Striatal dopaminergic activity (FDOPA-PET) associated with cognitive items of a depression scale (MADRS) in Parkinson's disease

Motor symptoms form the hallmark of Parkinson's disease (PD), although other features such as depression are often present. Currently-used depression rating scales measure affective and somatic symptoms. These somatic symptoms of depression can also be core PD symptoms, suggesting an overlap of symptoms between depression and PD. Using in vivo radiotracer methods, striatal dopaminergic dysfunction is found in both PD and depression. This study investigates to what extent the overlapping symptoms of depression and PD are associated with the striatal dopaminergic dysfunction typical of PD. Symptoms of depression were assessed in 23 PD patients who did not have major depression according to the Montgomery-Asberg depression rating scale (MADRS; cut-off < 18) and according to a trained psychologist who interviewed all patients. The striatal dopaminergic activity of patients was assessed with FDOPA-PET. Dopaminergic activity of the putamen and caudate nucleus was associated with MADRS total score and specifically with the symptom 'Concentration difficulties'. These results suggest that the typical striatal dopaminergic dysfunction of PD can cause symptoms that can also be categorized as symptoms of depression. In particular, cognitive symptoms measured with a depression rating scale may be based on the dopaminergic dysfunction of the striatum in PD patients.     

Position Emission Tomography/Single‐Photon Emission Tomography Neuroimaging for Detection of Premotor Parkinson's Disease

Premotor Parkinson's disease (PD) refers to a prodromal stage of Parkinson's disease (PD) during which nonmotor clinical features may be present. Currently, it is difficult to make an early diagnosis for premotor PD. Molecular imaging with position emission tomography (PET) or single‐photon emission tomography (SPECT) offers a wide variety of tools for overcoming this difficulty. Indeed, molecular imaging techniques may play a crucial role in diagnosing, monitoring and evaluating the individuals with the risk for PD. For example, dopaminergic dysfunctions can be identified by detecting the expression of vesicular monoamine transporter (VMAT2) and aromatic amino acid decarboxylase (AADC) to evaluate the conditions of dopaminergic terminals functions in high‐risk individuals of PD. This detection provides a sensitive and specific measurement of nonmotor symptoms (NMS) such as olfactory dysfunction, sleep disorders, and psychiatric symptoms in the high‐risk patients, especially at the premotor phase. Molecular imaging technique is capable of detecting the dysfunction of serotonergic, noradrenergic, and cholinergic systems that are typically associated with premotor manifestations. This review discusses the importance of SPECT/PET applications in the detection of premotor markers preceding motor abnormalities with highlighting their great potential for early and accurate diagnosis of premotor symptoms of PD and its scientific significance.     

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.     

Subcutaneous apomorphine and non-motor symptoms in Parkinson's disease

Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case–control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double-blind studies.     

Pathophysiology of Parkinson's disease

Parkinson's disease (PD) has classically been considered a disease of motor dysfunction, but it also includes psychiatric symptoms. To better understand the symptoms and signs that accompany PD, the interrelationships of deep brain structures and cortical areas involved with this neurodegenerative disease must be investigated.Current models of basal ganglia/cortical physiology attempt to integrate motor and nonmotor physiology and describe the pathophysiology attributable to PD. The cortical areas comprising basal ganglia/cortical loops include frontal structures involved in motor program as well as more prefrontal structures likely subserving non-motor functions such as cognition. The etiology of PD is not clear, but studies have implicated oxidative stress from exogenous stressors or endogenous neurotoxins. A large number of PD patients have been found to exhibit mitochondrial dysfunction. Lewy bodies are seen within dopaminergic and other neuronal populations affected in PD, and they stain positive for ubiquitin and alpha-synuclein. The small percentage of familial PD has often been found to coincide with dominantly inherited mutations in the gene for alpha-synuclein, or with the recessive gene mutation for parkin, which is involved in the ubiquitination pathway. Selected neuronal populations are affected in PD, and the neurodegeneration may include dopaminergic neurons outside the substantia nigra pars compacta, as well and non-dopaminergic neurons. The loss of these neuronal populations within the basal ganglia-frontal circuits can have a profound effect upon the motor and neurobehavioral symptoms in PD. L-dopa remains the most effective pharmacologic therapy for PD, however as the disease progresses, the drug loses its efficacy and troublesome sideeffects often occur. The renewal of surgical interventions for PD has increased the insight into the pathophysiology of PD,and surgical lesions have shown that motor and cognitive fronto-subcortical circuits are seemingly segregated in patients with PD. Investigation into these circuits helps provides models underlying motor and cognitive pathophysiology of PD.     

