Spinal cord lesions in sporadic Parkinson’s disease

In this autopsy-based study, α-synuclein immunohistochemistry and lipofuscin pigment-Nissl architectonics in serial sections of 100?μm thickness were used to investigate the spinal cords and brains of 46 individuals: 28 patients with clinically and neuropathologically confirmed Parkinson’s disease, 6 cases with incidental Lewy body disease, and 12 age-matched controls. α-Synuclein inclusions (particulate aggregations, Lewy neurites/bodies) in the spinal cord were present between neuropathological stages 2–6 in all cases whose brains were staged for Parkinson’s disease-related synucleinopathy. The only individuals who did not have Lewy pathology in the spinal cord were a single stage 1 case (incidental Lewy body disease) and all controls. Because the Parkinson’s disease-related lesions were observable in the spinal cord only after Lewy pathology was seen in the brain, it could be concluded that, within the central nervous system, sporadic Parkinson’s disease does not begin in the spinal cord. In addition: (1) α-Synuclein-immunoreactive axons clearly predominated over Lewy bodies throughout the spinal cord and were visible in medial and anterior portions of the anterolateral funiculus. Their terminal axons formed dense α-synuclein-immunoreactive networks in the gray matter and were most conspicuous in the lateral portions of layers 1, 7, and in the cellular islands of layer 9. (2) Notably, this axonopathy increased remarkably in density from cervicothoracic segments to lumbosacral segments of the cord. (3) Topographically, it is likely that the spinal cord α-synuclein immunoreactive axonal networks represent descending projections from the supraspinal level setting nuclei (locus coeruleus, lower raphe nuclei, magnocellular portions of the reticular formation). (4) Following the appearance of the spinal cord axonal networks, select types of projection neurons in the spinal cord gray matter displayed α-synuclein-immunoreactive inclusions: chiefly, nociceptive neurons of the dorsal horn in layer 1, sympathetic and parasympathetic preganglionic neurons in layer 7, the cellular pools of α-motoneurons in layer 9, and the smaller motoneurons in Onuf’s nucleus in layer 9 (ventral horn). The spinal cord lesions may contribute to clinical symptoms (e.g., pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic Parkinson’s disease.     

VPS35 Parkinson’s disease phenotype resembles the sporadic disease

Recently a new autosomal dominant Parkinson’s disease mutation (p.Asp620Asn) in the VPS35 gene was discovered. The clinical features of 14 PD patients with this mutation from three Austrian families were evaluated. Age at disease-onset appears lower and depression was more common in Austrian patients compared to sporadic PD patients. However, we were unable to identify a specific clinical maker of VPS35 patients, who otherwise resemble sporadic PD patients.     

LncRNAs as putative biomarkers and therapeutic targets for Parkinson’s disease

Neurological Sciences - Parkinson’s disease (PD) is known as one of the most common degenerative disorders related to the damage of the central nervous system (CNS). This brain disorder is...     

Hallucinations in Parkinson’s disease: cross-sectional study

The aim of this study was to estimate the prevalence and risk factors for the development of hallucinations in patients with Parkinson's disease (PD). This cross-sectional study included 180 consecutive, non-demented patients with PD. Out of them, 24 patients (13%) experienced some kind of hallucinations. Visual hallucinations were present in 22/24 (90%) subjects. Univariate logistic regression analysis has shown relationship between presence of hallucinations and the following variables: age of patients (p?=?0.025), PD duration (p?=?0.001), duration of levodopa treatment (p?=?0.001), total daily dose of levodopa (p?=?0.033), presence of levodopa-induced dyskinesia (p?=?0.002) and their duration (p?=?0.021), and experience of nightmares (p?=?0.042). Hallucinations were also associated with higher scores of the UPDRS (p?=?0.001), HDRS (p?=?0.001) and the NPI total score (p?=?0.001), and higher H-Y stages of the disease (p?=?0.001). Multivariate regression analysis has demonstrated that the duration of PD (p?=?0.024) as well as NPI total score (p?=?0.002) was significant independent risk factors for hallucinations in PD.     

Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease

Journal of Neurology - In recent years, numerous clinical trials for disease modification in Parkinson’s disease (PD) have failed, possibly because of a “one-size-fits all”...     

Treatment strategies for Parkinson’s disease

Parkinson’s disease (PD) is caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in the deficiency of DA in the striatum. Thus, symptoms are developed, such as akinesia, rigidity and tremor. The aetiology of neuronal death in PD still remains unclear. Several possible mechanisms of the degeneration of dopaminergic neurons are still elusive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium cytotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental factors, toxic action of nitric oxide, and apoptosis. All these factors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death. Considerable evidence suggests that free radicals and oxidative stress may play key roles in the pathogenesis of PD. However, currently, drug therapy cannot completely cure the disease. DA replacement therapy with levodopa (L-Dopa), although still being a gold standard for symptomatic treatment of PD, only alleviates the clinical symptoms. Furthermore, patients usually experience severe side effects several years after the L-Dopa treatment. Until now, no therapy is available to stop or at least slow down the neurodegeneration in patients. Therefore, efforts are made not only to improve the effect of L-Dopa treatment for PD, but also to investigate new drugs with both antiparkinsonian and neuroprotective effects. Here, the advantages and limitations of current and future therapies for PD were dicussed. Current therapies include dopaminergic therapy, DA agonists, MAO-B inhibitor, COMT inhibitors, anticholinergic drugs, surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), and stem cell transplantation.     

