Asterixis and dysarthria-clumsy hand originated of lacunar infarction: A series of six cases

Asterixis and dysarthria-clumsy hand are uncommon neurological signs following to movement disorders after a stroke, clinically are classified as a part of lacunar infarction and most of the cases resolved spontaneously within ten days to one month. The aim of this study was to describe the clinical characteristics of six patients with lacunar infarction and mild motor symptoms of dysarthria and asterixis with no signs of dementia. All patients had as comorbidities hypertension and/or type 2 diabetes. In conclusion, it is important due to the transience of the abnormal neurological movements, the promptly recognition of the characteristic clinical presentation and confirmation of the diagnosis with noninvasive studies. The patients should be treated to prevent recurrent stroke with more severe consequences.

Clinical Deep Phenotyping of ABCA7 Mutation Carriers

Background and ObjectivesPutative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.MethodsGenotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.ResultsWe confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56–92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.DiscussionOur study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Excessive Daytime Sleepiness Is Associated With Non-motor Symptoms of Multiple System Atrophy: A Cross-Sectional Study in China

Objectives: Excessive daytime sleepiness (EDS) in multiple system atrophy (MSA) has received scant attention in the literature, thus the present cross-sectional study aimed to investigate the prevalence of EDS and its potential risk factors among Chinese patients with MSA.Methods: A total of 66 patients with MSA (60.6% males) were consecutively recruited. Eighteen patients (27.3%, 13 men) with Epworth Sleepiness Scale score >10 were defined as having EDS. Demographic, motor [Unified Multiple-System Atrophy (UMSARS)] and non-motor symptoms [Non-Motor Symptoms Scale (NMSS)], and sleep parameters [polysomnography (PSG)] were compared between patients with MSA with and without EDS. A logistic regression analysis was used to calculate the risk factors of EDS in patients with MSA.Results: There were no significant differences in age, sex, MSA onset age, disease duration, MSA sub-type, and motor symptom severity between MSA patients with and without EDS. However, compared with the MSA patients without EDS, their counterparts with EDS had higher scores of NMSS (65.3 ± 23.1 vs. 43.4 ± 25.3, P = .0002), Hamilton Anxiety (HAMA) [15.3 (10.3–20.0) vs. 9.5 (3.0–15.0), P = 0.006], Hamilton Depression (HAMD) [13.7 (12.5–17.8) vs. 9.0 (4.0–13.0), P = 0.015], and Fatigue Severity Scale (FSS) [29.8 (17.3–47.8) vs. 18.7 (10.3–21.8), P = 0.040]. Conversely, the patients with EDS had lower score of Mini-Mental State Examination (MMSE) [23.3 (20.3–27.0) vs. 25.7 (22.0–29.0), P = 0.023]. Similarly, there was a significantly lower percentage of N3 sleep (%) [0.3 (0–0) vs. 2.0 (0–0), P = 0.007] and a higher apnea-hypopnea index (AHI/h) [30.5 (14.5–47.8) vs. 19.3 (5.0–28.7), P = 0.034] in patients with EDS. After adjusting for age, sex, disease duration, MSA sub-type, and UMSARS score, the odds ratio (OR) (95% CI) of EDS was higher while increasing scores in FSS [1.06 (1.02–1.11)], HAMA [1.16 (1.04–1.28)], HAMD [1.13 (1.02–1.25)], NMSS [1.04 (1.01–1.07)], and AHI [1.03 (1.00–1.10)]. The OR of EDS was lower while the MMSE score was increasing [0.85 (0.72–1.00)].Conclusions: The presence and severity of EDS may be significantly associated with the non-motor dysfunction, including fatigue, anxiety, depression, cognitive dysfunction, and sleep-related breathing disorder, but not with the motor dysfunction in MSA.

