Journal of Neural Transmission最新文献

The akinetic crisis is defined as an acute, potentially life-threatening, levodopa-resistant, severe aggravation of rigidity, severe akinesia, associated with high fever, disturbance of consciousness, dysphagia and autonomic symptoms often due to disruption of dopaminergic medication or infections. The akinetic crisis is a relatively rare event, however subacute mild-moderate motor symptom deterioration in Parkinson´s disease (PD) patients is a frequent cause of hospitalization. In this review, we propose that the akinetic crisis is the upper end of a continuous spectrum of acute akinetic states depending on the degree of the progressive levodopa-resistance. Clinical symptomatology, risk factors, and instrumental diagnostics as the DAT-SPECT reflecting a biomarker of levodopa-resistance will be discussed to evaluate the spectrum of akinetic states. Pathophysiological considerations about the potential role of proinflammatory cytokines on the progressive levodopa-resistance will be discussed and therapeutical, consensus-based guidelines will be presented.

Parkinson's Disease (PD) is a multifaceted and progressive disorder characterized by a diverse range of motor and non-motor symptoms. The complexity of PD necessitates a multidisciplinary approach to manage both motor symptoms, such as bradykinesia, gait disturbances and falls, and non-motor symptoms, including cognitive dysfunction, sleep disturbances, and mood disorders, which significantly affect patients' quality of life. Pharmacotherapy, particularly dopaminergic replacement therapy, has advanced to alleviate many symptoms. However, these medications can also induce side effects or aggravate symptoms like hallucinations or orthostatic dysfunction, highlighting the need for comprehensive patient management. The optimal care for PD patients involves a team of specialists, including neurologists, physical and occupational therapists, speech-language pathologists, psychologists, and other medical professionals, to address the complex and individualized needs of each patient. Here, we illustrate the necessity of such a multidisciplinary approach in four illustrative PD cases with different disease stages and motor and non-motor complications. The patients were treated in different treatment settings (specialized outpatient clinic, day clinic, inpatient care including neurorehabilitation). The biggest challenge lies in organizing and implementing such comprehensive care effectively across different clinical settings.

The ability to perform activities of daily living (ADL) function is a multifaceted construct that reflects functionality in different daily life situations. The loss of ADL function due to cognitive impairment is the core feature for the diagnosis of Parkinson's disease dementia (PDD). In contrast to Alzheimer's disease, ADL impairment in PD can be compromised by various factors, including motor and non-motor aspects. This narrative review summarizes the current state of knowledge on the association of cognition and ADL function in people with PD and introduces the concept of "cognitive ADL" impairment for those problems in everyday life that are associated with cognitive deterioration as their primary cause. Assessment of cognitive ADL impairment is challenging because self-ratings, informant-ratings, and performance-based assessments seldomly differentiate between "cognitive" and "motor" aspects of ADL. ADL function in PD is related to multiple cognitive domains, with attention, executive function, and memory being particularly relevant. Cognitive ADL impairment is characterized by behavioral anomalies such as trial-and-error behavior or task step omissions, and is associated with lower engagement in everyday behaviors, as suggested by physical activity levels and prolonged sedentary behavior. First evidence shows that physical and multi-domain interventions may improve ADL function, in general, but the evidence is confounded by motor aspects. Large multicenter randomized controlled trials with cognitive ADL function as primary outcome are needed to investigate which pharmacological and non-pharmacological interventions can effectively prevent or delay deterioration of cognitive ADL function, and ultimately the progression and conversion to PDD.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Interactions with others need social adjustment (i.e., the constant accommodation to changing social situations). Mixed evidence indicates positive as well as negative changes in social adjustment after subthalamic nucleus deep brain stimulation (STN-DBS) in people with Parkinson's Disease (PwPD). To date, however, no meta-analysis of these changes exists. Thus, the study aim was to review evidence of the effects of STN-DBS on social adjustment in PwPD. For this purpose, a systematic literature search in MEDLINE was conducted. The meta-analysis was performed using a random effects model and standardized mean differences (SMDs) with 95% confidence intervals (CIs). The MINORS tool was used to assess the methodological quality of the studies. The initial literature search identified 13,124 articles, of which 1,550 full texts were assessed for eligibility. Eight studies were finally included; for seven articles sufficient data for a meta-analysis was available. Most studies found mild impairment in social adjustment impairment pre-surgery. The meta-analysis revealed no significant changes but a statistical trend towards improvement in social adjustment up to six months (SMD = 0.25; 95%CI=-0.03,0.53; P = 0.08) and over 12 months (SMD = 0.26; 95%CI=-0.03,0.55; P = 0.07) post-surgery. Methodological quality was moderate in 87.5% of the studies and good in 12.5%. While mild impairment in social adjustment pre-surgery was reported in most studies, the data indicate that STN-DBS might yield beneficial effects toward this outcome. However, not enough data yet exists to draw firm conclusions. As a crucial skill for everyday functioning, social adjustment should be more often defined as an outcome in STN-DBS trials in PwPD and should be considered in clinical routines.

