Researchers have consistently observed in right-handed individuals across normal and disease states that the ‘dominant’ left hemisphere has greater ipsilateral control of the left side than the right hemisphere has over the right. We sought to determine whether this ipsilateral influence of the dominant hemisphere reported in Parkinson’s disease extends to treatments such as deep brain stimulation (DBS) and whether it affects outcome. We hypothesised that among Parkinson right-handers, unilateral left DBS would provide greater ipsilateral motor improvement compared with the ipsilateral motor improvement experienced on the right side.
A total of 73 Parkinson patients who underwent unilateral DBS of the subthalamic nucleus (STN) or globus palidus internus (GPi) participated. Left and right ‘composite scores’, were computed by separately adding all items on the left and right side from the motor section of the Unified Parkinson Disease Rating Scale. The change in the pre- and 4-month post-implantation score was the primary outcome measure. The mean motor scores improved by 4.96 ± 11.79 points (p < 0.001) post-surgery on the ipsilateral side of the DBS implantation. Regression analyses revealed that the side (left vs. right) and target (STN vs. GPi) did not significantly contribute in the effect of ipsilateral motor improvement (p = 0.3557).
While DBS on the ‘dominant’ left side failed to exert a greater ipsilateral influence compared with DBS on the non-dominant right side, significant ipsilateral motor improvements were observed after unilateral stimulation regardless of site of implantation and laterality.
Unilateral DBS; STN; GPi; Parkinson’s disease; UPDRS
The purpose of this review is to assess the current state of the literature on the topic of deep brain stimulation (DBS) and its effects on swallowing function in Parkinson’s disease (PD). Pubmed, Cochrane review, and web of science searches were completed on all articles addressing DBS that contained a swallowing outcome measure. Outcome measures included the penetration/aspiration scale, pharyngeal transit time, oropharyngeal residue, drooling, aspiration pneumonia, death, hyolaryngeal excursion, epiglottic inversion, UPDRS scores, and presence of coughing/throat clearing during meals. The search identified 13 studies specifically addressing the effects of DBS on swallowing. Critical assessment of the 13 identified peer-reviewed publications revealed nine studies employing an experimental design, (e.g. “on” vs. “off”, pre- vs. post-DBS) and four case reports. None of the nine experimental studies were found to identify clinically significant improvement or decline in swallowing function with DBS. Despite these findings, several common threads were identified across experimental studies and will be examined in this review. Additionally, available data demonstrate that, although subthalamic nucleus (STN) stimulation has been considered to cause more impairment to swallowing function than globus pallidus internus (GPi) stimulation, there are no experimental studies directly comparing swallowing function in STN vs. GPi. Moreover, there has been no comparison of unilateral vs. bilateral DBS surgery and the coincident effects on swallowing function. This review includes a critical analysis of all experimental studies and discusses methodological issues that should be addressed in future studies.
DBS; Dysphagia; Swallow; Aspiration pneumonia; Parkinson’s disease; Review
Complementary and Alternative Medicine (CAM) use is on the rise in both the US and Europe, despite questions about its safety, effectiveness and lack of national standards. We aimed to determine the prevalence and predictors of CAM and integrative medicine use (CAM-I) and perceived effectiveness compared to the standard treatment of botulinum toxin injections in patients with adult-onset primary dystonia.
This was a retrospective questionnaire study of 389 dystonia patients examining the effects age, gender, education level and number of anatomical regions affected on botulinum toxin and CAM-I use and their perceived effectiveness.
53% (208) of patients reported CAM-I use, while 90% (349) used the standard treatment (botulinum toxin), and 48% used both. Education was the only significant predictor of CAM-I use – individuals with bachelor’ s degrees were more likely to try CAM-I whereas those with high school diplomas were less likely. The mean effectiveness rate for botulinum toxin injections (59%) significantly exceeded that for and CAM-I (28%, p<0.0001).
