Parkinsonism & Related Disorders

Editorial Board

2010-02-01

A timeline for Parkinson's disease

Christopher H. Hawkes, Kelly Del Tredici, Heiko Braak — 2010-02-01

Abstract: It is reasonably well established that prior to the motor phase of classical Parkinson's disease (PD) there is a prodromal period of several years duration. Once typical motor features appear, the disease continues up to 20 years depending on multiple variables. The clinical features of the prodromal and motor phases may be correlated with pathological changes in the central and autonomic nervous systems to allow a sequential plan of disease progression. We present a ‘best guess’ for a typical individual presenting with PD in their sixties and speculate that the disease will last approximately 40 years from the earliest non-motor features to death. Appreciation of this concept may allow better strategies for slowing or halting disease progression.

The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population

2010-02-01

Abstract: The G2385R (SNP accession no. rs34778348) and R1628P (rs33949390) variants of leucine-rich repeat kinase 2 (LRRK2, PARK8) are emerging as an important risk factor for Parkinson's disease (PD) in the ethnic Chinese and Japanese populations. The purpose of this study was to investigate whether these variants are a genetic risk factor in sporadic PD patients in the Korean population. A total of 923 patients and 422 healthy subjects were included. The variants were screened by a SNaPshot assay. The LRRK2 G2385R variant was detected in 82 PD patients (8.9%, two homozygous and 80 heterozygous) and in 21 normal controls (5.0%, all heterozygous). The frequency of the LRRK2 G2385R variant in PD was significantly higher than in normal controls (adjusted odds ratio 1.83, p = 0.0170, 95% confidence interval 1.11–3.00). There were no differences in the mean age at onset or gender between the G2385R carriers and the non-carriers in PD patients. The LRRK2 R1628P variant was very rare (0.78% in patients versus 0.26% in controls) in the tested 384 patient–control pairs, and was not a significant risk factor. This study supports that the LRRK2 G2385R variant may be a genetic risk factor for sporadic PD in the Korean population.

The benefits of a standardized patient education program for patients with Parkinson's disease and their caregivers

2010-02-01

Abstract: The Patient Education Program Parkinson (PEPP) is a standardized psychosocial intervention aiming at improving the health-related quality of life (Hr-Qol) of patients with Parkinson's disease (PD) and caregivers. A randomized controlled trial was performed to assess its effectiveness. Sixty-four PD patients and 46 caregivers were allocated to either the intervention group (PEPP) or the control group (usual care). The intervention consisted of eight weekly sessions of 90-minute duration. Assessments were performed on psychosocial problems (BELA-P/A-k), Hr-Qol (PDQ-39/EQ-5D) and depression (SDS) at baseline and one week after the end of the PEPP. Participants rated their mood on a visual analogue scale before and after each session. A significant effect for the caregivers on psychosocial problems and need for help was found and a trend for significance for patients' quality of life. Patients' and caregivers' mood improved significantly after each session. This study provides indications that PD patients and caregivers benefit from the PEPP.

Risks of intracranial hemorrhage in patients with Parkinson's disease receiving deep brain stimulation and ablation

2010-02-01

Abstract: Objectives: This study analyzed risk factors for hemorrhage in a large series of deep brain stimulation (DBS) and ablation procedures in patients with advanced Parkinson's disease (PD).Methods: Six hundred and forty four subjects with advanced PD treated with DBS or ablation procedures between March 1999 and December 2007 were enrolled in the study. Procedures were performed by the same surgeon, and included DBS in 126 patients, ablation in 507 patients and DBS after prior unilateral ablation procedures in 11 patients. Of 796 target procedures, 207 were DBS including 202 subthalamic nucleus (STN) targets, 3 ventralis intermedius nucleus (Vim) targets and 2 globus pallidus internus (GPi) targets, and the others were 589 ablation procedures including 474 GPi targets and 115 Vim targets. Postoperative CT or MRI was performed in all patients within 24 h of lead implantation or ablation treatment. Statistical correlation analysis of risk factors for intracranial hemorrhage (ICH) was performed by stepwise logistic regression. Explanatory variables were patient age, sex, blood pressure, anatomical targets, the number of microelectrode recording (MER) penetrations and surgical modality.Results: Postoperative symptomatic ICH occurred in 10 cases (8 pallidotomy and 2 thalamotomy) and asymptomatic ICH in 14 cases (9 pallidotomy, 4 thalamotomy and 1 DBS). Hypertension and surgical modality were significant factors contributing to hemorrhage (both P < 0.05). The likelihood of hemorrhage in hypertensive patients was 2.5 times that in normotensive patients. The risk of hemorrhage during ablation was 5.4 times that in DBS. The number of MER trajectories did not significantly correlate with ICH occurrence (P = 0.07). No statistically significant difference was found in age, sex and anatomical targets.Conclusion: This study demonstrated that hypertension is a risk factor for ICH in PD patients. DBS is generally a safe surgical modality as compared with ablation. Increasing microelectrode trajectories seemed to increase the risk of ICH, but no statistically significant difference was found (P = 0.07).

