Cognitive function in early Parkinson’s disease: a population‐based study

Background and purpose: The study aims to describe the frequency, pattern and determinants of cognitive function in patients with newly diagnosed Parkinson’s disease (PD); to compare patients with impaired cognition to patients with intact cognition; and to compare to matched healthy controls. Methods: Patients were identified in a longitudinal population based study of idiopathic non‐drug induced parkinsonism. Eighty‐eight newly diagnosed patients with PD and no dementia were included during a four year period. The patients and 30 age‐ and sex‐matched healthy control subjects underwent a comprehensive neuropsychological assessment. Results: Patients performed significantly worse than healthy controls in a majority of neuropsychological tests. Test results in attention, psychomotor function, episodic memory (free recall), executive function and category fluency were significantly lower in the patient group. Comparison with normative data revealed that 30% of the patients had deficits in ≥1 cognitive domain (episodic memory, executive function and verbal function). Seventy per cent of the patients had normal performance. Unified Parkinson's Disease Rating Scale (UPDRS) III sub scores; speech, facial expression, rigidity and bradykinesia were significantly higher, and disease duration shorter amongst the cognitively impaired than amongst the cognitively intact patients. Tremor showed no difference. Education level was an independent predictor of dysfunction in patients with ≥2 cognitive domains affected. Conclusion: Cognitive dysfunction is common in untreated patients in early PD, affecting attention, psychomotor function, episodic memory, executive function and category fluency. Education level was an independent predictor of severe cognitive dysfunction.     

Prevalence of Parkinson’s disease in Korea

The prevalence of neurodegenerative disorders is not well documented in Korea. We assessed the prevalence of Parkinson's disease in an elderly population in a newly industrialized city in a rural region. Subjects for this study were randomly selected from a community-based cohort study. The sample in the cohort represented approximately 1.3% (4700) of 362 625 adults (age>18 years) listed in the city register in 1998. Among this group, 4218 subjects (1086 subjects aged>60 years) agreed to be interviewed and underwent a physical examination and neuropsychological tests administered by a neurologist and neuropsychologist. All participants were examined. Participants who had bradykinesia and at least one other possible cardinal sign of parkinsonism at the neurologic screening, and those who reported that they had Parkinson's disease, or were taking antiparkinsonian drugs were identified. In our study, 16 subjects showed evidence of Parkinson's disease. The prevalence in this population was 0.37%. Prevalence increased with age, and prevalence was 1.47% for those aged older than 60 years. Postural instability and gait disturbance were more common in the older age group. The results of neuropsychological tests were as follows: (1) only two subjects had low scores (<20) in the Korea-version mini-mental status examination; (2) seven subjects scored 0.5, one subject scored 2 and the other eight subjects scored 0 in the clinical dementia rating. The results of our prevalence study are similar to those of studies carried out in Western countries. Age is a risk factor for Parkinson's disease in Korea.     

Assessment of sexual dysfunction in patients with Parkinson’s disease: a case–control study

Background: Sexual dysfunction (SD) in patients with Parkinson’s disease (PD) has not been very well studied, as most of the research has methodological restrictions like having no control group, using invalid assessment tools, unidimensional investigation of sexual functions and inclusion of males/females only. This study aimed to examine different sexual functions in patients with PD and compare with matched non‐parkinsonian controls by using a valid instrument. Predicting factors of SD in PD were also investigated. Methods: The sample consisted of 45 patients with PD and 45 age‐ and sex‐matched healthy controls. Sexual functions were evaluated by Arizona Sexual Experiences Scale (ASEX). Results: Female patients had reduced sexual drive and they were less satisfied with orgasm, while male patients had easier orgasms than did the controls. Regression analysis identified increased age and female sex predictive of reduced sexual drive and sexual arousal. Ability to reach orgasm and satisfaction with orgasm were associated with female sex, while erection/lubrication was associated with marital status. The severity and duration of PD, as well as the severity of anxiety and depression were not associated with SD. Conclusion: Using ASEX in the detection of SD in PD might be important in directing patients to further evaluation and treatment.     

Slow wave sleep and dopaminergic treatment in Parkinson’s disease: a polysomnographic study

Background – In Parkinson’s disease (PD), there is entanglement of disease‐inherent and treatment‐induced sleep abnormalities. So far, there has been no study specifically investigating the influence of diurnal dopaminergic medication (DM) on nocturnal slow wave sleep (SWS). Methods – Polysomnographic analysis in 62 PD patients. Results – PD patients had a sleep efficiency of 70 ± 17% and an SWS amount of 16 ± 11%. Linear regression analysis showed no significant correlation between the amounts of SWS and DM. However, patients with a medium DM dosage (300–600 mg of levodopa equivalents) preserved a SWS percentage >25% (p = 0.035, χ² test) more frequently than patients with higher or smaller DM. The DM dosage had no effect on other main sleep parameters. Psychotropic comedication had no effect on SWS percentage. In contrast, SWS amount was inversely correlated with both disease duration and age. It was independent of rapid eye movement sleep amount. The natural female bonus effect on SWS amount was absent in women with PD. Conclusion – Diurnal dopaminergic treatment has no major impact on SWS in PD, which, however, decreases with disease duration. Disease‐dependent, but treatment‐independent decrease in SWS suggests primary degeneration of sleep‐regulating systems in PD.     