Our work highlights the need for scientifically sound studies to determine the safety, effectiveness and expense of CAM-I treatments for dystonia and other neurological disorders given that CAM-I use is steadily increasing, there is great variability in what is classified as CAM-I, and the effectiveness of some modalities may be significantly less than conventional medical treatments.
Dystonia; Complementary and Alternative Medicine (CAM); Botulinum toxin; Integrative medicine; Spasmodic dysphonia
A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.
The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.
In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.
The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.
Dystonia; RDP; DYT-12; Rapid-onset dystonia-parkinsonism
Impairment in computerized dynamic posturography scores has been documented in Huntington disease patients. Tetrabenazine is approved to treat chorea in Huntington disease, but its effect on posturography scores, and balance in general, is unknown.
Materials and Methods
We designed a study to test computerized dynamic posturography performance while taking tetrabenazine and after stopping tetrabenazine for at least three days.
10 Huntington disease patients were studied both ON and OFF tetrabenazine. The composite score was statistically different between ON and OFF conditions and both conditions were significantly worse than reference scores. There was no significant difference between ON and OFF trials in the number of falls. A significant improvement on Sensory Orientation Test conditions 3 (sway-referenced vision) and 5 (sway-referenced motion of the support surface and eyes closed) was seen while ON tetrabenazine. Strategy scores 1–3 were also significantly different while ON tetrabenazine.
These findings suggest that tetrabenazine aided patients in gating out of abnormal visual cues when other sensory modalities were available, as well as in gating out abnormal kinesthetic cues when visual cues were not available. It could not help with gating out of simultaneous abnormal visual and somatosensory cues. Thus, tetrabenazine can improve postural stability when one sensory modality is irrelevant, but this effect is not sustained when multiple abnormal sensory modalities are present. This is the first study supporting the use of any medicine to treat balance problems in Huntington disease.
Huntington disease; posturography; tetrabenazine; postural stability
We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population.
We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls.
During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (P <0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls.
Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.
Falls; Parkinson’s disease
Few studies have assessed parkinsonian motor features features across variants of primary progressive aphasia (PPA). Our objective was to compare degree of parkinsonian motor features features between two PPA variants.
Parkinsonian motor features were assessed with the Unified Parkinson’s Disease Rating scale in prospectively recruited PPA subjects, classified based on recently published criteria. Comparisons across groups were performed with Fisher’s exact test for binary data and Mann-Whitney U test for continuous data.
Twenty-three PPA subjects were diagnosed with logopenic (n=11) or nonfluent/agrammatic (n=12) aphasia. There were no significant differences in illness duration (agrammatic=3.4 years; logopenic=3.3 years) or age at onset (nonfluent/agrammatic =67.3; logopenic=62.0), but those with logopenic aphasia were more impaired on Mini-Mental State Examination (21.7/30 points vs. 26.1/30; p=0.04). In contrast, those with logopenic aphasia had fewer parkinsonian motor features than those with agrammatic aphasia (5.7/132 vs. 16.8/132; p=0.003) which was driven by bradykinesia (p=0.02) and speech facial/expression (p=0.04); less so rigidity (p=0.06). Dysarthria was more frequent in the nonfluent/agrammatic subgroup.
Nonfluent/agrammatic subjects have more parkinsonian motor features than logopenic subjects, likely reflecting underlying tau pathology in the agrammatic variant.
Parkinsonism; primary progressive aphasia; logopenic aphasia; agrammatic aphasia; extrapyramidal
Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson’s disease (PD).
To identify common genetic variants associated with motor and cognitive outcomes in PD.
The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn-Yahr Stage ≥4 (motor outcome), and either TICS-M ≤27 or AD-8 ≥2 (cognitive outcomes).
The SNP rs10958605 in the C8orf4 gene had the smallest p-value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42 – 2.31; p = 1.51 × 10−6). The SNP rs6482992 in the CLRN3 gene had the smallest p-value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47–2.79, p = 4.08 × 10−6). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p-values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.