Autoimmune polyendocrine syndrome type I and brain calcinosis

Alon Abraham, Ilan Ziv, Adam Steinmetz, David Groshar, Ruth Djaldetti — 2010-02-01

Abstract: Autoimmune polyendocrine syndrome (APS) is a rare disorder. One of the possible associated endocrinopathies in APS is hypoparathyroidism. We describe brain calcifications secondary to hypoparathyroidism in family members with APS and compare clinical manifestations, the extent of brain calcifications on CT scans and the result of PET–FDG scans. We found extensive brain calcifications and striatal hypometabolism in PET–FDG scan in the only symptomatic member of the family, which supports the assumption that extensive brain calcification and the presence of hypometabolism in PET–FDG scan are likely to be found in symptomatic patients with brain calcifications.

Factors related to clinically probable REM sleep behavior disorder in Parkinson disease

Ji E. Lee, Kyung S. Kim, Hae-Won Shin, Young H. Sohn — 2010-02-01

Abstract: Rapid eye movement sleep behavior disorder (RBD) is commonly accompanied in Parkinson disease (PD). However, the underlying mechanism linking RBD to PD remains unclear. We interviewed and examined 447 consecutive patients with PD to investigate factors associated with the presence of RBD in PD patients. Using the minimal diagnostic criteria for parasomnias provided in the International Classification of Sleep Disorders-Revised (ICSD-R), 164 patients (36.5%) were diagnosed with clinically probable RBD (cpRBD). PD patients with cpRBD were older, had a longer duration of PD, a more severe level of disability, a longer duration of antiparkinsonian medication, and a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) scores accounted for by tremor than those without RBD. Multivariate and univariate logistic regression analyses revealed that patient age, PD symptom duration (and, accordingly, more severe motor disability), tremor score, and proportion of the UPDRS score accounted for by tremor were significant factors associated with the presence of RBD in PD patients. The results of the present study support previous observations that PD with RBD may result from a different underlying pattern of neurodegeneration than PD without RBD.

LINGO1 rs9652490 is associated with essential tremor and Parkinson disease

2010-02-01

Abstract: Recently, a variant in LINGO1 (rs9652490) was found to associate with increased risk of essential tremor. We set out to replicate this association in an independent case-control series of essential tremor from North America. In addition, given the clinical and pathological overlap between essential tremor and Parkinson disease, we also evaluate the effect of LINGO1 rs9652490 in two case-control series of Parkinson disease. Our study demonstrates a significant association between LINGO1 rs9652490 and essential tremor (P = 0.014) and Parkinson disease (P = 0.0003), thus providing the first evidence of a genetic link between both diseases.

Histamine N-methyltransferase Thr105Ile is not associated with Parkinson's disease or essential tremor

2010-02-01

Abstract: A functional variant in the Histamine N-Methyltransferase gene (HNMT – rs11558538) resulting in a threonine to isoleucine substitution (Thr105Ile) has been shown to impair histamine degradation. Two recent studies reported that the threonine allele of this polymorphism might be a risk factor for Parkinson disease (PD) and essential tremor (ET) development. Although PD and ET are considered different entities, they share some clinical and pathological features, suggesting a possible joint etiology. In this study we assess the role of the Thr105Ile variant in PD and ET development, genotyping the variant in a North American Caucasian PD and ET case-control series. Statistical analysis did not identify any significant association between this variant and PD or ET; therefore, our findings do not support the HNMT Thr105Ile variant as a factor in disease development or a genetic link between the disorders.