Hyperhomocysteinemia recurrence in levodopa‐treated Parkinson’s disease patients

Background: Patients with Parkinson’s disease (PD) and chronically treated with L‐DOPA exhibit, in a percentage of 10–30%, supra‐physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper‐homocysteinemic PD patients, the time of hyper‐tHcy recurrence after discontinuation of 1‐month folate supplementation given to normalize plasma tHcy levels. Methods: Plasma tHcy, cobalamin and folate were assayed before and after 1‐month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontinuation in 29 PD patients (16M/13F, mean age 69.4 ± 6.9 years) stabilized on a mean L‐DOPA dose of 509.4 ± 312.1 mg/day. Results: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2‐month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper‐tHcy. Conclusions: One‐month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper‐homocysteinemic PD patients. Following folate discontinuation, hyper‐tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper‐homocysteinemic patients with PD.     

Calbindin‐1 association and Parkinson’s disease

Background and purpose: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient–control series. Methods: We genotyped rs1805874 in four independent Caucasian patient–control series (1543 PD patients, 1771 controls). Results: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82–1.31, P = 0.74). Discussion: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Neurotransmission in Parkinson’s disease: beyond dopamine

Parkinson’s disease (PD) is most frequently associated with characteristic motor symptoms that are known to arise with degeneration of dopaminergic neurons. However, patients with this disease also experience a multitude of non‐motor symptoms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some of which can be at least as debilitating as the movement disorders and have a major impact on patients’ quality of life. Many of these non‐motor symptoms may be evident prior to the onset of motor dysfunction. The neuropathology of PD has shown that complex, interconnected neuronal systems, regulated by a number of different neurotransmitters in addition to dopamine, are involved in the aetiology of motor and non‐motor symptoms. This review focuses on the non‐dopaminergic neurotransmission systems associated with PD with particular reference to the effect that their modulation and interaction with dopamine has on the non‐motor symptoms of the disease. PD treatments that focus on the dopaminergic system alone are unable to alleviate both motor and non‐motor symptoms, particularly those that develop at early stages of the disease. The development of agents that interact with several of the affected neurotransmission systems could prove invaluable for the treatment of this disease.     

Economic burden of Parkinson’s disease in Singapore

Background: This study was carried out to evaluate the economic burden of Parkinson’s disease (PD) and factors independently associated with individual components of total cost in Singapore. Methods: A consecutive sample of 195 patients with PD (mean age: 68.2, men: 51.8%) attending a tertiary neuroscience clinic were identified and interviewed using standardized questionnaires including a financial burden questionnaire, two Health Related Quality of Life (HRQoL) questionnaires and the Beck Depression Inventory questionnaire. Results: Annual total cost of PD from a societal perspective was SGD11345 (USD10129) per patient, with direct cost accounted for 38.5% and indirect cost 61.5%. The main cost components for direct medical cost, direct non‐medical cost, and indirect cost was pharmacotherapy (50.4%), home care (76.1%), and productivity loss (97.9%), respectively. In multiple linear regression analysis, higher education, younger age and longer duration of PD were associated with higher total cost. Conclusions: Parkinson’s disease exerts a considerable burden on patients, health care system and society in Singapore. As productivity loss accounts for a large share of the economic burden imposed by PD, treatments and health care programmes with potential for returning patients to higher productivity are urgently needed.     

Serum somatostatin in early‐stage Parkinson’s disease

Shiraishi M, Kobayashi T, Watanabe H, Kamo T, Hasegawa Y. Serum somatostatin in early‐stage Parkinson’s disease.
Acta Neurol Scand: 2010: 121: 225–229.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To compare levels of plasma digestive hormones in patients with and without nausea or vomiting during initial treatment of early‐stage Parkinson’s disease (PD). Methods – This was a 3‐week, open‐label, randomized study of treatment with an antiparkinson drug in untreated PD patients. We measured the levels of plasma digestive hormones before (baseline) and 3 weeks after administration of an antiparkinson drug. Results – Mean value of serum somatostatin at baseline was significantly increased in PD patients compared with the control group (P < 0.01). Serum somatostatin levels were significantly increased after treatment in subjects who experienced nausea or vomiting (P < 0.01). However, significant increase in serum somatostatin levels after treatment was not observed in PD patients without nausea or vomitting. Conclusion – Serum somatostatin in early‐stage PD patients before treatment was increased compared with healthy subjects. The nausea and vomiting induced by antiparkinson drugs may be related to uncontrolled somatostatin secretion through central vagus nerve dysfunction .     