This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.
Genome wide association studies; Parkinson’s disease; outcomes
Functional electrical stimulation; dystonia
Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.
Materials and methods
An IgM-MGUS neuropathy case cohort (n=207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n=414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.
Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p=0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p=0.025) and demyelinating nerve conductions (p=0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p=0.03) but not with NIS severity (p=0.57). Tremor occurrence associated with older age in controls, (p=0.004) but not in IgM-MGUS cases (p=0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p=0.04).
This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.
Tremor; Peripheral Neuropathy; IgM-MGUS
Difficulty switching between motor programs is a proposed cause of motor blocks in Parkinson disease (PD). Switching from one movement to another has been studied in the upper extremity and during postural control tasks, but not yetin the eyes and lower limb in PD. The purpose of this study was to compare movement orientation switching ability between people with PD and age-matched controls (CON) and to determine if switching ability is correlated between the eyes and lower limb. Twenty-six persons with PD and 19 age-matched controls participated. Movement orientation switching was studied in a seated position with the head fixed in a chinrest. In response to a randomly generated tone, participants switched from a continuous back-and-forth movement in either the horizontal or vertical orientation to the opposite orientation as quickly as possible. Lower limb movements were performed with the great toe pointing back and forth between targets positioned on a 45° angled floor platform. Eye movements were back and forth between the same targets. Eye and lower limb switch time was reduced in PD (p<0.01), but after normalizing switch time to movement velocity, no differences existed between PD and CON. Eye and lower limb switch times were correlated in PD (r=0.513, p<0.01) but not in CON. In PD, switch time and movement velocity of the lower limb, but not the eyes, correlated with bradykinesia and postural instability/gait. Our results suggest that individuals with PD experience movement switching deficits with both the eyes and lower limb, perhaps driven by overall bradykinesia.
Parkinson’s disease; eye movements; basal ganglia
In addition to classic midbrain pathology, Parkinson’s disease (PD) is accompanied by changes in pontine and medullary brainstem structures. These additional abnormalities may underlie non-motor features as well as play a role in motor disability.
Using novel magnetic resonance imaging (MRI) methods rotating frame adiabatic R1ρ (i.e., measurements of longitudinal relaxation during adiabatic full passage pulses) and modified magnetization transfer (MT) MRI mapping, we sought to identify brainstem alterations in nine individuals with mild-moderate PD (off medication) and ten age-matched controls at 4 Tesla.
We discovered significant differences in MRI parameters between midbrain and medullary brainstem structures in control subjects as compared to PD patients.
These findings support the presence of underlying functional/structural brainstem changes in mild-moderate PD.
Parkinson’s disease; medulla; MRI; magnetization transfer; R1ρ
An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1,114 subjects with mainly adult-onset primary dystonia (Neurology 2010;74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.
Dystonia; THAP1; DYT6; Spasmodic dysphonia; Tremor
Aims and objectives
A new pathomechanism of Parkinson’s disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability.
104 early-onset PD patients (EOPD, age at onset ≤ 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay.
PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C>A, P333P).
In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p=0.040; p=0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04 – 4.04; p=0.038).
Our results indicate that co-occurence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
Parkinson’s disease risk factors; PARK2; mitochondrial clusters; mitochondrial transcription factor A (TFAM)
To compare autonomic function of subjects with Parkinson’s disease (PD) and essential tremor (ET) relative to controls.
It has been reported that patients with PD have autonomic dysfunction while no literature exists regarding autonomic function in ET.
Subjects with PD, ET, and controls had autonomic function measured using the SCOPA-Autonomic questionnaire, with the total and domain scores transformed to a scale of 0–100 points.