帕金森病患者非运动症状的发生及对日常生活能力的影响

目的 研究帕金森病(PD)患者非运动症状(NMS)的发生情况,及其对PD患者日常生活能力(ADL)的影响.方法 对107例PD患者进行NMS问卷(NMS Quest)调查,分析NMS的分布状况及临床特征,并采用统一PD评定量表(UPDRS)、Hoehn-Yahr分期、左旋多巴等效剂量、ADL问卷、MMSE评分进行评估,采用多元逐步线性回归探讨NMS对ADL的影响.结果 97.2%(104/107)的PD患者伴发不同程度的NMS,其发生数平均(8±5)个,其中尿频、便秘、记忆力下降最常见,发生率均超过50%;UPDRS-Ⅲ评分(28.0±16.4)分,能解释ADL总分变化的48.1%(R~2=0.481,P=0.000),引入NMS分值后,ADL分值可被解释的部分增加到51.1%.结论 PD患者普遍伴发NMS,而影响患者的ADL.PD可能是由NMS和运动症状共同组成的多系统神经变性疾病.PD患者的NMS在临床上应引起同样的重视,运动症状与NMS同治,才能提高疗效和ADL.     

Non-motor symptoms of Parkinson’s disease: the patient’s perspective

Parkinson’s disease (PD) can be manifested in many different ways. Although motor dysfunction represents the best characterised of the symptoms, the non-motor symptoms (NMS) of the condition can be equally disabling for people. These have been highlighted as being an issue of particular importance by people with PD. A comprehensive postal survey of members of the charity Parkinson’s UK took place in 2008. This resulted in returns from 10,101 people with PD. The self-completed Non-Motor Questionnaire (NMSQuest) and quality of life scale (PDQ-8) were contained within the survey. The results showed that the percentage of people with PD experiencing NMS increased with the duration of the disease. However, people who had the younger onset form of the condition reported a greater impact of NMS, particularly in the areas of memory, depression and sleep function. There is an inverse correlation between NMS and (PDQ-8 scale). A significant number of people with PD reported that they experienced problems with olfaction, taste, nocturia and constipation prior to diagnosis and these may help to serve as a future biomarker for the condition. Although our understanding of PD-associated NMS has increased considerably in the recent past, there is still a general lack of awareness of the importance of NMS for people with PD. Further research is required to identify the best treatments that should be employed to address them.     

Cognitive and behavioral dysfunction in Parkinson’s disease: neurochemical and clinicopathological contributions

The cognitive and behavioral sequelae (i.e., nonmotor profile) of Parkinson's disease (PD), with executive dysfunction and depression being most prominent, have typically been overshadowed due to an emphasis on motor symptomatology. The apparent categorization of PD as a disorder isolated to the dopaminergic system may be a generalization of the disease pathology. Dopamine therapy, used for the treatment of motor symptoms, has not consistently been shown to resolve nonmotor impairments. Research evidence indicates that nondopaminergic neurotransmitter systems (i.e., serotonergic, noradrenergic, & cholinergic) are disrupted in PD and may contribute to cognitive and behavioral dysfunction. Furthermore, Lewy bodies within cortical and subcortical structures can add to the nonmotor profile in PD. Pharmacological interventions for the treatment of cognitive and behavioral impairments associated with PD are few, especially for nondemented patients. The current review of the literature highlights evidence that associates nonmotor dysfunctions with neurochemical and clinicopathological correlates of PD.     