Impact of age at onset on symptom profiles, treatment characteristics and health-related quality of life in Parkinson’s disease

Parkinson’s disease (PD) is typically considered an age-related disease, but the age at disease onset can vary by decades between patients. Aging and aging-associated diseases can affect the movement system independently of PD, and advanced age has previously been proposed to be associated with a more severe PD phenotype with accelerated progression. In this work, we investigated how interactions between PD progression and aging affect a wide range of outcomes related to PD motor and nonmotor symptoms as well as Health Related Quality of Life (HRQoL) and treatment characteristics. This population-based cohort study is based on 1436 PD patients from southern Sweden followed longitudinally for up to approximately 7.5 years from enrollment (3470 visits covering 2285 patient years, average follow-up time 1.7 years). Higher age at onset was generally associated with faster progression of motor symptoms, with a notable exception of dyskinesia and other levodopa-associated motor fluctuations that had less severe trajectories for patients with higher age at onset. Mixed results were observed for emergence of non-motor symptoms, while higher age at onset was generally associated with worse HRQoL trajectories. Accounting for these identified age-associated differences in disease progression could positively impact patient management and drug development efforts.

A striatal plasticity that supports the long-term preservation of motor function in Parkinsonian mice.

Motor deficits of Parkinsons disease (PD) such as rigidity, bradykinesia and akinesia result from a progressive loss of nigrostriatal dopamine neurons. No therapies exist that slow their degeneration and the most effective treatments for the motor symptoms: L-dopa -the precursor to dopamine, and deep brain stimulation can produce dyskinesias and are highly invasive, respectively. Hence, alternative strategies targeted to slow the progression or delay the onset of motor symptoms are still highly sought. Here we report the identification of a long-term striatal plasticity mechanism that delays for several months, the onset of motor deficits in a mouse PD model. Specifically, we show that a one-week transient daily elevation of midbrain dopamine neuron activity during depletion preserves the connectivity of direct but not indirect pathway projection neurons. The findings are consistent with the balance theory of striatal output pathways and suggest a novel approach for treating the motor symptoms of PD.

Transcranial Direct Current Stimulation on Parkinson's Disease: Systematic Review and Meta-Analysis

Background: Clinical impact of transcranial direct current stimulation (tDCS) alone for Parkinson's disease (PD) is still a challenge. Thus, there is a need to synthesize available results, analyze methodologically and statistically, and provide evidence to guide tDCS in PD.Objective: Investigate isolated tDCS effect in different brain areas and number of stimulated targets on PD motor symptoms.Methods: A systematic review was carried out up to February 2021, in databases: Cochrane Library, EMBASE, PubMed/MEDLINE, Scopus, and Web of science. Full text articles evaluating effect of active tDCS (anodic or cathodic) vs. sham or control on motor symptoms of PD were included.Results: Ten studies (n = 236) were included in meta-analysis and 25 studies (n = 405) in qualitative synthesis. The most frequently stimulated targets were dorsolateral prefrontal cortex and primary motor cortex. No significant effect was found among single targets on motor outcomes: Unified Parkinson's Disease Rating Scale (UPDRS) III – motor aspects (MD = −0.98%, 95% CI = −10.03 to 8.07, p = 0.83, I2 = 0%), UPDRS IV – dyskinesias (MD = −0.89%, CI 95% = −3.82 to 2.03, p = 0.55, I2 = 0%) and motor fluctuations (MD = −0.67%, CI 95% = −2.45 to 1.11, p = 0.46, I2 = 0%), timed up and go – gait (MD = 0.14%, CI 95% = −0.72 to 0.99, p = 0.75, I2 = 0%), Berg Balance Scale – balance (MD = 0.73%, CI 95% = −1.01 to 2.47, p = 0.41, I2 = 0%). There was no significant effect of single vs. multiple targets in: UPDRS III – motor aspects (MD = 2.05%, CI 95% = −1.96 to 6.06, p = 0.32, I2 = 0%) and gait (SMD = −0.05%, 95% CI = −0.28 to 0.17, p = 0.64, I2 = 0%). Simple univariate meta-regression analysis between treatment dosage and effect size revealed that number of sessions (estimate = −1.7, SE = 1.51, z-score = −1.18, p = 0.2, IC = −4.75 to 1.17) and cumulative time (estimate = −0.07, SE = 0.07, z-score = −0.99, p = 0.31, IC = −0.21 to 0.07) had no significant association.Conclusion: There was no significant tDCS alone short-term effect on motor function, balance, gait, dyskinesias or motor fluctuations in Parkinson's disease, regardless of brain area or targets stimulated.

