was more plaque pathology, supporting a more aggressive and linked phenotype. Our data suggest that the selection of similar study cohorts by pathology alone would not be able to differentiate the three different phenotypes identified. The data are also not consistent with a unitary concept of the pathogenesis of Lewy body disease.     

Characteristics of apathy in treatment-naïve patients with Parkinson’s disease

Introduction: Although apathy is a common psychiatric symptom of Parkinson’s disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD. Methods: Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups—apathetic or non-apathetic—based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters. Results: Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p?<?.004]; modified Hoehn & Yahr stage [p?=?.039]; Unified Parkinson’s Disease Rating Scale part III [p?<?.001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales. Conclusion: Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.     

Oxidative and nitrosative stress in serum of patients with Parkinson’s disease

Parkinson’s disease (PD) is one of the common neurodegenerative disorders. Oxidative stress is considered as a contributing factor to the development of PD. The present study aims to investigate serum oxidative stress status in patients with PD. Oxidative stress was assessed by measuring serum nitric oxide levels, lipid hydroperoxide concentrations, and nitric oxide synthase activity. In addition, total serum antioxidant capacity (TAC) was evaluated using the serum 2,2-Diphenyl-1-picryl-hydrazyl (DPPH) free-radical scavenging method in 32 patient with Parkinson’s disease and 32 control subjects. Our results indicated that serum nitric oxide and lipid hydroperoxide levels were significantly lower in patients with PD than controls. Moreover, nitric oxide levels were found to be negatively correlated with Unified Parkinson’s Disease Rating Scale (UPDRS). However, no statistical difference was observed in total serum antioxidant capacities and nitric oxide synthase activities between patients and controls. The present study indicates that although antioxidant capacity was not changed, lipid hydroperoxide (LPO) level was found decreased. This might show pre-oxidative process in these patients. In addition, decreased nitric oxide (NO) level and negative correlation observed between NO level and disease rating scale implicated a role for NO in the disease process.     

Family history of hand tremor in patients with early Parkinson’s disease

Some patients with Parkinson’s disease (PD) report hand tremors in their relatives. This study aimed to compare the clinical characteristics of early PD in patients with and without a family history of hand tremor. This study included 337 early and drug-naïve patients with PD. The family history of hand tremor was obtained from the patients and their caregivers. Motor and non-motor symptoms of PD were assessed using the appropriate scales. A family history of hand tremor was present in 27 of 337 patients with PD (8.0%). Patients with a family history of hand tremor had significantly higher scores for rest tremors than those without. No significant differences were found in action tremor, bradykinesia, rigidity, gait, or posture scores between the two groups. The proportion of tremor-dominant subtypes was higher in patients with a family history of hand tremor than in those without (51.8% vs. 28.7%). Patients with PD, with a family history of hand tremor, had significantly lower scores in the urinary and sexual subdomains of the Non-Motor Symptoms Scale for PD than in those without. A family history of hand tremor affects the motor and non-motor symptoms in patients with early PD. It is necessary to investigate the family history of hand tremor in patients with PD.     

Variations of mitochondrial DNA polymerase γ in patients with Parkinson’s disease

Parkinson’s disease is associated with mitochondrial dysfunction. The POLG1 gene encodes DNA-polymerase γ, which is responsible for the replication of mitochondrial DNA. Mutations in POLG1 cause neurodegenerative diseases such as progressive external ophthalmoplegia and Alpers syndrome. In this study, we investigated if mutations in POLG1 had any correlation with Parkinson’s disease. Subjects consisted of Finnish patients with early-onset Parkinson’s disease (EOPD, N = 441) or late-onset Parkinson’s disease (LOPD, N = 263). The POLG1 gene was screened for nine previously known mutations. Two patients were compound heterozygotes with respect to putatively pathogenic alleles. Twenty-eight patients harbored a heterozygous missense mutation, but the allele frequencies did not differ from those of the controls. Interestingly, the frequency of affected siblings was 4.6-fold higher (95 % confidence interval; 1.09, 19.5) among the patients with EOPD and with heterozygous POLG1 mutations than among patients without mutations. Clinically the patients with or without POLG1 mutations did not differ from each other. Our findings provide two lines of evidence suggesting a role for POLG1 mutations in Parkinson’s disease: (1) identification of patients with compound heterozygous mutations in POLG1, and (2) higher frequency of affected siblings among the EOPD patients with heterozygous POLG1 mutations than among EOPD patients without mutations.     