Neuropsychological changes 1-year after subthalamic DBS in PD patients: A prospective controlled study

2010-02-01

Abstract: Objective: This study aimed at investigating the neuropsychological effect of DBS of the Subthalamic Nucleus in patients with advanced Parkinson's disease (PD).Methods: A standardized neuropsychological test battery, assessing reasoning, memory and executive functions, was administered to 27 PD patients who underwent DBS-STN (DBS group) and to a matched control group of 31 PD patients under optimal medical treatment (MED group). Patients were evaluated at baseline and at the end of 1 year.Results: Change score analysis (T1 minus T0 scores) demonstrated a significant decline in phonemic verbal fluency in the DBS group compared with the MED group (p < 0.005), while there were no significant changes between the two groups for the other cognitive tests. Single cases analysis by means of multivariate normative comparisons revealed that 4 out of 27 DBS patients (15%) showed cognitive deterioration one year post surgery. These patients were significantly more compromised from a motor standpoint (UPDRS, section III) than the 23 DBS PD patients who had no cognitive decline post surgery.Conclusion: Results of this prospective controlled-study showed that phonemic verbal fluency declined one year after DBS-STN, while the other cognitive domains did not change significantly. Nevertheless, single case analysis highlighted the fact that a subgroup comprising 15% of DBS-STN patients (4/27) showed significant cognitive decline 1 year after surgery.

Malnutrition and associated factors in Chinese patients with Parkinson's disease: Results from a pilot investigation

2010-02-01

Abstract: Objective: This study was conducted to evaluate the prevalence of malnutrition among patients with Parkinson's disease (PD) and determine the associations between malnutrition and non-motor symptoms (NMS).Methods: We conducted a cross-sectional assessment of 117 consecutive outpatients with PD and their respective caregivers. The participants were interviewed and assessed using various scales, including the Mini Nutritional Assessment (MNA), Non-Motor Symptoms questionnaire for Parkinson's disease (NMS quest), Mini-mental State Examination (MMSE), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Geriatric Depression Scale (GDS), and Hamilton Anxiety Scale (HAMA). We also investigated the socio-demographic characteristics of the subjects.Results: The prevalence of malnutrition (MNA score < 17) was 1.71%, and 19.66% patients were at risk of malnutrition (17 ≤ MNA score ≤ 23.5). Poor nutrition (malnutrition and at risk of malnutrition) was associated with some of the NMS including the constipation, vomiting, loss of interest, inability to concentrate and sadness, and high scores in PSQI, GDS, and HAMA. Constipation (OR, 6.646; 95% CI, 1.561–28,300; P = 0.010) and GDS scores (OR, 1.166; 95% CI, 1.042–1.304; P = 0.007) were considered to be the 2 most important predictors of nutritional impairment.Conclusions: Nearly 22% of PD patients were malnourished or at the risk of malnutrition and the negative association between NMSs and nutritional care needs to be determined by further studies.

Olfaction and apathy in Parkinson's disease

Christina K. Cramer, Joseph H. Friedman, Melissa M. Amick — 2010-02-01

Abstract: Background: Olfactory deficits are frequent among patients with idiopathic Parkinson's disease (PD). Additionally, apathy (as quantified by the Apathy Evaluation Scale), is more prevalent in PD patients compared to the general population. Olfactory impairment and apathy are associated with dysfunction in overlapping brain regions. Neuroimaging studies indicate that the anterior cingulate gyrus and medial orbitofrontal cortex are hypoactive in apathetic patients and are also involved in secondary olfactory processing. However, no study until this point has been published investigating whether there is any association between olfactory dysfunction and apathy in PD patients.Methods: In our study seventy consecutive patients with PD took the Brief Smell Identification Test (B-SIT), completed the Apathy Evaluation Scale (AES) and were administered the Folstein Mini-Mental Status exam (MMSE).Results: Apathetic PD patients performed poorly on the B-SIT compared with non-apathetic PD patients and olfactory impairment correlated with apathy. The simultaneous disruption of olfaction and emotion in Parkinson's could be the result of disease pathology in brain regions involved in both olfactory and emotional processing and reinforces the idea that this link between olfaction and emotions may have clinical consequences.

The safety of transcranial magnetic stimulation with deep brain stimulation instruments

2010-02-01

Abstract: Objectives: Transcranial magnetic stimulation (TMS) has been employed in patients with an implanted deep brain stimulation (DBS) device. We investigated the safety of TMS using simulation models with an implanted DBS device.Methods: The DBS lead was inserted into plastic phantoms filled with dilute gelatin showing impedance similar to that of human brain. TMS was performed with three different types of magnetic coil. During TMS (1) electrode movement, (2) temperature change around the lead, and (3) TMS-induced current in various situations were observed. The amplitude and area of each evoked current were measured to calculate charge density of the evoked current.Results: There was no movement or temperature increase during 0.2 Hz repetitive TMS with 100% stimulus intensity for 1 h. The size of evoked current linearly increased with TMS intensity. The maximum charge density exceeded the safety limit of 30 μC/cm2/phase during stimulation above the loops of the lead with intensity over 50% using a figure-eight coil.Conclusions: Strong TMS on the looped DBS leads should not be administered to avoid electrical tissue injury. Subcutaneous lead position should be paid enough attention for forthcoming situations during surgery.