Sleep and circadian rhythms in Parkinson’s disease and preclinical models

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson’s disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson’s disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson’s disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson’s disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson’s reflect the sleep and circadian abnormalities of Parkinson’s disease observed in the clinic.

Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson’s disease patients

Background Parkinson’s disease (PD) is associated with enteric nervous system dysfunction and gut microbiota dysbiosis. Short-chain fatty acids (SCFAs), derived from gut microbiota, are supposed to anticipate PD pathogenesis via the pathway of spinal cord and vagal nerve or the circulatory system. However, the serum concentration of SCFAs in PD patients is poorly known. This study aims to investigate the exact level of SCFAs in PD patients and its correlation with Parkinson’s symptoms. Methods 50 PD patients and 50 healthy controls were recruited, and their demographic and clinical characteristics were collected. The serum concentration of SCFAs was detected using a gas chromatography-mass spectrometer. SCFAs were compared between PD and control groups. The correlation between serum SCFAs and Parkinson’s symptoms and the potential effects of medications on the serum SCFAs was analyzed. Results Serum propionic acid, butyric acid and caproic acid were lower, while heptanoic acid was higher in PD patients than in control subjects. However, only the serum level of propionic acid was correlated with Unified Parkinson’s Disease Rating Scale (UPDRs) part III score (R = -0.365, P = 0.009), Mini-mental State Examination (MMSE) score (R = -0.416, P = 0.003), and Hamilton Depression Scale (HAMD) score (R = 0.306, P = 0.03). There was no correlation between other serum SCFAs and motor complications. The use of trihexyphenidyl or tizanidine increased the serum concentration of propionic acid. Conclusions Serum SCFAs are altered in PD patients, and the decrease of serum propionic acid level is correlated with motor symptoms, cognitive ability and non-depressed state. Thus, the gut microbial-derived SCFAs potentially affect Parkinson’s symptoms through the blood circulation. Propionic acid supplementation might ameliorate motor and non-motor symptoms of PD patients, although clinical trials are needed to test this hypothesis.

The complex syndrome of functional neurological disorder

Background Patients with functional neurological disorders (FND) often present with multiple motor, sensory, psychological and cognitive symptoms. In order to explore the relationship between these common symptoms, we performed a detailed clinical assessment of motor, non-motor symptoms, health-related quality of life (HRQoL) and disability in a large cohort of patients with motor FND. To understand the clinical heterogeneity, cluster analysis was used to search for subgroups within the cohort. Methods One hundred fifty-two patients with a clinically established diagnosis of motor FND were assessed for motor symptom severity using the Simplified Functional Movement Disorder Rating Scale (S-FMDRS), the number of different motor phenotypes (i.e. tremor, dystonia, gait disorder, myoclonus, and weakness), gait severity and postural instability. All patients then evaluated each motor symptom type severity on a Likert scale and completed questionnaires for depression, anxiety, pain, fatigue, cognitive complaints and HRQoL. Results Significant correlations were found among the self-reported and all objective motor symptoms severity measures. All self-reported measures including HRQoL correlated strongly with each other. S-FMDRS weakly correlated with HRQoL. Hierarchical cluster analysis supplemented with gap statistics revealed a homogenous patient sample which could not be separated into subgroups. Conclusions We interpret the lack of evidence of clusters along with a high degree of correlation between all self-reported and objective measures of motor or non-motor symptoms and HRQoL within current neurobiological models as evidence to support a unified pathophysiology of ‘functional’ symptoms. Our results support the unification of functional and somatic syndromes in classification schemes and for future mechanistic and therapeutic research.

The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.