There is a renewed interest on eye movements analysis and retinal alterations in Parkinson's disease. This may identify markers for at-risk subpopulation, early diagnosis and evolutive profiles for research or personalized medicine.

A patient-tailored therapy of the heterogeneous, neuropsychiatric disorder of Parkinson's disease (PD) aims to improve dopamine sensitive motor symptoms and associated non-motor features. A repeated, individual adaptation of dopamine substituting compounds is required throughout the disease course due to the progress of neurodegeneration. Therapeutic drug monitoring of dopamine substituting drugs may be an essential tool to optimize drug applications. We suggest plasma determination of levodopa as an initial step. The complex pharmacology of levodopa is influenced by its short elimination half-life and the gastric emptying velocity. Both considerably contribute to the observed variability of plasma concentrations of levodopa and its metabolite 3-O-methyldopa. These amino acids compete with other aromatic amino acids as well as branched chain amino acids on the limited transport capacity in the gastrointestinal tract and the blood brain barrier. However, not much is known about plasma concentrations of levodopa and other drugs/drug combinations in PD. Some examples may illustrate this lack of knowledge: Levodopa measurements may allow further insights in the phenomenon of inappropriate levodopa response. They may result from missing compliance, interactions e.g. with treatments for other mainly age-related disorders, like hypertension, diabetes, hyperlipidaemia, rheumatism or by patients themselves independently taken herbal medicines. Indeed, uncontrolled combination of compounds for accompanying disorders as given above with PD drugs might increase the risk of side effects. Determination of other drugs used to treat PD in plasma such as dopamine receptor agonists, amantadine and inhibitors of catechol-O-methyltransferase or monoamine oxidase B may refine and improve the value of calculations of levodopa equivalents. How COMT-Is change levodopa plasma concentrations? How other dopaminergic and non-dopaminergic drugs influence levodopa levels? Also, delivery of drugs as well as single and repeated dosing and continuous levodopa administrations with a possible accumulation of levodopa, pharmacokinetic behaviour of generic and branded compounds appear to have a marked influence on efficacy of drug treatment and side effect profile. Their increase over time may reflect progression of PD to a certain degree. Therapeutic drug monitoring in PD is considered to improve the therapeutic efficacy in the course of this devastating neurologic disorder and therefore is able to contribute to the patients' precision medicine. State-of-the-art clinical studies are urgently needed to demonstrate the usefulness of TDM for optimizing the treatment of PD.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). NMS including sleep disturbances, depression, anxiety, and constipation are diverse, can precede motor symptoms, and significantly impact patients` quality of life. The severity and type of NMS vary based on age, disease severity, and motor symptoms, and while some respond to dopaminergic treatments, others may be induced or exacerbated by such treatments. NMS also play a role in differentiating PD from drug-induced parkinsonism and are related to gait dysfunction in both early and advanced stages. Genetic factors play a significant role in the development of NMS in PD, with mutations in genes such as SNCA, LRRK2, PRKN, and GBA being associated with severe and early NMS. Familial studies and identification of susceptibility factors have provided insights into the genetic underpinnings of NMS in PD. Neurobehavioral changes, including cognitive decline, are common NMS in PD, and their genetic basis involves a spectrum of mutations shared with other neurodegenerative disorders. Further research is needed to elucidate the functional implications of these genetic factors and their contributions to the pathogenesis of NMS in PD.