Modafinil for Parkinson’s disease fatigue

Fatigue is common in Parkinson’s disease (PD), occurring in up to 42% of patients (2). There is no recognized treatment. This is a study of modafinil for Parkinson’s disease related fatigue. Ethical approval was given. Patients with idiopathic PD were recruited from a Movement Disorders clinic. Those with depression, dementia, and other causes for fatigue were excluded. Patients were assessed using the Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS), self-rating of improvement, Epworth Sleepiness Scale (ESS), and UPDRS. Modafinil was titrated up over 4 weeks to maximum of 400 mg/day. There followed a 5 week maintenance phase before reassessment. Thirteen patients participated. No significant change was seen in any safety measure. The FSS did not change significantly, however those on modafinil rated an improvement in their fatigue compared to placebo. The Modafinil group had a statistically significant improvement on ESS (p < 0.05). This is a small study of modafinil in selected PD patients. There is a suggestion of improvement on the global clinical impression scale for fatigue, but no significant change on FSS. A larger study is needed to further evaluate this drug in PD fatigue. This study highlights the problems with recruitment when trialing treatments of non-motor symptoms in PD. A significant improvement in EDS was seen.     

Non-motor symptoms in Huntington’s disease: a comparative study with Parkinson’s disease

Journal of Neurology - The presence of non-motor symptoms in Huntington’s disease (HD) has not been systematically assessed so far. Our objective was to know their prevalence and to compare...     

Parkinson’s disease: a multi-faceted disease

Journal of Neurology -     

Advanced therapies in Parkinson’s disease: Long-term retrospective study

BackgroundLevodopa/carbidopa intestinal gel infusion (LCIG) and subthalamic nucleus deep brain stimulation (STN-DBS) are approved therapies for advanced Parkinson’s disease (PD) whose long-term comparability remains unclear.MethodsWe reviewed the 5-year data on activities of daily living (ADL) and motor complications (OFF time, dyskinesia duration, and dyskinesia severity), as measured by the Unified Parkinson Disease Rating Scale (UPDRS) section-II and section-IV (items 39, 32, and 33, respectively) in 60 PD patients exposed to STN-DBS (n = 20), LCIG (n = 20), and oral medical therapy (OMT) (n = 20) at similar baseline disability and cognitive state.ResultsSTN-DBS and LCIG showed a similar magnitude of deterioration in ADL (+6.1 vs. +5.7 UPDRS-II; p = 0.709), but lesser than with OMT (+13.7 UPDRS-II; p = 0.005). OFF time also improved to the same extent in STN-DBS and LCIG (−62% vs. −54.5%; p = 0.830), while worsened with OMT (+78.6%; p < 0.001). STN-DBS and LCIG yielded greater improvement on dyskinesia compared to OMT (dyskinesia duration: −66.1% vs. −9.0% vs. +24.2% [p = 0.001]; dyskinesia severity: −68.8% vs. −18.0% vs. +16.2% [p = 0.002]), with relative superiority of STN-DBS over LCIG (p = 0.004 for duration; p = 0.014 for severity). The annualized rate of complication was lower in STN-DBS vs. LCIG (0.13 vs. 0.68; p < 0.001) but not different between STN-DBS and OMT (0.13 vs. 0.10; p = 0.795).ConclusionsSTN-DBS and LCIG showed comparable efficacy in ADL and OFF time, superior to OMT. STN-DBS yielded greater improvement in dyskinesia and lower long-term rate of complications than LCIG.     

Parkinson’s disease: Surgical options

The introduction of levodopa revolutionized the treatment of Parkinson’s disease. However, complications of therapy that diminish functional capacity eventually develop in the majority of patients. Studies in animal models have demonstrated that the parkinsonian state is associated with overactivity in the output nuclei of the basal ganglia. This provides a rationale for surgically targeting these nuclei to diminish this overactivity and reestablish a more balanced output (compensatory strategy). Lesioning and high-frequency stimulation of either the pallidum or the subthalamic nuclei are effective, but many questions remain regarding what surgery is best. Even more questions remain regarding the place of a restorative strategy, namely implantation of fetal midbrain tissue to replace the missing dopamine cells and "cure" the disease. Practical, ethical, and legal issues that complicate the use of human tissue have encouraged initial attempts at xenotransplantation using porcine fetal tissue.     

