Non-coding RNA transcripts: Sensors of neuronal stress,modulators of synaptic plasticity,and agents of change in the onset of Alzheimer's disease

Non-protein-coding RNAs (ncRNAs) play critical roles on many levels of cellular information processing and pervasive expression of ncRNAs in the nervous system could help explain brain complexity. NcRNAs are enriched in the central nervous system and are associated with specific neuroanatomical regions. Additionally, several recent publications have revealed an important role for deregulation of ncRNAs in various human neuropathologies, such as Alzheimer's disease, Parkinson's disease and Fragile X mental retardation. Herein, we summarize reports on functional ncRNA molecules involved in cellular stress response, particularly related to Alzheimer's disease. We conclude that ncRNAs have a prominent role in maintaining precise physiological levels of gene products directly implicated in Alzheimer's disease pathology.     

α‐Synuclein: The Long Distance Runner

Parkinson's disease is characterized by α‐synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of α‐synuclein pathology in Parkinson's disease. Recent experimental studies have demonstrated that α‐synuclein can transfer from cell to cell. In this review, we highlight the involvement of α‐synuclein in Parkinson's disease and in Braak's staging of Parkinson's disease pathology. We discuss whether a prion‐like mechanism of α‐synuclein spread might contribute to Parkinson's disease pathology. We describe recent studies investigating cell‐to‐cell transfer of α‐synuclein and focus our review on the long‐distance axonal transport of α‐synuclein along neurons.     

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.     

Variance in the identification of microRNAs deregulated in Alzheimer's disease and possible role of lincRNAs in the pathology: The need of larger datasets

Non-coding RNAs, such as microRNAs and long non-coding RNAs, represent the next major step in understanding the complexity of gene regulation and expression. In the past decade, tremendous efforts have been put mainly into identifying microRNAs that are changed in Alzheimer's disease, with the goal to provide biomarkers of the disease and to better characterize molecular pathways that are deregulated concomitantly to the formation of Tau and amyloid aggregates. This review underlines the importance of correctly defining, in a deluge of high-throughput data, which microRNAs are abnormally expressed in Alzheimer's disease patients. Despite a clear lack of consensus on the topic, miR-132 is emerging as a neuronal microRNA being gradually down-regulated during disease and showing important roles in the maintenance of brain integrity. Insight into the biological importance of other classes of non-coding RNAs also rapidly increased over the last years and therefore we discuss the possible implication of long non-coding RNAs in Alzheimer's disease.     

An overview of sleep and circadian dysfunction in Parkinson's disease

Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co‐morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field.     

Ageing and Parkinson's disease: Why is advancing age the biggest risk factor?

As the second most common age related neurodegenerative disease after Alzheimer's disease, the health, social and economic impact resulting from Parkinson's disease will continue to increase alongside the longevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinson's disease. Although research into the mechanisms leading to cell death in Parkinson's disease has shed light on many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question, what specific age related factors predispose some individuals to develop this common neurodegenerative disease. In this review we focus specifically on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death and many of the symptoms seen in Parkinson's disease. We review the evidence that ageing is important for the development of Parkinson's disease and how age related decline leads to the loss of neurons within this disease, before describing exactly how advancing age may lead to substantia nigra neuronal loss and Parkinson's disease in some individuals.     

No allelic association between Parkinson's disease and dopamine D2, D3, and D4 receptor gene polymorphisms

Parkinson's disease is thought to be caused by a combination of unknown environmental, genetic, and degenerative factors. Evidence from necropsy brain samples and pharmacokinetics suggests involvement of dopamine receptors in the pathogenesis or pathophysiology of Parkinson's disease. Genetic association studies between Parkinson's disease and dopamine D2, D3 and D4 receptor gene polymorphisms were conducted. The polymorphism was examined in 71 patients with Parkinson's disease and 90 controls. There were no significant differences between two groups in allele frequencies at the D2, D3, and D4 dopamine receptor loci. Our findings do not support the hypothesis that susceptibility to Parkinson's disease is associated with the dopamine receptor polymorphisms examined. © 1994 Wiley-Liss, Inc.     

Lrrk2 mutations in South America: A study of Chilean Parkinson's disease

Pathogenic substitutions in the leucine-rich repeat kinase 2 protein (Lrrk2), R1441G and G2019S, are a prevalent cause of autosomal dominant and sporadic Parkinson's disease in the Northern Spanish population. In this study we examined the frequency of these two substitutions in 166 Parkinson's disease patients and 153 controls from Chile, a population with Spanish/European-Amerindian admixture. Lrrk2 R1441G was not observed, however Lrrk2 G2019S was detected in one familial and four sporadic Parkinson's disease patients. These findings suggest Lrrk2 G2019S may play an important role in Parkinson's disease on the South American Continent and further studies are now warranted.     

Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson's disease

Aberrant detoxification of environmental agents may be the basis for an inherited predisposition to Parkinson's disease. A CYP2D6 genetic marker of the debrisoquine hydroxylase “poor metabolizer” phenotype was found to be significantly increased in Parkinson's disease patients compared to controls, as has been shown in previous studies. Presence of this marker gives an odds ratio of 1.86 for Parkinson's disease (95% confidence interval 1.33–2.39, P < 0.02). For comparison, a CYP1A1 polymorphism, which is not known to be associated with aberrant drug metabolism, showed no association with Parkinson's disease in our study. © 1993 Wiley-Liss, Inc.     

Brief Report: Bradyphrenia in Parkinson's Disease,Huntington's Disease,and Schizophrenia

The current paper assessed bradyphrenia, or slowed thinking, in patients with Parkinson's disease, Huntington's disease, and schizophrenia using a modified planning measure designed to maximise the demands on cognitive processing. Findings indicated normal performance in schizophrenia but prolonged thinking time in Parkinson's disease and, to a lesser degree, Huntington's disease and a relationship between thinking time and task complexity.     

Leucine-Rich Repeat Kinase 2 (LRRK2) Cellular Biology: A Review of Recent Advances in Identifying Physiological Substrates and Cellular Functions

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common forms of inheritable Parkinson's disease and likely play a role in sporadic disease as well. LRRK2 is a large multidomain protein containing two key groups, a Ras-like GTP binding domain and a serine, threonine kinase domain. Mutations in the LRRK2 gene that associate with Parkinson's disease reside primarily within the two functional domains of the protein, suggesting that LRRK2 function is critical to the pathogenesis of the disease. The most common LRRK2 mutation increases kinase activity, making LRRK2 kinase inhibition an attractive target for small molecule drug development. However, the physiological function of LRRK2 kinase as well as its endogenous protein substrates remains poorly understood and has hindered drug development efforts. Recent advances in LRRK2 biology have revealed several potential cellular roles, interacting proteins, and putative physiological substrates. Together, a picture emerges of a complex multifunctional protein that exists in multiple cellular compartments. Through unclear mechanisms, LRRK2 kinase regulates cytoskeleton architecture through control of protein translation, phosphorylation of cytoskeletal proteins, and response to cellular stressors. This article will briefly cover some interesting recent studies in LRRK2 cellular biology and highlight emerging cellular models of LRRK2 kinase function.     

Trace amine metabolism in Parkinson's disease: Low circulating levels of octopamine in early disease stages

Recent evidence suggests that trace amines such as tyramine and octopamine, alternative products of tyrosine metabolism (an aminoacid parent of dopamine and noradrenaline), play a role in the homeostasis of the extrapyramidal system. However, the relevance of these trace amines in the pathogenesis of Parkinson's disease is still largely unknown. Here, we assessed the plasma levels of octopamine and noradrenaline in three sub-groups of PD patients, namely de novo, non-fluctuating and fluctuating patients, versus age-matched control subjects. We show that octopamine is detectable in plasma of all subjects, the mean levels of which are significantly lower in PD patients, including de novo patients, when compared to controls (p < 0.001). Unlike this, no changes in plasmatic noradrenaline levels were found in the de novo patients, but only in plasma of fluctuating and non-fluctuating PD patients. These findings raise the possibility that Parkinson's disease is firstly characterized by abnormalities of tyrosine decarboxylase, rather than tyrosine hydroxylase, enzyme activity. Given the role of this enzyme in the production of trace amines, circulating octopamine levels may hold promise as a biomarker of early Parkinson's disease.     

Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression

OBJECTIVE:

To compare verbal fluency among Alzheimer''s disease, Parkinson''s disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity.

METHODS:

Patients from an outpatient university center with a clinical diagnosis of Alzheimer''s disease, Parkinson''s disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson''s disease, major depression, and Alzheimer''s disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals).We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model.

RESULTS:

The mean digit span and verbal fluency scores were lower in patients with Alzheimer''s disease (n = 34) than in patients with major depression (n = 52) or Parkinson''s disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer''s disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson''s disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson''s disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer''s disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases.

CONCLUSIONS:

Verbal fluency provides a better characterization of Alzheimer''s disease, major depression, and Parkinson''s disease, even at later stages.     