Efficacy of budipine and placebo in untreated patients with Parkinson’s disease

Summary. Previous studies demonstrated the efficacy of budipine on motor symptoms of treated patients with Parkinson’s disease (PD) with rating scales. However rating procedures may be subjective and variable. Therefore additional use of instrumental motor tests are helpful to reflect therapeutic benefits. Objective was to test the efficacy of 20 mg budipine (t.i.d.) in 51 previously untreated idiopathic PD patients in a monocenter, double-blind, placebo-controlled trial with a 2:1 randomisation over a three month interval. Budipine was not superior to placebo application. However a detailed analysis of rating results shows, that budipine but not placebo treated patients significantly improved. Budipine caused significant better outcomes of motor tests with execution of complex movements, but did not change results of tasks, which demand for simple motions. Placebo significantly improved dopamine sensitive motor test results. These outcomes may result from improved non dopaminergic neurotransmission due to budipine. Placebo caused better results of dopamine sensitive tests, since placebo may release endogenous dopamine.     

Prevalence and treatment strategies of dyskinesia in patients with Parkinson’s disease

Summary A study into the prevalence and treatment of dyskinesia in Parkinson’s disease (PD) patients was performed with 380 PD specialists’ completed interviews relating to PD and retrospectively completed 1900 patient record forms for patients with dyskinesia. Physicians reported, that 34% of their PD patients experience dyskinesia, 57% of dyskinetic PD patients were affected by moderately-to-completely disabling dyskinesia. Treatment of dyskinesia was looked upon as not satisfactory, fractionating of levodopa dose was used as first choice therapeutic option of dyskinesia.     

Decreased serum proNGF concentration in patients with Parkinson’s disease

Parkinson’s disease (PD), a progressive and age-related neurodegenerative condition, is a common neurodegenerative disorder. However, no validated biomarkers for PD have been identified to date. Accumulating evidence supports the role of proNGF-p75NTR-sortilin signaling in the neurodegeneration and pathogenesis of PD. The aim of our study was to investigate alterations in serum proNGF concentrations in PD patients and related anxiety. Seventy-seven consecutive PD patients and 39 healthy controls were enrolled, and clinical data were collected. Modified Hoehn-Yahr Staging Scale, Unified Parkinson’s Disease Rating Scale (UPDRS), and Hamilton Anxiety (HAMA) Scale scores were assessed upon admission. Serum proNGF concentration was compared between that of PD patients and healthy controls. Pearson correlation coefficients were determined to explore the relationship between proNGF concentration and UPDRS, Hoehn-Yahr, and HAMA scores. Received operating characteristic (ROC) curves and proNGF optimal cutoff point were used to distinguish PD and related anxiety. The median concentration of proNGF was significantly lower (p = 0.000) in PD patients (94.91 ng/L, range 85.92–118.06 ng/L) compared with that of healthy controls (106.67 ng/L, range 102.39–122.06 ng/L). The optimal proNGF cutoff point for distinguishing PD patients was 102.29 ng/L, and the sensitivity and specificity values were 87.0 and 100%, respectively. proNGF concentration positively correlated with UPDRS (r = 0.281, p = 0.013), Hoehn-Yahr (r = 0.260, p = 0.023), and HAMA (r = 0.276, p = 0.015) scores. Our results indicate that serum proNGF concentration may represent a biomarker for PD and its role in the pathogenesis of PD thus warrants further investigation.     

Cardiac sympathetic denervation in Parkinson’s disease patients with SWEDDs

Dopamine transporter scans of some patients who have been clinically diagnosed with Parkinson’s disease (PD) fail to reveal abnormal dopaminergic functioning and are referred to as scans without evidence of dopaminergic deficits (SWEDDs). In this study, we investigated the differences between SWEDDs patients and PD patients using ¹²³I-metaiodobenzylguanidine (MIBG) scans. This study enrolled 20 patients with SWEDDs, 30 patients with early PD and 50 healthy controls. Cardiac ¹²³I-MIBG scans were performed on all subjects, and parameters including the early and delayed heart-to-mediastinum ratios (H/M) and the washout rate were compared among the three groups. The mean delayed H/M ratio in the PD group (mean ± standard deviation, 1.45 ± 0.23) was the lowest of the three groups, and the scans in the group without evidence of dopaminergic deficits exhibited a lower mean delayed H/M ratio (2.15 ± 0.48) than the control group (2.56 ± 0.55) (p < 0.05). The intermediate status of cardiac MIBG uptake in the SWEDDs patients in our study may have been due to the heterogeneity of the SWEDDs patients; some of these patients had Parkinsonism with unknown characteristics, some may have had early PD with false-negative dopamine transporter imaging, and some have had primary dystonia that was misdiagnosed as PD. These uncharacterised SWEDDs patients accounted for a larger proportion of the heterogeneous SWEDDs than observed in previous studies, but our results suggest that cardiac ¹²³I-MIBG scans may help to differentiate patients with SWEDDs from patients with PD.     

Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease.ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group.MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease.ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%).ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.