The unmet timely diagnosis requirements, that take place years after substantial neural loss and neuroperturbations in neuropsychiatric disorders, affirm the dire need for biomarkers with proven ...efficacy. In Parkinson's disease (PD), Mild Cognitive impairment (MCI), Alzheimers disease (AD) and psychiatric disorders, it is difficult to detect early symptoms given their mild nature. We hypothesize that employing fine motor patterns, derived from natural interactions with keyboards, also knwon as keystroke dynamics, could translate classic finger dexterity tests from clinics to populations in-the-wild for timely diagnosis, yet, further evidence is required to prove this efficiency. We have searched PubMED, Medline, IEEEXplore, EBSCO and Web of Science for eligible diagnostic accuracy studies employing keystroke dynamics as an index test for the detection of neuropsychiatric disorders as the main target condition. We evaluated the diagnostic performance of keystroke dynamics across 41 studies published between 2014 and March 2022, comprising 3791 PD patients, 254 MCI patients, and 374 psychiatric disease patients. Of these, 25 studies were included in univariate random-effect meta-analysis models for diagnostic performance assessment. Pooled sensitivity and specificity are 0.86 (95% Confidence Interval (CI) 0.82-0.90, I
= 79.49%) and 0.83 (CI 0.79-0.87, I
= 83.45%) for PD, 0.83 (95% CI 0.65-1.00, I
= 79.10%) and 0.87 (95% CI 0.80-0.93, I
= 0%) for psychomotor impairment, and 0.85 (95% CI 0.74-0.96, I
= 50.39%) and 0.82 (95% CI 0.70-0.94, I
= 87.73%) for MCI and early AD, respectively. Our subgroup analyses conveyed the diagnosis efficiency of keystroke dynamics for naturalistic self-reported data, and the promising performance of multimodal analysis of naturalistic behavioral data and deep learning methods in detecting disease-induced phenotypes. The meta-regression models showed the increase in diagnostic accuracy and fine motor impairment severity index with age and disease duration for PD and MCI. The risk of bias, based on the QUADAS-2 tool, is deemed low to moderate and overall, we rated the quality of evidence to be moderate. We conveyed the feasibility of keystroke dynamics as digital biomarkers for fine motor decline in naturalistic environments. Future work to evaluate their performance for longitudinal disease monitoring and therapeutic implications is yet to be performed. We eventually propose a partnership strategy based on a "co-creation" approach that stems from mechanistic explanations of patients' characteristics derived from data obtained in-clinics and under ecologically valid settings. The protocol of this systematic review and meta-analysis is registered in PROSPERO; identifier CRD42021278707. The presented work is supported by the KU-KAIST joint research center.
•Probiotics reduce markers of peripheral inflammation in PD.•Preclinical evidence suggests neuroprotective properties of probiotics in PD.•Probiotics activate the GLP-1 and PPAR-γ pathway in ...PD.•Future research should further explore the effects of probiotics on neuropsychiatric aspects of PD.
There is increasing evidence highlighting the potential role of the gut-brain axis in the pathogenesis of Parkinson’s disease (PD) and on the use of probiotics as a therapeutic strategy for this neurodegenerative disorder. While several studies have been published on the topic in recent years, there is still a lack of a comprehensive understanding of the effects of probiotics in PD and their possible underlying mechanisms. Through this systematic review, we collected a total of 17 articles, consisting of preclinical and clinical models of PD investigating the effect of probiotics on (1) energy metabolism, (2) inflammation and oxidative stress, (3) neurodegeneration, as well as (4) motor and (5) non-motor function. Articles were obtained from PubMed/Medline, Scopus, Web of Science and Embase databases. Findings from preclinical studies suggest that treatment with probiotics increases glucose metabolism (increased secretion of glucagon-like peptide-1), reduces peripheral and central inflammation (reduced interleukin-6 and tumor necrosis factor-α (TNF-α)), reduces peripheral and central oxidative stress (reduced peripheral superoxide anion levels and increased central antioxidant glutathione levels), decreases neurodegeneration (increased numbers of tyrosine hydroxylase dopaminergic neurons and levels of brain-derived neurotrophic factor), increases motor function (increased motor agility) and non-motor function (decreased memory deficits). Similarly, findings from clinical studies suggest that probiotics increase glucose metabolism (reduced insulin resistance), reduce peripheral inflammation (reduced peripheral TNF-α expression and C-reactive protein levels), and increase motor and non-motor function (decreased overall PD symptomatology and constipation); however, findings on oxidative stress were inconclusive across studies. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of probiotics on molecular and cellular mechanisms, as well as behavioural phenotypes, in either preclinical or clinical studies in PD. However, additional and more robust studies are still needed to confirm these outcomes, and should aim to focus more on bench-to-bedside approaches, in order to address the existing gaps between preclinical and clinical findings in this field.
