Lisa Klingelhoefer

Pathogenesis of Parkinson disease—the gut–brain axis and environmental factors

Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.

Therapeutic options for nocturnal problems in Parkinson's disease and atypical parkinsonian disorders

Sleep disturbances in Parkinson’s disease and parkinsonism (such as atypical parkinsonian disorders like multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies and corticobasal degeneration) are multifactorial and as such treatment needs to be tailored to the specific patient case and sleep dysfunction. One also has to consider drug-related effects on sleep architecture. This article provides an overview of the therapeutic options for nocturnal problems in Parkinson`s disease and atypical parkinsonian disorders.

Parkinson's disease as a multisystem disorder.

This article summarises the noteworthy contribution of Professor Jellinger to the understanding of Parkinson’s disease (PD) as a disease affecting multiple body- and neurotransmitter-systems. Phosphorylated alpha-synuclein and the formation of Lewy pathology as neuropathological hallmarks of PD seem to spread from the enteric nervous system and the olfactory bulb in a rostrocranial direction to the CNS. Subsequently, a progressive degeneration of the dopaminergic–nigrostriatal system and widespread extranigral pathology affecting different anatomical structures and neurotransmitters are induced causing the various non-motor and motor symptoms of PD.

The Gut and Nonmotor Symptoms in Parkinson's Disease

Gastrointestinal (GI) symptoms are one of the most common nonmotor symptoms (NMS) in patients with Parkinsons disease (PD) involving the whole GI tract (GIT) and being evident throughout the whole course of the disease. Furthermore, constipation serves as a risk factor for PD as well as an early prodromal NMS of PD. The gut as gateway to the environment with its enteric nervous system (ENS) plays a crucial role in the neurodegenerative process that leads to PD. Alpha-synucleinopathy as the pathological hallmark of PD could be found within the whole GIT in a rostrocaudal gradient interacting with the ENS, the gut microbiome, and enteric glial cells. Bidirectional interactions between the ENS and the central nervous system (CNS) via a brain-gut-enteric microbiota axis have been reported. As well as there is evidence out of animal, autopsy, and epidemiological studies that α-synuclein spreads via rostrocranial transmission by transsynaptic cell-to-cell transfer via the sympathetic and parasympathetic nervous system to the CNS causing the typical neuropathological changes of PD. Recognition of GI NMS as prodromal markers of PD as well as a better understanding of the brain-gut connection offers new insights in the pathophysiology of PD and might provide the opportunity of PD diagnosis before CNS involvement. Hereby the opportunity for development of neuroprotective and disease-modifying therapeutics, respectively, seem to be promising. This chapter covers the variety of GI NMS and its consequences in PD as well as the important role of the gut as part of the pathological process in PD.

Accelerated Age-Dependent Hippocampal Volume Loss in Parkinson Disease With Mild Cognitive Impairment

Background: Patients with Parkinson disease are at high risk of developing dementia. During the course of the disease, a substantial number of patients will experience a cognitive decline, indicating the dynamics of the underlying neuropathology. Magnetic resonance imaging (MRI) has become increasingly useful for identifying structural characteristics in radiological brain anatomy existing prior to clinical symptoms. Whether these changes reflect pathology, whether they are aging related, or both often remains unclear. We hypothesized that aging-associated brain structural changes would be more pronounced in the hippocampal region among patients with Parkinson disease having mild cognitive deficits relative to cognitively unimpaired patients. Methods: Using MRI, we investigated 30 cognitively healthy patients with Parkinson disease and 33 patients with nondemented Parkinson disease having mild cognitive impairment. All participants underwent structural MRI scanning and extensive clinical and neuropsychological assessments. Results: Irrespective of the study participants’ cognitive status, older age was associated with reduced cortical thickness in various neocortical regions. Having mild cognitive impairment was not associated with an increased rate of cortical thinning or volume loss in these regions, except in the hippocampus bilaterally. Conclusion: Patients with Parkinson disease having mild cognitive impairment show an accelerated age-dependent hippocampal volume loss when compared with cognitively healthy patients with Parkinson disease. This may indicate pathological processes in a key region for memory functioning in patients with Parkinson disease at risk of developing dementia. Structural MRI of the hippocampal region could potentially contribute to identifying patients who should receive early treatment aimed at delaying the clinical onset of dementia.

