Peripheral Neuropathy in de novo Patients with Parkinson's Disease

PurposeThis study aimed to investigate the prevalence of peripheral neuropathy (PNP) and its related serum metabolites in de novo patients with Parkinson''s disease (PD). PNP is a type of frequent comorbidity in PD. Although the administration of levodopa has been described as a presumptive risk factor in its development, few studies have explored its effect on unmedicated PD patients.Materials and MethodsThis study included 105 drug-naïve de novo PD patients. A standardized nerve conduction study (NCS) technique was used to evaluate motor or sensory neuropathy. We analyzed serologic tests including metabolic markers of vitamin B12, homocysteine (Hcy), and uric acid (UA).ResultsWe found abnormal nerve conduction velocity findings in 24 out of 105 total patients. Among them, 20 patients showed a type of combined motor-sensory, while three were a type of pure sensory and one was a pure motor. Nine patients had carpal tunnel syndrome. PD with PNP group demonstrated higher serum levels of Hcy and UA compared to PD without PNP group.ConclusionOur data demonstrated a potential role of Hcy and UA on PNP in de novo patients with PD. These results suggest the contribution of the inherent metabolic pathway in deterioration of the peripheral nervous system in PD.     

The Epidemiology of Dementia Associated with Parkinson's Disease

Parkinson''s disease (PD) is the second most common neurodegenerative illness after Alzheimer''s disease (AD). Cognitive impairment and dementia are common features in PD and characterized by a wide range of cognitive deficits distinct from those seen in AD. Mild cognitive impairment occurs even early in PD and is associated with shorter time to dementia. The purpose of this review is to present recent findings on clinical aspects of dementia in PD and to elucidate underlying clinical and neurobiological risk factors.     

Quantitative plasma DNA analysis in Parkinson's disease

Parkinson disease (PD) is a neurodegenerative disease resulting from the loss of the dopaminergic neurons from the substantia nigra pars compacta (SNpc). It is characterized by bradykinesia, rigidity, resting tremor and/or postural instability. The diagnosis of PD is essentially clinical and there is no reliable biological marker to assess its progression. Recently, investigations have been performed on the potential use of circulating cell-free deoxyribonucleic acid (DNA) in the plasma for clinical diagnosis, prognosis and monitoring of human diseases. The aim of this work was to assess the role of free DNA as a biological marker of PD. Forty-two patients with PD (19 men, 23 women) and 20 healthy (7 men, 13 women) subjects were enrolled in this study. Mean ± SD plasma DNA concentration in PD patients and control subjects were, respectively, 16,487 ± 16,378 (range: 100–62,034) kilogenomes-equivalents/L and 37,975 ± 17,832 (range: 15,143–78,783) kilogenomes-equivalents/L. There was a significant difference between control and PD groups (p < 0.001). There was no correlation between plasma DNA levels and demographic or clinical parameters in PD patients. Free DNA does not seem to be a reliable marker of PD progression. Further research is warranted to confirm the present results to have some value as biomarkers in other neurodegenerative diseases.     

Mortalin is Expressed by Astrocytes and Decreased in the Midbrain of Parkinson's Disease Patients

Mortalin, an essential mitochondrial chaperone protein, has previously been implicated in the pathogenesis of a wide array of diseases, including neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease. Previous reports have consistently described mortalin protein levels to be lower in the brain tissue of patients with neurodegenerative disease, with expression demonstrated to be lower in neurons of post‐mortem PD brain specimens. However, to date, mortalin expression has not yet been evaluated in astrocytes of post‐mortem brain tissue from either normal or PD subjects. Mortalin expression was demonstrated in mouse primary astrocyte cultures by Western blot and quantitative polymerase chain reaction (PCR). Furthermore, confocal microscopy studies in human post‐mortem tissue indicated co‐localization of mortalin within astrocytes. Utilizing a quantitative immunofluorescence staining approach, the protein was found to be moderately reduced (～35%) in this cell type in the substantia nigra pars compacta, but not structures of the corpus striatum, in PD subjects as compared to age‐/gender‐matched controls. These findings highlight the potential contribution of disrupted astroglial function in the pathogenesis of PD.     

