Parkinson's disease related pain: a review of recent findings

In this review we summarize progress in research on Parkinson's disease-related pain as reported in articles published in the Journal of Neurology in the years 2011 and 2012.     

Transcranial sonography findings in Parkinson's disease

Interest in diagnostic biomarkers that improve identification of Parkinson's disease (PD) in the early stages has been recently increasing. Accurate diagnosis of PD is currently a challenge for clinical neurologists. In addition, recent advances in basic research towards neuroprotective strategies for PD are increasingly highlighting the need for diagnostic biomarkers that improve identification of PD in the early stages. As such, substantia nigra hyperechogenicity visualized by transcranial sonography (TCS) has gained increasing attention and has been implemented in PD diagnosis globally. As substantia nigra hyperechogenicity offers unique information supplementary to those provided by other neuroimaging techniques, and this echofeature is stable during the disease course, it is very helpful in early and differential diagnosis of PD. The pathophysiologic conditions underlying this echofeature are not fully understood; however, it maybe associated with increased amounts of iron. It should be reminded that there are several limitations in conducting TCS. The main limitation is that in Japanese subjects the rate of temporal bone window sufficient for an adequate sonographic analysis prominently decreases with advancing age, particularly in females. Another limitation is that measurements may vary between two laboratories. Therefore, investigators are required to generate their own reference values. Despite these limitations, TCS can be recommended as a useful technique for the diagnosis of PD owing to its fast and easy use, low cost, and noninvasive nature. This review summarizes the TCS technique, the typical findings, and their value in the diagnosis and differential diagnosis of PD.     

Advances in genetic models of Parkinson's disease

Parkinson's disease (PD) is the second most common neurological cause of death, after Alzheimer's disease, in elderly people. PD is characterized by a variety of motoric dysfunctions resulting from the loss of striatal dopamine, which accompany progressive degeneration of dopaminergic neurons in the substantia nigra. While the causes of PD remain elusive in most cases, recent molecular genetic studies have linked mutations in the α-synuclein gene with a rare form of familial PD and mutations in the parkins gene with an autosomal recessive form of familial PD. Identification of these genes is allowing for creation of genetic models where in vivo degenerative processes can be studied. In particular, various transgenic animals expressing human α-synuclein variants have demonstrated that α-synuclein abnormalities can lead to neurodegenerative changes in vivo. These and other genetic models of nigrostriatal degeneration will allow investigators to define in vivo cellular mechanisms that are relevant to PD pathogenesis.     

The neuropathology of genetic Parkinson's disease

Pathological data from autopsies genotyped for Parkinson's disease (PD)-related mutations in alpha-synuclein, Parkin, PINK1, DJ1, LRRK2, and glucocerebrosidase have accumulated in recent years. The aim of this review is to systematically review all pathological reports of mutation carriers and to identify pathological patterns and gaps in the currently available data. A systematic review of the English literature was done using the terms "Parkinson's disease," "brain pathology," "autopsy," the specific gene nomenclature, and any combination of the above. Most studies included reports of convenience samples: either cases that were preidentified as mutation carriers before autopsy or screens of Lewy body brain banks. Nineteen autopsies of alpha-synuclein mutation carriers, 49 of LRRK2 mutation carriers, nine of Parkin mutation carriers, one of a PINK1 mutation carrier, and 86 of glucocerebrosidase mutation carriers were identified. Most autopsies of alpha-synuclein, LRRK2 G2019S, and glucocerebrosidase mutation carriers demonstrated Lewy body pathology, as opposed to Parkin and LRRK2 non-G2019S mutation carriers. However, there was a marked variability in pathological findings, even among carriers of identical mutations. Pathological data from DJ1 mutation carriers, nonmanifesting mutation carriers (e.g., of LRRK2 mutations), and carriers of a single Parkin mutation were lacking. In gathering together all studies of PD autopsies with an identified genetic risk, this review highlights the wealth of information generated as well as shortcomings in the available data. In particular, there is a need for larger, unbiased pathological studies. Differential association of Lewy pathology with specific mutations may reflect heterogeneity in pathogenic mechanisms among the different PD-related genes.     

The genetic basis of Parkinson's disease

Although the mechanisms underlying neurodegeneration in Parkinson's disease are not fully understood, considerable evidence suggests that genetic factors can influence susceptibility to the disease. In this article, we critically review this evidence and examine studies estimating patterns of inheritance. In a few families, Parkinson's disease is clearly inherited in a Mendelian fashion, and in some of these the disease causing genes have already been identified. Possible pathogenic mechanisms by which these genes cause Parkinson's disease are discussed. Further candidate genes and systematic efforts to identify genes influencing susceptibility to the disease in general are also summarised. The identification of such susceptibility genes will eventually enable us to more accurately classify this complex disease.     

SPECT findings in Alzheimer's disease and Parkinson's disease with dementia

We examined, with single photon emission tomography (SPECT) and (^99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD) and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non-demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD.     

Neuropathological findings in PINK1-associated Parkinson's disease

IntroductionBiallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1 patients with brain autopsy have been reported in the literature.MethodsWe describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing.ResultsClinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4–5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region.ConclusionWe describe the first clinical and pathological characterization of a PINK1 patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.     

Parkinson's disease: a genetic study

A sample of 122 patients with Parkinson's Disease was studied for the purpose of investigating if the frequency of relatives affected with Parkinson in this group was higher than in a control group and to see if the genetic load was more important in some of the subtypes of Parkinson described by Barbeau and Pourcher (1982). In our 122 patients, we found that 1.7% were post-encephalic parkinsonian, 12.3% were symptomatic cases and 86% of the idiopathic variety. There were 16.1% early onset patients in the idiopathic group and among these we found 23.5% with a positive family history of Parkinson in the first-degree relatives. In 6 cases with the tremor onset form of the disease, the family history was positive and 5 patients, 4.7% had familial essential tremor-related Parkinsonism. Our results support Barbeau's hypothesis that Parkinson is a heterogeneous disease in which some subtypes (such as early onset Parkinson) have an important genetic susceptibility component.     