62 subjects with PD, 84 with ET, and 291 controls were included. Women were more prevalent in control (69%) compared to PD (44%) and ET (44%) groups, and mean age was significantly younger in PD (73 yrs) and older in ET (83) compared to controls (81). The mean SCOPA-Aut Total score in PD was significantly higher than controls, with no difference in ET. No autonomic dysfunction was found in any domain in ET but in PD there were significant abnormalities in gastrointestinal, cardiovascular, urinary, and thermoregulatory domains. Individual question data revealed a significantly higher percentage of subjects with dysfunction on 11/23 questions in the PD group but only 1 question (sialorrhea) in the ET group compared with controls.
Autonomic scores, particularly gastrointestinal, cardiovascular, urinary, and thermoregulatory were increased in patients with PD, as assessed by SCOPA-Aut. Patients with ET did not exhibit autonomic dysfunction, with the exception of sialorrhea.
Autonomic dysfunction; Parkinson’s disease; Essential tremor
Levodopa–carbidopa intestinal gel (LCIG) delivered continuously via percutaneous endoscopic gastrojejunostomy (PEG-J) tube has been reported, mainly in small open-label studies, to significantly alleviate motor complications in Parkinson’s disease (PD). A prospective open-label, 54-week, international study of LCIG is ongoing in advanced PD patients experiencing motor fluctuations despite optimized pharmacologic therapy. Pre-planned interim analyses were conducted on all enrolled patients (n = 192) who had their PEG-J tube inserted at least 12 weeks before data cutoff (July 30, 2010). Outcomes include the 24-h patient diary of motor fluctuations, Unified Parkinson’s Disease Rating Scale (UPDRS), Clinical Global Impression-Improvement (CGI-I), Parkinson’s Disease Questionnaire (PDQ-39), and safety evaluations. Patients (average PD duration 12.4 yrs) were taking at least one PD medication at baseline. The mean (±SD) exposure to LCIG was 256.7 (±126.0) days. Baseline mean “Off” time was 6.7 h/day. “Off” time was reduced by a mean of 3.9 (±3.2) h/day and “On” time without troublesome dyskinesia was increased by 4.6 (±3.5) h/day at Week 12 compared to baseline. For the 168 patients (87.5%) reporting any adverse event (AE), the most common were abdominal pain (30.7%), complication of device insertion (21.4%), and procedural pain (17.7%). Serious AEs occurred in 60 (31.3%) patients. Twenty-four (12.5%) patients discontinued, including 14 (7.3%) due to AEs. Four (2.1%) patients died (none deemed related to LCIG). Interim results from this advanced PD cohort demonstrate that LCIG produced meaningful clinical improvements. LCIG was generally well-tolerated; however, device and procedural complications, while generally of mild severity, were common.
Parkinson’s disease; Levodopa–carbidopa intestinal gel; Motor fluctuations; PEG-J procedure; Pump administration
We conducted a cross-sectional analysis with 901 Parkinson’s disease (PD) patients in China to understand the epidemiological characteristics of PD-pain among Chinese patients. In addition, we searched PubMed and CHKD for epidemiological studies of pain and fatigue among PD patients from 1999 to 2011 to understand the prevalence of these symptoms around the world and associated clinical features. The 901 PD cases were recruited from 42 university affiliated hospitals randomly selected from seven provincial capitals across four economic-regions of China. We documented motor and non-motor symptoms via clinical examinations and questionnaire surveys. Using logistic regression models, we evaluated factors that were associated with PD-pain among these Chinese patients. Of the 901 Chinese patients, 269 (29.9%) had PD-related pain. After adjusting for confounders, only dyskinesias (OR =2.66) and depression (OR =2.88) were independently associated with PD-pain. The literature search identified a total of 16 eligible studies on PD-pain and 19 on PD-fatigue with various tools for symptom assessment. The data suggest a crude prevalence of 33.7% for PD-pain in Asia and 79.4% in Northern-Europe; the prevalence for PD-fatigue was 35.4% in Northern-Europe and 59.1% in Western-Europe. Interestingly, Northern-European PD patients reported the highest prevalence of pain, but the lowest prevalence of fatigue. These studies suggest that motor complications and depression are likely key predictors for PD-pain, while disease severity, depression and sleep disturbance are associated with PD-fatigue. More studies with standardized methods would be needed to better understand the prevalence of PD-pain and fatigue across various regions of the world.