Vascular Degeneration in Parkinson's Disease

Vascular degeneration plays a significant role in contributing to neurodegenerative conditions such as Alzheimer's disease. Our understanding of the vascular components in Parkinson's disease (PD) is however limited. We have examined the vascular morphology of human brain tissue from both PD and the control cases using immunohistochemical staining and image analysis. The degenerative morphology seen in PD cases included the formation of endothelial cell “clusters,” which may be contributed by the fragmentation of capillaries. When compared to the control cases, the capillaries of PDs were less in number (P < 0.001), shorter in length (P < 0.001) and larger in diameter (P < 0.01) with obvious damage to the capillary network evidenced by less branching (P < 0.001). The level of degeneration seen in the caudate nucleus was also seen in the age‐matched control cases. Vessel degeneration associated with PD was, however, found in multiple brain regions, but particularly in the substantia nigra, middle frontal cortex and brain stem nuclei. The data suggest that vascular degeneration could be an additional contributing factor to the progression of PD. Thus, treatments that prevent vascular degeneration and improve vascular remodeling may be a novel target for the treatment of PD.     

Palliative Care in Parkinson's Disease: Role of Cognitive Behavior Therapy

Background:

Parkinson''s disease (PD) is a chronic, progressive, neurodegenerative disorder that leads to the classic features of akinesia (encompassing hypokinesia and bradykinesia), tremor, rigidity and postural instability. Other non-motor complications include depression, fatigue, pain, and sleep disturbances. For the management of these complications, non-pharmacological techniques, such as Cognitive-behavioral therapy (CBT) can be used. This can focus on overt behavior and underlying cognitions and train the patient in coping strategies to obtain better symptom control.

Objectives:

To review studies on CBT as palliative care in PD patients.

Materials and Methods:

A survey was conducted for all available English-language studies by means of a MEDLINE search. Keywords in the searches included Parkinson''s disease, palliative care, and cognitive behavior therapy. All articles that reported the cognitive behavior therapy and palliative care in a group of PD patients regardless of the method used by the researchers were identified and analyzed.

Result and Conclusion:

CBT has a strong evidence base for its use and has proven to be an effective treatment in management of people with chronic pain, fatigue syndrome, depression and sleep disturbances, with efficacy that lasts beyond the duration of treatment. Although PD patients suffer from these complications, there are only a few studies on administration of CBT on them. Considering its effectiveness, CBT can be used as an option for palliative care for PD patients, directed toward improving the patient''s functional status, clinical disability and quality of life. Further studies are required in this area.     

再生障碍性贫血线粒体突变与端粒长度相关性的研究

目的：研究再生障碍性贫血患者线粒体突变及端粒长度情况,了解两者间的相关性。方法选择2010~2014年确诊为再生障碍性贫血的患者45例,留取骨髓及口腔黏膜上皮标本以进行线粒体DNA ( mitochondrial DNA, mtDNA)突变和端粒长度的检测。线粒体全测序检测到了151个突变,分布在18个基因中,其中包括了40个沉默突变及28个框移突变。同时使用HBG作为内参基因,检测了再障患者和健康志愿者端粒的相对长度( relative T/S value,端粒长度)。结果分析发现非沉默突变的mtDNA突变与白细胞数、血红蛋白水平及血小板数成负相关。端粒长度与白细胞数、血红蛋白水平及血小板数成正相关性,而且非沉默突变的mtDNA突变与端粒长度呈负相关性。结论研究提示突变导致线粒体氧化呼吸链功能紊乱及端粒的缩短是再障患者骨髓衰竭病程中的一个重要因素,而且这两者还会互相影响。     

Mitochondrial DNA sequence analysis of four Alzheimer's and Parkinson's disease patients

The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer's disease (AD) exhibiting AD plus Parkinson's disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD + PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA^Gln gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD + PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD + PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber's hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a causal role for these base substitutions in neurodegenerative disease. © 1996 Wiley-Liss, Inc.     

Analysis of EIF4G1 in Parkinson's disease among Asians

Sequence analysis of all the exons of EIF4G1 in 96 Asian patients with Parkinson's disease (PD) did not reveal any pathogenic mutations. A novel coding variant (Pro693Ser) in exon 15 (position 2077) was detected in one PD patient but not in 539 control subjects. Analysis of a coding polymorphic variant (rs2178403) in 1330 subjects revealed similar frequency between control subjects (0.638) and PD patients (0.640). EIF4G1 is an uncommon cause of PD in our Asian cohort.     

