Pathoanatomy of Parkinson’s disease

Parkinson’s disease is a widespread degenerative illness affecting the human central, peripheral, and enteric nervous systems. The underlying pathological process progresses slowly but relentlessly and involves multiple neuronal systems. The disease is the consequence of changes in the neuronal cytoskeleton developing in only a few susceptible types of nerve cells. Afflicted neurons eventually produce Lewy bodies in their perikarya and Lewy neurites in their neuronal processes.

Immunoreactions against the presynaptic protein α-synuclein have revealed many kinds of inclusion bodies ranging from inconspicuous dot- or thread-like forms to particularly voluminous types. The selective vulnerability of nerve cells induces a distinctive distribution pattern of lesions which remains remarkably consistent across cases. Components of the limbic system and the motor system have been shown to be particularly vulnerable to severe destruction. Some subnuclei of the substantia nigra also undergo major changes. This damage is consistently accompanied by extranigral alterations, with predilection sites including the entorhinal region, the second sector of the Ammon’s horn, and important subnuclei of the amygdala. In addition, the nucleus of the stria terminalis, components of the hypothalamus, all of the non-thalamic nuclei with diffuse projections to the cerebral cortex, and most of the centers regulating autonomic functions exhibit severe lesions.

     

Psychiatric aspects of Parkinson’s disease

Abstract. In patients with Parkinsons disease (PD) disturbances of mental state constitute some of the most difficult treatment challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability and poor quality of life. This article provides an update on the current knowledge of these complications and the use of old and new drugs in their management. Mental state alterations in PD include depression, anxiety, cognitive impairment, apathy, and treatment-related psychiatric symptoms. The latter range from vivid dreams and hallucinations to delusions, manic symptoms, hypersexuality, dopamine dysregulation syndrome and delirium. While some of these symptoms may be alleviated by anti-parkinsonian medication, especially if they are off-period related, treatment-related phenomena are usually exacerbated by increasing the number or dosage of antiparkinsonian drugs. Elimination of exacerbating factors and simplification of drug regimes are the first and most important steps in improvement of such symptoms. However, the advent of atypical antipsychotics such as clozapine has dramatically helped the management of treatment-related psychiatric complications in PD. In patients with dementia associated with PD cognitive functioning and behavioural problems appear to respond to cholinesterase inhibitors, such as rivastigmine or donepezil. Depression is a common problem in early as well as advanced PD, and selective serotonin reuptake inhibitors, reboxetine, and tricyclic antidepressants have been reported to be effective and well tolerated antidepressants. Randomised, controlled studies are required to assess the differential efficacy and tolerability of antidepressants in patients with PD, including the newer antidepressants with serotonergic and noradrenergic properties.     

Toxin-induced models of Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.     

Genetic association of Parkinson’s disease

Totally three articles regarding associations of Nurr1 gene mutations, LRRK2 gene polymorphism sites S1647T and R1398H, and polymorphism of PARK2 gene mutations with Han Chinese patients with Parkinson’s disease were published in Neural Regeneration Research. We hope that our readers find these papers useful to their research.     

Occurrence of Crohn's disease with Parkinson’s disease

We retrospectively investigated the co-occurrence of Crohn's disease in a cohort of 876 patients with Parkinson’s disease, based on the observation that LRRK2 is a shared genetic risk factor. We identified 2 patients with Crohn's disease; this number was consistent with the number of cases expected in the general population.     

Quality of life in Parkinson’s disease: Italian validation of the Parkinson’s Disease Questionnaire (PDQ-39-IT)

Translation and cross-cultural adaptation of the 39-item Parkinson’s Disease Questionnaire (PDQ-39) to the Italian culture was performed by Oxford University Innovation in 2008, but this version has never been validated. Therefore, we performed the process of validation of the Italian version of the PDQ-39 (PDQ-39-IT) following the “Consensus-Based Standards for the Selection of Health Status Measurement Instruments” checklist. The translated PDQ-39-IT was tested with 104 patients diagnosed with Parkinson’s disease (PD) who were recruited between June and October 2017. The mean age of the participants was 65.7?±?10.2 years, and the mean duration of symptoms was 7.4?±?5.3 years. The internal consistency of the PDQ-39-IT was assessed by Cronbach’s alpha and ranged from 0.69 to 0.92. In an assessment of test-retest reliability in 35 of the 104 patients, the infraclass correlation coefficient (ICC) ranged from 0.85 to 0.96 for the various subitems of the PDQ-39-IT (all p?<?0.01). Spearman’s rank correlation coefficient for the validity of the PDQ-39-IT and the Italian version of the 36-Item Short Form (SF-36) was ??0.50 (p?<?0.01). The results show that the PDQ-39-IT is a reliable and valid tool to assess the impact of PD on functioning and well-being. Thus, the PDQ-39-IT can be used in clinical and research practice to assess this construct and to evaluate the overall effect of different treatments in Italian PD patients.     