Mutations in the Parkinson's disease genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA), are not associated with essential tremor

2010-02-01

Abstract: We evaluated an association between essential tremor (ET) and the Parkinson's disease (PD) genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA). Clinical studies demonstrate an association between ET and PD, suggesting possible shared pathophysiologies, yet LRRK2 has rarely been studied in ET, and GBA, not at all. ET cases (n = 275, including 42 with rest tremor) and controls (n = 289) were enrolled in an epidemiological study (Columbia University). Post-mortem brain tissue samples were obtained on 24 additional ET cases, including 3 with brainstem Lewy bodies. We performed a comprehensive analysis of the LRRK2 gene by genotyping 4 LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C), 2 rare LRRK2 variants (L1114L and I1122V) and 19 LRRK2 SNPs. All GBA exons were sequenced in a subset of 93 Ashkenazi Jewish (AJ) cases, 62 AJ controls and 24 ET brains. LRRK2 mutations were not found in any ET cases or ET brains and none of the LRRK2 SNPs was associated with ET. GBA mutations were found in 7.5% (7/93) of AJ ET cases and 4.8% (3/62) of AJ controls (p = 0.75). 8.3% (2/24) of ET brains carried a GBA mutation. Four different heterozygous mutations were identified, including 3 previously reported mutations (N370S, R496H, and E326K) and 1 new missense variant (R44C). As suggested by several smaller prior reports, the known mutations for the LRRK2 gene are not risk factors for ET. Furthermore, a similar frequency of GBA mutations in AJ ET cases and controls suggests that GBA is not a common cause of ET either.

Low frequency of the PARK2 gene mutations in Polish patients with the early-onset form of Parkinson disease

2010-02-01

Abstract: Objective: Mutations in the PARK2 (Parkin) gene result in an early-onset autosomal recessive form of Parkinson Disease (EO-PD). Although the frequency of the PARK2 mutations in EO-PD patients according to several studies is high and has been reported in up to 50% in familial and 19% in sporadic cases, these data remain controversial.Methods: We performed PARK2 gene analysis for a group of 79 Polish EO-PD patients with onset of disease below the age of 40. All exons were directly sequenced and the exons' copy number variations were analyzed.Results: Mutations in PARK2 gene were found in 3 patients (3.8%), in two sporadic cases in both alleles (2.5%) and in a familial case in only one allele (1.3%). We identified point mutations as well as exon rearrangements (duplication, deletion).Conclusions: The frequency of the PARK2 mutations our Polish group with EO-PD seems to be lower than in other previously described groups.

A computerized survey of pain in Parkinson's disease patients: A pilot feasibility study

David B. Page, Frances Weaver, Diana J. Wilkie, Tanya Simuni — 2010-02-01

Abstract: Approximately two thirds of Parkinson's disease (PD) patients exhibit bothersome pain symptoms that oftentimes go unrecognized. In this study, 14 patients with PD volunteered to complete a computerized version of the McGill Pain Questionnaire using the PAINReportIt® interactive software to assess the feasibility of acquiring real-time pain data in a clinical setting. 100% of the subjects completed >90% of questions in an average of 19.9 min; however, some subjects (n = 4, 28.6%) required physical assistance. 92.9% (n = 13) of subjects supported use of PAINReportIt® across all measures. PAINReportIt® was feasible as a data-collection modality among our PD cohort, and with modifications may be used as both an investigative instrument and clinical tool for the evaluation of PD-related pain syndromes.

Consecutive analyses of cerebrospinal fluid axonal and glial markers in Parkinson's disease and atypical parkinsonian disorders

2010-02-01

Abstract: Cerebrospinal fluid (CSF) levels of neurofilament light protein (NFL), a marker of neuronal damage, are normal in Parkinson's disease (PD) but elevated in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Therefore, CSF NFL can help differentiate between PD on one hand and MSA/PSP on the other. In the present study of 10 patients with PD, 21 with MSA, 14 with PSP, 11 with corticobasal degeneration (CBD), and 59 healthy controls, this previous observation is confirmed and also extended to include CBD by showing that similarly high CSF NFL levels are seen not only in MSA and PSP but also in CBD. CSF levels of glial fibrillary acidic protein (GFAP), a protein expressed mainly in fibrillary astrocytes, were similar in all investigated groups. In addition, consecutive analyses of CSF NFL and CSF GFAP levels showed relatively stable levels over time in all the investigated parkinsonian disorders, suggesting that the rate of neuronal degeneration is rather constant over time. Our results suggest that measurements of CSF NFL but not GFAP can be useful in the differential diagnosis of PD versus atypical parkinsonian disorders (APD). However they do not help differentiate between the different APD.