Link between non-motor symptoms and cognitive dysfunctions in de novo, drug-naive PD patients

Little is known about the relationship between cognitive dysfunctions and the non-motor complex in subjects with newly diagnosed untreated Parkinson's disease (PD). The aim of this study was to explore the association between non-motor symptoms (NMS) and cognitive dysfunctions in an incident cohort of de novo, drug-naive, PD patients. Sixty-six non-demented, early, untreated PD patients completed a semi-structured interview on NMS and a battery of neuropsychological tests that assess verbal memory, visuospatial abilities, and attention/executive functions. Scores were age- and education-corrected. Patients who failed at least two tests for each cognitive domain were diagnosed as having mild cognitive impairment (MCI). All but three (95.4%) PD patients complained of at least one NMS. A total of 37.8% was diagnosed with MCI. There was a relationship between sleep-NMS and cognitive dysfunctions. Specifically, both REM behavioral sleep disorders (RBD) and insomnia were associated with lower scores on several cognitive tests. Moreover, RBD was closely related to MCI. NMS and MCI are very common even in the early phase of PD, before patients are treated. Given the correlation between sleep disturbances and cognitive impairment, it is possible that sleep symptoms in PD patients might be considered as an early marker of dementia.     

Synuclein deposition and non-motor symptoms in Parkinson disease

Parkinson disease (PD) is a multisystem neurodegenerative disorder clinically characterized by motor and non-motor (NM) symptoms. The causes of NM symptoms in PD, many of which antedating motor dysfunction, are multifocal and unlikely explained by single lesions. They include olfactory, autonomic, sensory, skin, sleep, visual, neuropsychiatric, and other manifestations. Most NM features in PD are related to α-synuclein pathology which, in addition to the dopaminergic striatonigral system, involves non-nigral brainstem nuclei, sympathetic, parasympathetic, enteric and pelvic plexuses, cardiac systems, submandibular gland, adrenal medulla, skin, retina, and other visceral organs. This suggests a topographical and chronological spread of lesions, particularly in the prodromal stages of the disease, which, however, awaits further confirmation. A few animal models are available that recapitulate NM symptoms in human PD, but their validity is under discussion. More studies are warranted to refine the exact correlations between presymptomatic and late-developing NM features of PD and α-synuclein pathology as a basis for more effective preventive and therapeutic options of this devastating disease.     

Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders

Using data from the PRIAMO study, we investigated non-motor symptoms (NMS) versus frontal lobe dysfunction in patients with idiopathic Parkinson disease (PD); 808 patients with PD and 118 with atypical parkinsonisms (AP) were consecutively enrolled at 55 Centers in Italy. Twelve categories of NMS were investigated. Cognitive impairment was defined as a Mini-Mental Status Evaluation score ≤ 23.8 and frontal lobe dysfunction as a Frontal Assessment Battery (FAB) score ≤ 3.48. Multivariable logistic regression was used to identify predictor of frontal lobe dysfunction in 524 PD patients, and a generalized linear model was used for each of the six FAB items. Not only the total FAB scores but also the single FAB items were lower in AP versus PD (p ≤ 0.005). Age (OR = 1.05), cognitive impairment (OR = 9.54), lack of cardiovascular symptoms (OR = 3.25), attention or memory problems (OR = 0.59) and treatment with L: -DOPA (OR = 5.58) were predictors of frontal lobe dysfunction. MMSE was negatively associated with all FAB items (β ≤ -0.16) and age with all FAB items but prehension behavior (β ≤ -0.01). Previous use of L: -DOPA was negatively associated with verbal fluency (β = -0.32) possibly acting as surrogate marker of disease duration. Cognitive impairment is a predictor of frontal lobe dysfunction. Among NMS, lack of attention or memory problems were negatively associated with frontal impairment. Further studies are nonetheless needed to better identify the predictors of frontal impairment in PD patients.     

Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models?

Parkinson's disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non-motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non-motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological symptoms.     

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.     