Restless legs syndrome

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterised by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. The pathophysiology is only partially known and a genetic component together with dopaminergic and brain iron dysregulation plays an important role. Secondary causes for RLS need to be excluded. Treatment depends on the severity and frequency of RLS symptoms, comprises non-pharmacological (eg lifestyle changes) and pharmacological interventions (eg dopaminergic medication, alpha-2-delta calcium channel ligands, opioids) and relieves symptoms only. Augmentation is the main complication of long-term dopaminergic treatment of RLS. This article will provide a clinically useful overview of RLS with provision of diagnostic criteria, differential diagnoses, possible investigations and different treatment strategies with their associated complications.

Non-Motor Symptoms Assessed by Non-Motor Symptoms Questionnaire and Non-Motor Symptoms Scale in Parkinson's Disease in Selected Asian Populations

Background: Ethnic variations have been described in medical conditions, such as hypertension, diabetes, and multiple sclerosis. Whether ethnicity plays a role in Parkinsons disease (PD), particularly with regard to non-motor symptoms (NMS), remains unclear. Existing literature is diverse, controversial, and inadequately documented. This review aims to analyse and report the currently available literature on NMS, specifically in Asian PD patients. Summary: We conducted a literature review using PubMed, searching for articles and currently available publications that reference and assess NMS in PD patients living in Asia using the validated NMS Questionnaire (NMS Quest) and NMS Scale (NMSS). In total, 24 articles were included: 12 using the NMS Quest and 12 using the NMSS. Symptoms of constipation, memory impairment, and nocturia were the most frequently self-reported symptoms (NMS Quest) in selected Asian populations, while symptoms within the domains sleep/fatigue, attention/memory, and mood/apathy were most prevalent when applying the health-professional completed NMSS. Key Messages: NMS are generally prevalent and highly burdensome within selected Asian PD populations living in countries included in this review. Our review suggests that NMS-driven phenotypic heterogeneity is present in Asian patients, and compared to Western PD populations there might be variations in assessed NMS.

Parkinson’s Disease and Gastrointestinal Non Motor Symptoms: Diagnostic and Therapeutic Options – A Practise Guide

Gastrointestinal (GI) disturbances in Parkinsons disease (PD) are varied, involve the upper and lower GI tract and are evident in all stages of the disease. Recognition and re-evaluation of these non motor symptoms (NMS) due to the course of PD is important. They have a major impact on the efficacy of oral anti-parkinsonian medication and health related quality of life. Treatment needs to be tailored to the specific patient case with evaluation of PD stage, the specific GI NMS and comorbidities. This article provides an overview of the pharmacological and non-pharmacological therapeutic options for GI NMS in PD.

The Non-motor Parkinson’s Disease

Parkinson’s disease (PD) is the second commonest neurodegenerative condition, and non-motor symptoms (NMS) are integral to the condition [62]. Besides the common visible motor symptoms such as tremor, rigidity and bradykinesia, patients experience NMS thorough the course of the disease including the prodromal and palliative phase of PD. For some time now, evidence has shown that PD has a multiple neurotransmitters deficiency involving the central and the extra central nervous system. Recently the concept of NMS subtypes has emerged with potential subtype specific treatment options in the future.

Surgical Treatment of Parkinson’s Disease, Transplantations and Restorative Therapies for Parkinson’s Diseases

Deep brain stimulation (DBS) is a well-established treatment modality for patients with Parkinson’s disease (PD), especially in those with motor complications such as fluctuations and dyskinesias. There is good long-term evidence confirming the efficacy of DBS in improving motor symptoms and quality of life in advanced PD. A recent study has additionally confirmed significant benefit where DBS is utilised earlier in the course of PD. In carefully selected patients, improvements in non-motor symptoms are also seen. The key challenge with DBS, therefore, remains the careful selection of suitable patients, facilitated by multidisciplinary assessment.