Astrocytes and therapeutics for Parkinson’s disease

Astrocytes play direct, active, and critical roles in mediating neuronal survival and function in various neurodegenerative disorders. This role of astrocytes is well illustrated in amyotrophic lateral sclerosis (ALS), in which the removal of glutamate from the extracellular space by astrocytes confers neuroprotection, whereas astrocytic release of soluble toxic molecules promotes neurodegeneration. In recent years, this context-dependent dual role of astrocytes has also been documented in experimental models of Parkinson’s disease. The present review addresses these studies and some potential mechanisms by which astrocytes may influence the neurodegenerative processes in Parkinson’s disease, and in particular examines how astrocytes confer neuroprotection either through the removal of toxic molecules from the extracellular space or through the release of trophic factors and antioxidant molecules. In contrast, under pathological conditions, astrocytes release proinflammatory cytokines and other toxic molecules that are detrimental to dopaminergic neurons. These emerging roles of astrocytes in the pathogenesis of Parkinson’s disease constitute an exciting development with promising novel therapeutic targets.     

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer’s disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of β-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson’s disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as γ-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.     

Rasagiline for dysexecutive symptoms during wearing-off in Parkinson’s disease: a pilot study

Wearing-off refers to the predictable worsening of motor and sometimes non-motor symptoms of Parkinson’s disease occurring at the end of levodopa dose that improves with the next drug dose. Here, we investigated the efficacy of rasagiline on executive functions at the end of levodopa dose in patients displaying symptoms of wearing-off. Rasagiline was well-tolerated and produced a significant improvement at the Frontal Assessment Battery, together with improvement of motor symptoms at the end of levodopa dose. These results suggest that treatment of motor symptoms of wearing-off with rasagiline may be accompanied by improvement of executive functions, and further support the need for optimizing dopamine replacement therapy in fluctuating Parkinson’s disease patients.     

Parkinson’s disease: recent advances

While a curative treatment for Parkinson’s disease remains elusive, our understanding of disease mechanisms as well as preclinical and pre-motor early manifestations has improved greatly over the past years. An agent with proven disease modifying properties has not yet been identified but symptomatic treatment options for affected patients have improved. For patients with motor complications, this includes invasive approaches such as deep brain stimulation and continuous device-aided drug delivery. The many facets of non-motor problems patients are faced with have finally been fully recognized and have become the target of treatment trials, as have been non-pharmacological approaches.     

Imaging movement-related activity in medicated Parkin-associated and sporadic Parkinson’s disease

Treatment-related motor complications such as dyskinesias are a major problem in the long-term management of Parkinson’s disease (PD). In sporadic PD, a relatively early onset of the disease is known to be associated with an early development of dyskinesias. Although linked with early onset, patients with Parkin-associated PD often show a stable long-term response to dopaminergic therapy without developing treatment-induced motor complications. Therefore, we reasoned that this difference in vulnerability to develop dyskinesias under long-term dopaminergic therapy may be associated with differences in movement-related activation patterns in Parkin-associated compared to sporadic PD. To test this hypothesis, medicated non-dyskinetic patients with either Parkin-associated or sporadic PD underwent functional magnetic resonance imaging (fMRI) while performing externally specified or internally selected movements. Patients with Parkin-associated and sporadic PD showed no difference in movement-related activation patterns. Moreover, the covariates ‘age’ and ‘disease duration’ similarly influenced brain activation in both patient groups. The present finding suggests that a stable long-term motor response in some patients with Parkin-associated PD may not be related to differences in cortical recruitment. In conclusion, our findings corroborate a substantial pathophysiologic overlap between Parkin-associated and sporadic PD and lend further support to the notion that Parkin-associated PD is a suitable genetic model for sporadic PD.     

Alpha-synuclein and oxidative stress enzymes as biomarkers of Parkinson’s disease

The principal mechanism of the pathogenesis of Parkinson’s disease is accumulation and aggregation of alpha-synuclein. While the normal function of alpha-synuclein is the control of vesicular neurotransmission, its pathogenic effects influence different cell functions, including the activities of mitochondria and proteasomes, as well as autophagic protein degradation. It is noteworthy that the same functions are affected when the renewal of macromolecules and organelles is impaired as a result of normal aging. Since aging is the principal risk factor for Parkinson’s disease, it is very important to analyze its molecular and cellular consequences in the context of alpha-synuclein pathology. Here, we review the similarities and differences between normal brain aging and Parkinson’s disease, with a focus on nigral dopaminergic neurons, which seem to be specifically sensitive to the combined damage induced by alpha-synuclein and aging. Elucidating the mechanism that underlies the death of dopaminergic neurons in Parkinson’s disease is essential not only for the understanding of its general pathogenesis but also for the development of approaches to its early preclinical diagnosis and preventive therapy.