帕金森病康复治疗及其作用机制研究进展

帕金森病是渐进性黑质致密部多巴胺能神经元退行性变导致的疾病,康复治疗可以延缓病情进展,改善运动症状和非运动症状,提高患者日常生活活动能力。康复训练改善帕金森病症状的机制复杂,涉及多种分子学机制,本文系统阐述康复训练对帕金森病症状的改善作用,以及神经递质、营养因子、突触可塑性和免疫系统等方面的分子学机制。     

The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease

We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0–32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ‐39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales. © 2009 Movement Disorder Society     

帕金森病相关认知功能障碍

帕金森病认知功能障碍起病隐匿,是帕金森病常见非运动症状,包括帕金森病轻度认知损害和帕金森病痴呆,尤以执行功能障碍突出,亦可见视空间能力、记忆力和言语功能等认知域损害。主要危险因素包括男性、高龄、低受教育程度、严重运动症状、基线认知功能较差和白天过度嗜睡。主要病理改变是脑组织路易小体形成,也可见阿尔茨海默病样病理改变。脑脊液总α-突触核蛋白和β-淀粉样蛋白1~42水平降低作为生物学标志物的价值尚存争议。相关基因研究较少且无法获得肯定结论。PET显像发现多巴胺能通路和乙酰胆碱能通路均参与帕金森病认知功能障碍的发生;MRI研究发现皮质及皮质下结构萎缩与帕金森病认知功能障碍有关。嗅觉障碍可能是帕金森病认知功能障碍的预测因素之一。帕金森病痴呆与路易体痴呆具有共同的生物学特性,二者鉴别诊断困难。胆碱酯酶抑制剂和美金刚有助于改善临床症状,应注意个体化治疗。认知行为疗法具有潜在临床价值,尚待更多研究。     

Gastrointestinal symptoms in Parkinson's disease

We have investigated the prevalence of gastrointestinal (GI) symptoms in 98 individuals with Parkinson's disease (PD) and in a control group of 50. Seventy-nine of those with PD were being treated with dopaminergic medications and 19 were untreated. Those symptoms occurring more frequently in PD patients than in controls included abnormal salivation, dysphagia, nausea, constipation, and defecatory dysfunction. Except for defecatory dysfunction, symptoms did not correlate with treatment but instead correlated with disease severity. This suggests that the GI symptoms of PD reflect direct involvement in the GI tract by the primary disease process.     

Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson's disease

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson??s disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk^?/?) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk^/? mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk^?/? mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.     

Impaired cognitive performance in Parkinson's disease is related to caudate dopaminergic hypofunction and hippocampal atrophy

Frontal lobe dysfunction and other cognitive deficits have been described in Parkinson's disease (PD), which may lead to dementia. Both striatal dopaminergic deficiency and regional or global brain volume loss have been suggested to contribute to cognitive decline in PD. We therefore performed a neuropsychological evaluation, structural brain MRI and Fdopa PET in patients with PD and healthy elderly volunteers. PD patients had impaired cognitive performance in many neuropsychological tests compared to controls, not limited just to frontal lobe function tests. Caudate Fdopa correlated positively with performance in verbal (immediate and delayed) and visual memory. Patients with PD showed atrophy in the hippocampus and the prefrontal cortex and hippocampal atrophy was related to impaired memory. Our findings suggest that striatal dopaminergic depletion and global brain volume loss contribute to cognitive impairment in non-demented PD patients, but dysfunction of extra-striatal dopaminergic or non-dopaminergic systems probably plays a role especially in more generalized cognitive impairment.     

Autonomic dysfunction in 3414 Parkinson's disease patients enrolled in the German Network on Parkinson's disease (KNP e.V.): the effect of ageing

We analysed non-motor symptoms (NMS) related to autonomic dysfunction in 3414 patients with Parkinson's disease (PD) enrolled in the multicentre registry of the German Competence Network on PD. Orthostatic hypotension (>20 mmHg systolic or >10 mmHg diastolic) was reported for 10% of women and 11% of men, urinary incontinence for 22% of women and 21% of men, sexual dysfunction for 8% of women and 30% of men (50% of whom reported erectile dysfunction) and sleep disturbances for 43% of women and 35% of men. Autonomic symptoms occurred in a frequency similar to severe disabling dyskinesia which was reported for 16% of women and 11% of men. A logistic regression analyses with age, sex and disease duration as covariates revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and disease duration whilst sexual dysfunction was related to age only. These observations suggests that the effects of the PD process and ageing contribute to non-levodopa responsive NMS. Sleep disturbances were more common in women and a correlation was found with disease duration only supporting the notion that sleep is specifically affected in PD.