Pervasive and diffuse muscle activity during REM sleep and non-REM sleep characterises multiple system atrophy in comparison with Parkinson's disease

Multiple system atrophy (MSA) and Parkinson's disease (PD) may share overlapping features particularly at early disease stage, including sleep alterations, but have profoundly different prognoses. Certain sleep phenomena and disorders of motor control are more prevalent in multiple system atrophy, such as REM sleep behaviour disorder (RBD). We quantitatively tested whether pervasive muscle activity during sleep occurs in subjects with multiple system atrophy versus Parkinson's disease. Laboratory polysomnographic studies were performed in 50 consecutive subjects with Parkinson's disease and 26 age- and gender-matched subjects with multiple system atrophy at <5 years from disease onset. The distributions of normalised electromyographic activity of submentalis, wrist extensor, and tibialis anterior muscles in different wake–sleep states during the night were analysed. Subjects with multiple system atrophy had significantly higher activity of submentalis, wrist extensor, and tibialis anterior muscles than subjects with Parkinson's disease during non-REM sleep, including separately in stages N1, N2, and N3, and during REM sleep, but not during nocturnal wakefulness. The activity of wrist extensor and tibialis anterior muscles during non-REM sleep and the activity of tibialis anterior muscles during REM sleep were also significantly higher in subjects with multiple system atrophy and RBD than in subjects with Parkinson's disease and RBD. In conclusion, with respect to Parkinson's disease, multiple system atrophy is characterised by a pervasive and diffuse muscle overactivity that involves axial and limb muscles and occurs not only during REM sleep, but also during non-REM sleep and between subjects with comorbid RBD.     

The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations

Background

Parkinson''s disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson''s disease in sibships from North America.

Objective

To make a thorough assessment of the SPR gene region in sporadic Parkinson''s disease.

Methods

A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson''s disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non‐parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models.

Results

Significant LOD scores between 2 and 3 were obtained at the two SPR‐flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p‐value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter‐correlated SNPs were significantly associated with Parkinson''s disease affection status (p‐value 0.004).

Conclusions

DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson''s disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson''s disease.     

Clinical practice guidelines based on evidence for cognitive‐behavioural therapy in Parkinson's disease comorbidities: A literature review

The purpose of this review is to provide psychologists and other health care professional enough knowledge about available cognitive‐behavioural interventions for comorbidities in Parkinson's disease that include depression, anxiety, impulsive disorder, pain, and sleep disturbances. This review has clear clinical practical suggestions how to adapt psychological interventions and techniques to the motor and/or cognitive impairments of patients with Parkinson's disease, based on earlier available research results. Every available research that could be found with the help of search engines from Medline, Springer, PsychINFO, and Google Scholar, which used cognitive‐behavioural therapy to treat Parkinson's comorbidities, was cited and explained. Cognitive‐behavioural interventions and techniques are presented based on available research results for Parkinson's comorbidities. It is recommended to use treatment plans and interventions that are earlier suggested as efficient in patients with Parkinson's disease. Strongest available research based recommendations are available for depression and anxiety. There are only few available research studies that used cognitive and/or behavioural interventions for pain, impulsive disorder, or sleeping disturbances, except insomnia in Parkinson's disease. Cognitive‐behavioural therapy is safe to use and should be adapted to the specific needs of patients and with the scientific approved treatment interventions and techniques. Psychologists should be careful on how they adapt their treatment plan for patients.     

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson''s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson''s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson''s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson''s disease identified so far. It is especially frequent among cases with familial Parkinson''s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson''s disease.     

Investigation of C9orf72 repeat expansions in Parkinson's disease

Large repeat expansions in the C9orf72 gene were recently reported to be a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Given some of the clinical and pathologic overlap between these 2 diseases and Parkinson's disease, we sought to evaluate the presence of these expansions in a cohort of French-Canadian patients with Parkinson's disease. No pathologic expansion was found in our cohort of patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.     

Obstructive sleep apnea and risk of Parkinson's disease: a population‐based cohort study

Sleep disorders could be associated with neurodegenerative diseases. This study aimed to determine the risk of Parkinson's disease in patients with obstructive sleep apnea. The incident cases of newly diagnosed obstructive sleep apnea were identified between 2000 and 2009 from the medical claims database of National Health Institute of Taiwan. The risk of Parkinson's disease onset at least 1 year after the diagnosis of obstructive sleep apnea was measured during and up to 11 years of period, compared to that of age‐ and gender‐matched controls estimated in the same period. A total of 5864 patients with newly diagnosed obstructive sleep apnea and 23 269 subjects without obstructive sleep apnea were identified for data analysis. The study reported that the incidence of Parkinson's disease in the obstructive sleep apnea cohort was approximately two times higher than that in the control cohort (2.57 versus 1.32 per 1000 person‐years), with an adjusted hazard ratio of 1.84. Furthermore, the risk of Parkinson's disease was particularly greater for the obstructive sleep apnea with insomnia subgroup (adjusted hazard ratio = 1.97, 95% confidence interval = 1.44–2.69) than for the control cohort. The sex–age‐specific analysis further discovered that the most elevated risk of Parkinson's disease onset was noted in female obstructive sleep apnea patients aged 50–69 years (adjusted hazard ratio = 2.82). This population‐based study indicated that patients with obstructive sleep apnea, especially those who suffered from insomnia, are at an increased risk of Parkinson's disease onset.