FGF20 rs12720208 SNP and microRNA-433 variation: No association with Parkinson's disease in Spanish patients

DNA variation at the FGF20 gene has been associated with Parkinson's disease (PD). In particular, SNP rs12720208 in the 3′ untranslated region (3′ UTR) was linked to PD-risk through a mechanism that would implicate a differential binding to microRNA-433 (miR-433). The reduction of the affinity of miR-433 to the 3′ UTR would result in increased FGF20 expression and upregulation of alpha-synuclein, which could in turn promote dopaminergic neurons degeneration. We genotyped the rs12720208 SNP in a total of 512 PD patients and 258 healthy controls from Spain, and searched for miR-433 variants in the patients. We did not find significant differences in allele and genotype frequencies between patients and controls. None of the patients had miR-433 variants. In conclusion, our work did not confirm the association between rs12720208 and PD, or an effect of miR-433 variants on this disease.     

Alpha‐Synuclein as a Biomarker for Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α‐synuclein (α‐syn)‐rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease‐specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α‐syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α‐syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α‐syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α‐syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α‐syn, to improve diagnostic accuracy is also likely required.     

Normal CAG and CCG repeats in the Huntington's disease genes of Parkinson's disease patients

The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease. © 1995 Wiley-Liss, Inc.     

The Treatment of Cognitive Impairment Associated with Parkinson's Disease

Cognitive impairment and dementia associated with Parkinson''s disease (PD) are common and often have devastating effects upon the patient and their family. Early cognitive impairment in PD is frequent, and the functional impact may be underestimated. Optimal management will rely upon better identification of the predominant symptoms and greater knowledge of their pathophysiological basis. The management of dementia in PD (PD‐D) also has to consider the significant neuropsychiatric burden that frequently accompanies the cognitive decline, as well as fluctuations in attention. Atypical anti‐psychotics have a limited role at present in treating PD‐D, although new drugs are under development. The mainstay of drug management for people with PD‐D is cholinesterase inhibitors, although recent trials have suggested that the N‐methyl‐D aspartate antagonist memantine may also have some benefit. Disease modification remains the ultimate goal for preventing the inexorable decline in PD‐D, although effective interventions are still some way off. Limited benefit may, however, be possible through exercise programmes and so‐called “medical foods”, although randomised trials are required to confirm largely anecdotal observations.     

Presence of Tissue Transglutaminase in Granular Endoplasmic Reticulum is Characteristic of Melanized Neurons in Parkinson's Disease Brain

Parkinson's disease (PD) is characterized by the accumulation of α‐synuclein aggregates and degeneration of melanized neurons. The tissue transglutaminase (tTG) enzyme catalyzes molecular protein cross‐linking. In PD brain, tTG‐induced cross‐links have been identified in α‐synuclein monomers, oligomers and α‐synuclein aggregates. However, whether tTG and α‐synuclein occur together in PD affected neurons remains to be established. Interestingly, using immunohistochemistry, we observed a granular distribution pattern of tTG, characteristic of melanized neurons in PD brain. Apart from tTG, these granules were also positive for typical endoplasmic reticulum (ER)‐resident chaperones, that is, protein disulphide isomerase, ERp57 and calreticulin, suggesting a direct link to the ER. Additionally, we observed the presence of phosphorylated pancreatic ER kinase (pPERK), a classical ER stress marker, in tTG granule positive neurons in PD brain, although no subcellular colocalization of tTG and pPERK was found. Our data therefore suggest that tTG localization to granular ER compartments is specific for stressed melanized neurons in PD brain. Moreover, as also α‐synuclein aggregates were observed in tTG granule positive neurons, these results provide a clue to the cellular site of interaction between α‐synuclein and tTG.     