Parkinson’s disease; pain; fatigue; epidemiology
The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
Autosomal Dominant Parkinsonism; LRRK2; alpha-Synuclein; Ubiquitin; Deep Brain Stimulation; Suicide
A mean of 10 years elapse before patients with Parkinson’s disease (PD) reach Hoehn & Yahr (H&Y) stage 4, and 14 years for stage 5. A small proportion of PD patients survive and are ambulatory for ≥20 years. We sought to identify features associated with long-duration PD (dPD).
This five-center, case–control study compared 136 PD patients with ≥20 years of duration and H&Y stage ≤4 (dPD) to 134 H&Y-, age- and gender-matched PD patients between 10 and 15 years of disease (cPD).
By study design, there were no between-group differences in age, gender and H&Y. dPD subjects were younger at onset (p < 0.0001), had more psychosis (p: 0.038), were receiving higher levodopa equivalent daily doses (p: 0.02), were predominantly left-handed (p: 0.048), and had greater frequency of left-sided onset (p: 0.015) compared to cPD subjects. Both groups had similar rates of resting tremor, dementia and REM sleep behavior disorder.
Early disease onset, left-handedness and left-sided onset are associated with long disease and ambulatory PD survival. The neurobiological basis of the prognostic value of lateralization deserves further investigation.
Parkinson’s disease; Longevity; Handedness
The aims of this project were to determine the risk factors for and clinical characteristics of mild cognitive impairment (MCI) in Parkinson’s disease (PD). We performed a retrospective record review of 72 non-demented PD patients (age: 57.79 ± 10.57, duration of PD: 7.32 ± 4.97) who completed a standardized neurological assessment, including a full neuropsychological battery, as part of their diagnostic work-up. Of these participants, 47.2% were cognitively normal and 52.8% met criteria for MCI. The majority of MCI patients had single domain MCI (23/38), the affected domains being memory (n = 9), executive function (n = 6), visuospatial skills (n = 6), and language (n = 2). The MCI group had longer duration of disease and higher postural instability and gait disorder subscale scores than the cognitively normal group. This report provides further support for use of the concept of MCI in PD research. There may be certain disease characteristics that could alert practitioners to the emergence of cognitive changes in patients. Future studies should focus on additional risk factors for MCI subtypes and their possible progression to frank dementia.
Parkinson’s disease; Mild cognitive impairment; Dementia; Motor dysfunction; Cognition
Patient telephone calls are a major form of unreimbursed healthcare utilization in Parkinson’s disease (PD), yet little is known about potential risk factors for frequent calling behavior.
Prospective cohort study of 175 non-demented outpatients with PD. Our primary outcome measure was the frequency of patient telephone calls over a three-month period relative to baseline demographics, State-Trait Anxiety Index (STAI) and Beck Anxiety Inventory (BAI) scores, Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores, and medication use. Based on the median call rate (1 call/3 months), subjects were dichotomized into frequent (≥2 calls) and infrequent (≤1 call) caller groups.
A total of 297 calls were received, of which 264 (89%) were from the frequent caller group (n = 63 subjects), and only 33 (11%) were from the infrequent caller group (n = 112 subjects). Compared with calls from infrequent callers, those from frequent callers more commonly related to somatic symptoms of PD (46.8% vs. 19.4%, p = 0.007). In multivariate logistic regression analysis, independent predictors of frequent calling were: anxiety (STAI ≥55; adjusted OR = 2.62, p = 0.02), sleep disorders (adjusted OR = 2.36, p = 0.02), dyskinesias (adjusted OR = 3.07, p = 0.03), and dopamine agonist use (adjusted OR = 2.27, p = 0.03). Baseline demographics, UPDRS motor scores, and levodopa use were similar in both groups.