Autonomic dysfunction in recent onset and advanced Parkinson's disease

Cardiovascular autonomic nerve function and its relation to the clinical variables of untreated recent onset and levodopa-treated advanced disease parkinsonian patients were studied. Heart rate variations were diminished in both groups when compared with age-matched controls. An orthostatic blood pressure drop was found in both disease groups. The drop was stronger and related to the levodopa dose in the advanced disease group. In conclusion, 1) in Parkinson's disease a parasympathetic damage occurs which worsens during the course of the disease, 2) the orthostatic fall in blood pressure, indicating a sympathetic dysfunction, is partly due to the disease itself and partly due to levodopa treatment.     

Magnetic resonance imaging findings of shoulders in Parkinson's disease

The aim of this study is to evaluate shoulder disturbances in Parkinson's disease (PD) patients using magnetic resonance imaging (MRI) which is the best tool in the demonstration of complex shoulder pathologies; and to determine probable relations between shoulder pathologies and PD clinical features. Twenty‐eight PD patients with a total of 56 shoulders were used as the study group while 13 age‐matched cases with 26 shoulders were used as the control group (CG) in the study. Both patients with PD and the CG underwent shoulder MRI. The Hoehn and Yahr (H&Y) disability scale and Unified Parkinson's Disease Rated Scale (UPDRS) were used to determine the severity of the disease. Our results showed that patients with full‐thickness supraspinatus (SSP) tear have statistically significant higher UPDRS (P = 0.012), tremor (P = 0.023), rigidity (P = 0.023), and total (P = 0.002) scores. Mild group patients (P = 0.045) showed significantly higher frequency resting tremor and subcoracoid effusion than those of severe group patients (P = 0.002). Subcoracoid effusion was observed in patients with significantly higher UPDRS (P = 0.045) and rigidity (P = 0.022) scores. When the resting tremor and subcoracoid effusion groups were compared according to the severity of the resting tremor but not according to the H&Y, higher frequency of full‐thickness tear in SSP tendon was detected in the group of resting tremor (P = 0.053). Longer duration of disease was also observed in patients with full‐thickness SSP tear (P = 0.029) and acromioclavicular joint changes (P = 0.018). Higher UPDRS, tremor, rigidity and total scores and longer PD duration appear as the predisposing factors for the development of shoulder disturbances in PD in this study. © 2010 Movement Disorder Society     

Neurochemical findings in the MPTP model of Parkinson's disease

Summary. Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD. Received March 1, 2001; accepted July 11, 2001     

Advances in the genetic studies in Parkinson's disease

Genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted based on the studies of the familial form of the disease and progress in molecular genetic techniques. To date, specific mutations have been identified in five separate genes and several chromosomal loci have been linked for different forms of familial parkinsonism. The discovery of alpha-synuclein, ubiquitin C-terminal hydrolase, parkin, tau and DJ-1 mutations and analysis of the biochemical and molecular properties of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the basic mechanism leading to neurodegeneration also in sporadic form of the disease. Lewy bodies, even in sporadic PD, contain some of these gene products, particularly abundant fibrillar alpha-synuclein. Studies of familial parkinsonism provide evidence that PD is genetically heterogeneous. Evidence elucidated from genetic studies in PD suggests that parkinsonism is a complex disorder in which multiple gene-gene and gene-environment interactions play a critical role in the development of the disease and phenotypic variability. Further genetic studies in familial parkinsonism will enhance our knowledge of pathogenesis of PD and allow the development of neuroprotective treatments of PD and perhaps other forms of parkinsonism as well.     

Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease

Myocardial ¹²³Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ‐1, PINK1, and leucine‐rich repeat kinase 2 ‐LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin‐associated Parkinsonisms, in 1 of the 2 patients with DJ‐1 mutations, in 1 of the 2 brothers with PINK1 mutations, in 3 of the 6 unrelated patients with Gly2019Ser mutation in the LRRK2 gene, whereas it was impaired in all patients with idiopathic PD. MIBG was preserved in all control subjects. Our study shows that myocardial MIGB uptake was normal in 8 of 14 patients with genetic PD, suggesting that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. Our findings also demonstrate that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation. © 2007 Movement Disorder Society     

Impact of psychiatric disorders on Parkinson's disease

OBJECTIVES : To analyze whether hospitalization for a psychiatric disorder predicts Parkinson's disease (PD) in men and women in different age groups after accounting for socioeconomic status and geographical region. METHODS : Data from the MigMed database were used to identify all people in Sweden hospitalized for psychiatric disorder and PD during the study period (1987 to 2001). Standardized incidence ratios (SIRs) with 95% confidence intervals (CI) for PD were calculated among those with and without hospitalization for psychiatric disorder. RESULTS : There were 1876 cases of PD among those with psychiatric disorder during the study period. The risk of developing PD was strongest among those under age 50; the SIR was 11.56 (95% CI 9.15-14.41). The risk was attenuated with increasing age in both men and women. There were similar risk patterns in all subtypes of psychiatric disorders in PD patients. The overall risk of PD among people with psychiatric disorders was higher for women than men. CONCLUSIONS : A psychiatric disorder is an appreciable risk factor for the development of PD, particularly in people under age 50. The association between PD and psychiatric disorders should be taken into account by clinicians and health care providers.