Restless legs syndrome associated with narcolepsy and somnambulism

Hortensia Alonso-Navarro, Félix Javier Jiménez-Jiménez — 2010-02-01

Narcolepsy is a disabling disorder characterized by excessive daytime sleepiness, that can be accompanied by abnormal rapid eye movement (REM) sleep manifestations that include: cataplexy (sudden onset falling due to loss of muscle tone), sleep paralysis (inability to move when falling asleep or while waking up), hypnagogic hallucinations (visual, auditory or, less frequently, cenesthetic – i.e. somatic hallucinations that are visceral in origin)-, are present at sleep onset (or more rarely at sleep termination), and sleep onset REM periods.

The deep brain stimulation of the pedunculopontine tegmental nucleus: The (un)certainty of the stimulating site

Eugenio Scarnati — 2010-02-01

I have carefully read the short communication: Effects of deep brain stimulation of the pedunculopontine area on working memory tasks in patients with Parkinson's disease by A. Costa (corresponding author), G.A. Carlesimo, C. Caltagirone, P. Mazzone, M. Pierantozzi, A. Stefani and A. Peppe, (Parkinsonism and Related Disorders 2009 doi:10.1016/j.parkreldis.2009.05.009).

Effects of deep brain stimulation of the pedunculopontine area on working memory tasks in patients with Parkinson's

Alberto Costa — 2010-02-01

We have read carefully the letter from Prof. Scarnati relating to our recent publication in Parkinsonism and Related Disorders (“Effects of deep brain stimulation of the pedunculopontine area on working memory tasks in patients with Parkinson's disease” by A. Costa, et al. doi:10.1016/j.parkreldis.2009.05.009). The letter does indeed introduce an important point referring to our description of the neurosurgical procedure that deserves clarification. We acknowledge that it was inappropriate to raise an old dispute and that the paragraph in which the surgical procedure was described has lead to some misunderstanding. However, in his letter the author states a paradoxical concept when he writes: “in conclusion, the authors appear to deny the validity of the neurosurgical technique that they have employed in this…”. In fact, how could we deny a basic aspect of our work? Specifically, the neurosurgeon participated in the study as he performed the DBS implantation on the PD patients. It's possible that this section of the paper suffers from some inaccuracy because it was written from the perspective of a clinical neurologist. As well the fact that we mentioned the debate on PPN area in the method section could have caused confusion. We recognize that the surgical approach to target the PPTg was correct, and in order to have a more detailed description of the neurosurgical procedure employed and of the neural stimulated target we cross-refer the reader to recent publications of the neurosurgeon participating in the present research . It should be noted, however, that the clarification provided by the letter does not contradict the functional results of the present study. Rather, the comment indicating that the location of DBS electrodes was the PPTg itself reinforces our conclusion regarding the specific role of this structure in modulating the speed processing of information in the content of working memory.

Converting the UPDRS part III to the Hoehn and Yahr staging may not be adequate for a research database

Hubert H. Fernandez, Charles E. Jacobson, Michael S. Okun — 2010-02-01

We read with interest the article by Scanlon, et al. recommending a formula for using items in the Unified Parkinson Disease Rating Scale-Motor Subscale (UPDRS Part III) for conversion to the Hoehn and Yahr staging (H & Y) . We appreciate its potential usefulness because H & Y generally has wide utilization and acceptance and progressively higher stages have correlated with neuroimaging studies of dopaminergic loss. Moreover, high correlations exist between the H & Y scale and some standardized scales of motor impairment, disability and quality of life . H & Y is therefore a simple scale that grades a Parkinson patient's impairment or disability in 5 stages , albeit heavily weighted on gait and postural instability.

A revised formula for the conversion of UPDRS-III scores to Hoehn and Yahr stage

2010-02-01

In their letter, Dr. Fernandez and colleagues highlight some areas of our proposed formula that might benefit from clarification. We appreciate their attention to this matter and are thankful for the opportunity to shed further light on the intention and utility of the formula.