Visual feedback has differential effects on reaching movements in Parkinson’s and Alzheimer’s disease

We examine the role of visual feedback in the programming and execution of reaching movement in patients with Parkinson’s disease without cognitive impairment and patients with Alzheimer’s disease without extrapyramidal signs. Controls were normally aging subjects. All subjects moved a cursor to targets on a digitizing tablet without seeing their limb. Starting and target positions were always visible on a screen while, during movement, cursor position was either visible or blanked. They were instructed to make uncorrected movements, as fast and as accurate as possible without minimizing reaction time. In absence of visual feedback, movement accuracy in patients with AD was severely impaired. Hand paths of parkinsonian patients were as accurate as normal subjects’ with similar temporal velocity profiles and movement speed. With cursor feedback, accuracy was the same in the three groups, although movement speed and transport phase in patients with Alzheimer’s disease were significantly reduced compared to the other groups. Also, movements of parkinsonian patients showed shorter transport phase and lower mean velocity than controls’. The different characteristics of the motor performance suggests that in the two diseases visual information is used differently for both motor programming and execution: patients with Alzheimer’s disease, while scarcely using feed forward commands, relied on continuous on-line external cues. The correlation of motor performance with cognitive impairment argues against the hypothesis of basal ganglia involvement in AD. The motor abnormalities we found may represent early subclinical manifestation of apraxic disturbance. Parkinsonian patients showed higher reliance on feedback commands only with cursor feedback: this could be explained by their difficulty in engaging effectively automatic routines when distractors are present.     

Longitudinal study of the socioeconomic burden of Parkinson’s disease in Germany

Objective: To determine the health economic burden on patients with Parkinson’s disease (PD) in Germany over a 12‐month observation period and provide a comprehensive analysis of cost‐driving factors. Methods and patients: Patients with PD (n = 145) were recruited from two clinical departments, two office‐based neurologists and 12 GPs. Clinical evaluations were performed at baseline, 3, 6 and 12 months. Disease severity was measured using the Unified Parkinson’s Disease Rating Scale (UPDRS). Cost data were assessed based on a patient diary and via personal structured interviews at the respective time‐points. Costs were calculated from the societal perspective (2009 €). Cost‐driving factors were identified by multivariate regression analysis. Results: Mean annual costs totalled €20 095 per patient. Amongst direct costs, the highest expenditures (€13 158) were for drugs (€3526) and inpatient care including nursing homes (€3789). Indirect costs accounted for 34.5% (€6937) of total costs. Costs of home care provided by family accounted for 20% of direct costs. Cost‐driving factors were identified for total costs (UPDRS, fluctuations, dyskinesia and younger age), direct costs (UPDRS, fluctuations), patient expenditures (UPDRS, depression) and drug costs (younger age). Conclusion: Parkinson’s disease has a chronic course with growing disability and considerable socioeconomic burden. Disease progression leads to an increasing number of patients who require costly institutionalized care. Home care is a major factor influencing patients’ families. Healthcare programmes aimed at reducing the burden of PD on society and individuals should consider cost‐driving factors of PD.     

Death‐associated protein kinase 1 variation and Parkinson’s disease

Background and purpose: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson’s disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer’s disease. Methods: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson’s disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson’s disease, 344 controls) and five separate Caucasian series’ (combined sample size 1962 Parkinson’s disease patients, 1900 controls). Results: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson’s disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. Conclusion: These specific DAPK1 intronic variants do not increase the risk of Parkinson’s disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.     

Parkinson’s disease mimicking senile dementia of the Alzheimer type: a clinicopathological study of four autopsy cases

This report concerns four Japanese autopsy cases of Parkinson’s disease (PD) mimicking senile dementia of the Alzheimer type. Three patients with a clinical diagnosis of senile dementia of the Alzheimer type developed memory disturbance as the initial sign, and a patient with a clinical diagnosis of atypical senile dementia presented with hallucination and delusion as the initial sign. Dementia was evident in all four patients, and slight parkinsonism appeared in the middle to late stages of the disease in two patients. Macroscopical examination of the brain disclosed slight depigmentation of the substantia nigra and pro‐minent depigmentation of the locus ceruleus in all four cases. Histological examination of the four patients showed neuronal loss with astrocytosis and the appearance of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. The nucleus basalis of Meynert was involved in three cases, in which this structure was examined. The total Lewy body scores of the four cases were 1 in three cases and 0 in the other, compatible with PD. Massive appearance of senile plaques, consistent with Braak stage C, was found in one case, and the slight appearance of senile plaques, consistent with Braak stage A, was evident in two cases. One case had no evidence of senile plaques. In all four cases, slight neurofibrillary changes were present in the limbic areas, compatible with Braak stages II to III. Based on these clinicopathological findings and a review of the literature, we concluded that PD simulating Alzheimer’s disease without overt parkinsonism rarely exists. Furthermore, we postulate that the clinical features of PD are more widespread than previously believed.     

Transcranial magnetic stimulation and Parkinson’s disease

While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson’s disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at ‘rest’, or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed ‘central silent period’, which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABA_B receptors. The so-called ‘short-interval intracortical inhibition’, which is possibly mediated by GABA_A receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.