Frequent patient telephone calls in PD are independently associated with anxiety, sleep disorders, dyskinesias, and dopamine agonist use, with a minority of patients accounting for the majority of calls. Aggressive treatment of these non-motor symptoms and motor complications might potentially reduce the burden of patient telephone calls in PD.
Parkinson’s disease; Telephone; Healthcare; Resource; Utilization; Non-motor; Anxiety; Sleep disorder; Motor complications; Dopamine agonist; Quality of care
Neuroinflammation is closely associated with the pathogenesis of Parkinson’s disease (PD) and other neurological disorders. The hallmark of neuroinflammation is microglial activation. Increasing evidence suggests that inhibition of microglia-mediated neuroinflammation might represent a promising therapeutic potential for PD and related disorders. Fluoxetine, a selective serotonin reuptake inhibitor, is commonly used for the treatment of major depression due to its tolerability and safety profiles. Recent studies have shown that fluoxetine affords robust neuroprotection in a series of neurological disease models. However, the mechanism underlying fluoxetine-mediated neuroprotection remains unclear. Here, by using rat primary midbrain neuron-glia cultures, we report that both R and S isomers of fluoxetine attenuated chronic neurodegeneration induced by a commonly used inflammogen lipopolysaccharide (LPS). Reconstituted cell culture studies further revealed that microglia were required for fluoxetine-mediated neuroprotection. Fluoxetine significantly inhibited LPS-induced activation of microglia and subsequent release of multiple pro-inflammatory and cytotoxic factors including tumor necrosis factor-α, interleukin-1β, nitric oxide, and reactive oxygen species. Furthermore, inhibition of microglial NF-κB signaling pathway participated in fluoxetine-mediated neuroprotection. Collectively, fluoxetine exerted neuroprotection against microglia-mediated neurotoxicity. Thus, fluoxetine not only can relieve depression, a common nonmotor symptom of PD, but might also hold a potential to retard inflammation-mediated chronic neurodegenerative process of this disease.
fluoxetine; neuroinflammation; microglia; neuroprotection; anti-inflammation
Although initially thought to be important primarily in neural development, a number of trophic proteins have been found to have neuroprotective and neuroregenerative activity in the adult central system, particularly for midbrain dopamine neurons (MDN). Neurorestoration is potentially feasible for MDN since there is an initial loss of phenotype for these neurons in Parkinson's disease (PD) rather than neuronal death. There is a considerable recent literature on trophic properties of TGF-ß superfamily proteins for MDN's, including glial cell-derived neurotrophic factor (GDNF), neurturin, and bone morphogenetic proteins (BMPs). This paper will review studies with the factors listed above, as well as describe more recent studies with two newly described trophic proteins, MANF and CDNF. Data will be presented from various animal models of PD suggesting that these trophic proteins may eventually lead to PD therapeutics in man. In addition, some data on small molecules with neuroprotective properties (AP4A, retinoic acid and vitamin D3) will also be described.
Deep brain stimulation is a treatment for select cases of medication refractory movement disorders including Parkinson’s disease. Deep brain stimulation has not been recommended for treatment in multiple system atrophy patients. However, the paucity of literature documenting the effects of deep brain stimulation in multiple system atrophy patients and the revelation of a levodopa-responsive subtype of multiple system atrophy suggests further investigation is necessary.
This study summarizes the positive and negative effects of deep brain stimulation treatment in two pathologically confirmed multiple system atrophy patients from the University of Florida Deep Brain Stimulation-Brain Tissue Network. Clinical diagnosis for the two patient cases did not match the neuropathological diagnosis. We noted that in both pathologically confirmed multiple system atrophy patients, death occurred as a result of myocardial infarction. Importantly, there was reported transient benefit in levodopa responsive features that indicate deep brain stimulation may be an option for select multiple system atrophy patients.
Deep Brain Stimulation; Pathology; Multiple System Atrophy