Early descriptions of subtypes of Parkinson’s disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic ...features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.
Abstract Background Alzheimer's disease (AD) and Parkinson's disease (PD) are the two common neurodegenerative diseases characterized by progressive neuronal dysfunction in the presence of ...pathological microglial activation. Methods 10 AD, 10 mild cognitive impairment (MCI), 11 PD dementia (PDD), and 16 controls underwent magnetic resonance imaging, 11C(R)PK11195 (1-2-chlorophenyl-N-methyl-N-1-methyl-propyl-3-isoquinoline carboxamide), 11CPIB (11C-Pittsburgh compound B), 18FFDG-PET (18F-2-fluoro-2-deoxyglucose positron emission tomography) scans. Parametric images were interrogated using region of interest (ROI), biological parametric mapping (BPM) and statistical parametric mapping analysis, and neuropsychometric tests. Results Using BPM analysis, AD, MCI, and PDD subjects demonstrated significant correlation between increased microglial activation and reduced glucose metabolism (rCMRGlc). AD and MCI subjects also showed significant positive correlation between amyloid and microglial activation. Levels of cortical microglial activation were negatively correlated with Mini-Mental State Examination in both AD and PDD. Conclusion The significant inverse correlations between cortical levels of microglial activation and rCMRGlc in AD and PDD suggest cortical neuroinflammation may drive neuronal dysfunction in these dementias.
Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies ...have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment.
In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3–8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day range 14–18 was acceptable) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121).
Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h SD 1·50) significantly reduced off time compared with placebo (−2·47 h per day SD 3·70 in the apomorphine group vs −0·58 h per day 2·80 in the placebo group; difference −1·89 h per day, 95% CI −3·16 to −0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events.
Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy.
Britannia Pharmaceuticals.
Compared to other neurodegenerative diseases, Parkinson's disease (PD) is distinctive in terms of marked symptomatic variability and prognosis, as well as for the wide variety of symptomatic ...treatment options. Despite several decades of advances in medications and neurosurgical approaches, there remains an unmet need for symptomatic motor control. Better control of tremor, gait and balance, posture, dexterity, and communication skills are major challenges for better therapeutics of the PD movement disorder. Non-motor symptoms (NMS), which often precede motor impairments, add complexity to the burden of PD and its management. Recognized by James Parkinson MD two centuries ago, and despite 21st century neurological advances, a range of NMS plague the patient's journey, from prodromal to palliative stages. Characterizing the clinical phenotype of the entire non-motor profile of PD is challenging. Further research and understanding are needed for discovering biomarkers of certain NMS, such as dementia, fatigue, pain, sleep, and apathy. More work is needed to gather a robust evidence base for guiding treatment of troubling NMS, which exert a major impact on quality of life for people with PD and their caregivers.
•There remain unmet needs for improving the symptomatic control of PD motor features.•Nonmotor symptoms (NMS) are a major cause of morbidity, yet remain under-recognized.•NMS predominate prodromal PD and may serve as endpoints in neuroprotection trials.•NMS-dominant PD endophenotypes are prominent and call for personalized management.•Other unmet needs include animal models, translational research and biomarkers.
Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies ...supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a concept further strengthened by the predominantly non-motor spectrum of symptoms in prodromal PD. Preclinical and clinical studies support early dysfunction of noradrenergic transmission in both the CNS and peripheral nervous system circuits in patients with PD that results in a specific cluster of non-motor symptoms, including rapid eye movement sleep behaviour disorder, pain, anxiety and dysautonomia (particularly orthostatic hypotension and urinary dysfunction). Cluster analyses of large independent cohorts of patients with PD and phenotype-focused studies have confirmed the existence of a noradrenergic subtype of PD, which had been previously postulated but not fully characterized. This Review discusses the translational work that unravelled the clinical and neuropathological processes underpinning the noradrenergic PD subtype. Although some overlap with other PD subtypes is inevitable as the disease progresses, recognition of noradrenergic PD as a distinct early disease subtype represents an important advance towards the delivery of personalized medicine for patients with PD.
PDF