Akt signal transduction dysfunction in Parkinson's disease

Significant attention has been drawn to the potential role of defective PI3-kinase-Akt (PKB) signalling in Parkinson's disease (PD) neurodegeneration and to the possibility that activation of Akt may provide neuroprotection in PD. However, little knowledge exists on the integrity of the Akt system in PD. Results of the present study show diminished levels of both total and active phospho^Ser473-Akt in the brain in PD. This was evident by western blot analysis of midbrain fractions from PD compared to non-PD control brain, but more specifically by immunofluorescence microscopy of the substantia nigra pars compacta (SNpc). Here, double immunofluorescence microscopy found Akt and phospho^Ser473-Akt to be expressed at high levels in tyrosine hydroxylase (TH) immunopositive dopaminergic neurons in control human brain. Selective loss of these neurons was accompanied by a marked decrease of Akt and phospho^Ser473-Akt expression in the PD brain, however Akt and active phospho^Ser473-Akt are still evident in degenerating dopaminergic neurons in the disease. This suggests that it may be possible to target neuronal Akt in advanced PD. Converse to the marked loss of neuronal Akt in PD, increased Akt and phospho^Ser473-Akt levels were observed in small non-TH positive cells in PD SNpc, whose increased number and small nuclear size indicate they are glia. These findings implicate defective Akt as a putative signalling pathway linked to loss of dopaminergic neurons in PD.     

Risk of Pneumonia is associated with Antipsychotic Drug Use among older patients with Parkinson's Disease: A Case-control Study

Objective: To investigate the risk of pneumonia associated with the use of antipsychotic drugs in older-adult patients with Parkinson''s disease (PD) in Taiwan.Methods: This case-control study was based on data from the longitudinal health insurance database in Taiwan. We analyzed the data of 51,158 older patients with PD for the period between 2001 and 2016. To reduce the potential confounding caused by unbalanced covariates in nonexperimental settings, we used propensity score matching to include older patients without pneumonia to serve as the control group.Results: Compared with patients who had never taken antipsychotics, current (adjusted odds ratios [aOR] =1.63, 95% confidence interval [CI] = 1.51-1.75), recent (aOR = 1.63, 95% CI = 1.52-1.74), and past (aOR = 1.89, 95% CI = 1.80-2.00) users of antipsychotics had a higher risk of incident pneumonia. Among typical and atypical antipsychotics, haloperidol and clozapine were associated with higher risks of incident pneumonia, respectively. By contrast, aripiprazole was not associated with a higher risk of pneumonia.Conclusion: Older patients with PD receiving typical antipsychotics or atypical antipsychotics had a higher risk of pneumonia. Among these antipsychotics, clozapine had the highest risk of pneumonia. Clinicians should pay attention to the risk of pneumonia in older patients with PD who receive typical antipsychotics and atypical antipsychotics.     

The Brainstem Pathologies of Parkinson's Disease and Dementia with Lewy Bodies

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are among the human synucleinopathies, which show alpha‐synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine nucleus). Despite several studies about brainstem pathologies in PD and DLB, there is currently no detailed information available regarding the presence of alpha‐synuclein immunoreactive inclusions (i) in the cranial nerve, precerebellar, vestibular and oculomotor brainstem nuclei and (ii) in brainstem fiber tracts and oligodendroctyes. Therefore, we analyzed the inclusion pathologies in the brainstem nuclei (Lewy bodies, LB; Lewy neurites, LN; coiled bodies, CB) and fiber tracts (LN, CB) of PD and DLB patients. As reported in previous studies, LB and LN were most prevalent in the substantia nigra, ventral tegmental area, pedunculopontine and raphe nuclei, periaqueductal gray, locus coeruleus, parabrachial nuclei, reticular formation, prepositus hypoglossal, dorsal motor vagal and solitary nuclei. Additionally we were able to demonstrate LB and LN in all cranial nerve nuclei, premotor oculomotor, precerebellar and vestibular brainstem nuclei, as well as LN in all brainstem fiber tracts. CB were present in nearly all brainstem nuclei and brainstem fiber tracts containing LB and/or LN. These findings can contribute to a large variety of less well‐explained PD and DLB symptoms (eg, gait and postural instability, impaired balance and postural reflexes, falls, ingestive and oculomotor dysfunctions) and point to the occurrence of disturbances of intra‐axonal transport processes and transneuronal spread of the underlying pathological processes of PD and DLB along anatomical pathways.