Animal models of Parkinson’s disease progression

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology is not understood. This disease occurs both sporadically and through inheritance of single genes, although the familial types are rare. Over the past decade or so, experimental and clinical data suggest that PD could be a multifactorial, neurodegenerative disease that involves strong interactions between the environment and genetic predisposition. Our understanding of the pathophysiology and motor deficits of the disease relies heavily on fundamental research on animal models and the last few years have seen an explosion of toxin-, inflammation-induced and genetically manipulated models. The insight gained from the use of such models has strongly advanced our understanding of the progression and stages of the disease. The models have also aided the development of novel therapies to improve symptomatic management, and they are critical for the development of neuroprotective strategies. This review critically evaluates these in vivo models and the roles they play in mimicking the progression of PD.     

Impact of drooling in Parkinson’s disease

Drooling is a well known problem in patients with Parkinson's disease (PD). The aim of this study was to investigate the severity and consequences of drooling in PD. A comprehensive drooling questionnaire was sent to 105 PD outpatients, who had volunteered drooling during a previous questionnaire (n = 216). Among 63 patients who responded and confirmed drooling, 27% experienced severe saliva loss. Social and emotional consequences were reported by 17% to 77% of patients, and significantly more often by those with severe drooling. We conclude that drooling is a frequent, disabling and apparently undertreated symptom of PD. History taking ought to be detailed and specific to understand the full impact of drooling for an individual patient. Therapeutic options should be evaluated more intensively.     

Pharmacotherapy of Parkinson’s disease in Germany

Treatment standards or guidelines have been developed for most features of Parkinson’s disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson–Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 ± 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximately € 399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non–motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.     

Neuroimaging in Parkinson’s disease

In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson’s disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.     

Depression in Parkinson’s disease

Among the recently well appreciated non-motor symptoms in Parkinson’s disease (PD), depression plays a prominent role due to its frequency and impact on quality of life. However, depression may be confounded by motor symptoms, especially akinesia and other non-motor symptoms such as apathy, anxiety and dementia. Data on specific diagnostic tools or treatment for depressive symptoms in PD patients are still sparse. Here we summarize an expert opinion based on available data and clinical experience.

     

Depression and Parkinson’s disease

Abstract.   Depression occurs in approximately 45% of all patients with Parkinsons disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.     

The role of autophagy in Parkinson’s disease

Although Parkinson’s disease is the most common neurodegenerative movement disorder, the mechanisms of pathogenesis remain poorly understood. Recent findings have shown that deregulation of the autophagy-lysosome pathway is involved in the pathogenesis of Parkinson’s disease. This review summarizes the most recent findings and discusses the unique role of the autophagy-lysosome pathway in Parkinson’s disease to highlight the possibility of Parkinson’s disease treatment strategies that incorporate autophagy-lysosome pathway modulation.     

Management of non-motor complications in Parkinson’s disease

The problem of diagnosing vasculitic neuropathy is discussed based on case reports of two patients with Wegener’s granulomatosis. One patient developed de novo 6^th nerve palsy as an isolated relapse manifestation and the second patient a sequence of multiple cranial nerve palsies. Brain imaging with CT and MRI and the laboratory provided no clues suggesting active vasculitis. However, in both patients the neuropathies fully recovered in response to standard induction protocols of vasculitis. In the absence of organspecific proof of vasculitis, these treatment decisions were guided by the overall clinical presentations. Cranial neuropathy may be the first obvious vasculitic manifestation preceding other organ disease, and since single reliable tests for its diagnosis are lacking, a multidisciplinary approach is advocated here to detect vasculitic manifestations in other organs.     

Changes of hand preference in Parkinson’s disease

This study focused on the difference between pre-morbid and current hand preference of patients with Parkinson's disease (PD). A survey instrument comprised items measuring pre-morbid and current hand preference and question related to the side of occurrence of initial symptoms. These questions were administered to 471 PD patients. The results show a significant change of pre-morbid right hand preference toward using the left when the side of PD onset was on the right hand and vice versa. Disease duration does not predict the amount of hand preference shift.     

CSF markers of neurodegeneration in Parkinson’s disease

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease with a multifactorial etiology. Protein accumulation is speculated by some to play a prominent role in the pathogenesis of PD. The severity of neurodegeneration should correlate with cerebrospinal fluid (CSF) levels of these neurodegenerative markers (NDMs). The aims of the study were to assess the CSF levels of tau protein, beta-amyloid (1–42), cystatin C, and clusterin in patients suffering from PD and in a control group, to compare the CSF levels between the two groups and to correlate them to PD duration. NDMs in the CSF were assessed in 32 patients suffering from PD and in a control group (CG) of 30 patients. The following statistically significant differences in the CSF were found: higher tau protein (p = 0.045) and clusterin levels (p = 0.004) in PD patients versus CG; higher tau protein levels (p = 0.033), tau protein/beta-amyloid (1–42) ratio (p = 0.011), and clusterin (p = 0.044) in patients suffering from PD for <2 years versus patients suffering PD for more than 2 years. No differences between beta-amyloid (1–42) and cystatin C CSF levels were found in the CG and PD patients groups. Significantly higher tau protein and clusterin CSF levels in the group of PD patients with disease duration of <2 years probably reflect the fact that most neurodegenerative changes in PD patients occur in the initial stage of disease.