Cerebral hemodynamics and cognitive functions in the acute and subacute stage of mild ischemic stroke: a longitudinal pilot study.

The association between cerebral hemodynamics and cognitive impairment has been reported in neurodegenerative and cerebrovascular disorders (CVD). However, it is still unclear whether changes occur in the acute phase of CVD. Here we investigated cognitive and hemodynamic parameters and their association in patients with CVD during the acute and subacute phases. Seventy-three patients with mild stroke, not undergoing endovascular treatment, were recruited. All subjects were devoid of intracranial or external carotid stenosis, significant chronic cerebrovascular pathology, dementia or non-compensated cardiovascular diseases. Patients were evaluated within 7 days from symptoms onset (T1) and after 3 months (T2). Clinical and demographic data were collected. NIHSS, MoCA, FAB, and Word-Color Stroop test (WCST) were used to evaluate disease severity and cognitive functions. Basal hemodynamic parameters in the middle cerebral artery were measured with transcranial Doppler. Differences between T2 and T1, correlations between cognitive and hemodynamic variables at T1 and T2, as well as correlations between the T2-T1 variation in cognitive and hemodynamic parameters were assessed. At T1, cognitive performance of MoCA, FAB, and WCST was lower compared with T2; and pulsatility index, a parameter reflecting distal vascular resistance, was higher. However, no correlations between the changes in cognitive and hemodynamic variables were found; therefore, the two seems to be independent phenomena. In the acute phase, the linear association between cerebral blood flow and cognitive performances was lost, probably due to a differential effect of microenvironment changes and vascular-specific phenomena on cognition and cerebral hemodynamics. This relationship was partially restored in the subacute phase.

Turning When Using Smartphone in Persons With and Those Without Neurologic Conditions: Observational Study.

BACKGROUND: Turning during walking is a relevant and common everyday movement and it depends on a correct top-down intersegmental coordination. This could be reduced in several conditions (en bloc turning), and an altered turning kinematics has been linked to increased risk of falls. Smartphone use has been associated with poorer balance and gait; however, its effect on turning-while-walking has not been investigated yet. This study explores turning intersegmental coordination during smartphone use in different age groups and neurologic conditions. OBJECTIVE: This study aims to evaluate the effect of smartphone use on turning behavior in healthy individuals of different ages and those with various neurological diseases. METHODS: Younger (aged 18-60 years) and older (aged >60 years) healthy individuals and those with Parkinson disease, multiple sclerosis, subacute stroke (<4 weeks), or lower-back pain performed turning-while-walking alone (single task [ST]) and while performing 2 different cognitive tasks of increasing complexity (dual task [DT]). The mobility task consisted of walking up and down a 5-m walkway at self-selected speed, thus including 180° turns. Cognitive tasks consisted of a simple reaction time test (simple DT [SDT]) and a numerical Stroop test (complex DT [CDT]). General (turn duration and the number of steps while turning), segmental (peak angular velocity), and intersegmental turning parameters (intersegmental turning onset latency and maximum intersegmental angle) were extracted for head, sternum, and pelvis using a motion capture system and a turning detection algorithm. RESULTS: In total, 121 participants were enrolled. All participants, irrespective of age and neurologic disease, showed a reduced intersegmental turning onset latency and a reduced maximum intersegmental angle of both pelvis and sternum relative to head, thus indicating an en bloc turning behavior when using a smartphone. With regard to change from the ST to turning when using a smartphone, participants with Parkinson disease reduced their peak angular velocity the most, which was significantly different from lower-back pain relative to the head (P<.01). Participants with stroke showed en bloc turning already without smartphone use. CONCLUSIONS: Smartphone use during turning-while-walking may lead to en bloc turning and thus increase fall risk across age and neurologic disease groups. This behavior is probably particularly dangerous for those groups with the most pronounced changes in turning parameters during smartphone use and the highest fall risk, such as individuals with Parkinson disease. Moreover, the experimental paradigm presented here might be useful in differentiating individuals with lower-back pain without and those with early or prodromal Parkinson disease. In individuals with subacute stroke, en bloc turning could represent a compensative strategy to overcome the newly occurring mobility deficit. Considering the ubiquitous smartphone use in daily life, this study should stimulate future studies in the area of fall risk and neurological and orthopedic diseases. TRIAL REGISTRATION: German Clinical Trials Register DRKS00022998; https://drks.de/search/en/trial/DRKS00022998.

Four Days Are Enough to Provide a Reliable Daily Step Count in Mild to Moderate Parkinson's Disease through a Commercial Smartwatch.

Daily steps could be a valuable indicator of real-world ambulation in Parkinson's disease (PD). Nonetheless, no study to date has investigated the minimum number of days required to reliably estimate the average daily steps through commercial smartwatches in people with PD. Fifty-six patients were monitored through a commercial smartwatch for 5 consecutive days. The total daily steps for each day was recorded and the average daily steps was calculated as well as the working and weekend days average steps. The intraclass correlation coefficient (ICC) (3,k), standard error of measurement (SEM), Bland-Altman statistics, and minimum detectable change (MDC) were used to evaluate the reliability of the step count for every combination of 2-5 days. The threshold for acceptability was set at an ICC ≥ 0.8 with a lower bound of CI 95% ≥ 0.75 and a SAM < 10%. ANOVA and Mann-Whitney tests were used to compare steps across the days and between the working and weekend days, respectively. Four days were needed to achieve an acceptable reliability (ICC range: 0.84-0.90; SAM range: 7.8-9.4%). In addition, daily steps did not significantly differ across the days and between the working and weekend days. These findings could support the use of step count as a walking activity index and could be relevant to developing monitoring, preventive, and rehabilitation strategies for people with PD.

The impact of cerebral vasomotor reactivity on cerebrovascular diseases and cognitive impairment.

The regulation of cerebral blood flow (CBF) is a complex and tightly controlled function ensuring delivery of oxygen and nutrients and removal of metabolic wastes from brain tissue. Cerebral vasoreactivity (CVR) refers to the ability of the nervous system to regulate CBF according to metabolic demands or changes in the microenvironment. This can be assessed through a variety of nuclear medicine and imaging techniques and protocols. Several studies have investigated the association of CVR with physiological and pathological conditions, with particular reference to the relationship with cognitive impairment and cerebrovascular disorders (CVD). A better understanding of the interaction between CVR and cognitive dysfunction in chronic and particularly acute CVD could help improving treatment and rehabilitation strategies in these patients. In this paper, we reviewed current knowledge on CVR alterations in the context of acute and chronic CVD and cognitive dysfunction. Alterations in CVR and hemodynamics have been described in patients with both neurodegenerative and vascular cognitive impairment, and the severity of these alterations seems to correlate with CVR derailment. Furthermore, an increased risk of cognitive impairment progression has been associated with alterations in CVR parameters and hemodynamics. Few studies have investigated these associations in acute cerebrovascular disorders and the results are inconsistent; thus, further research on this topic is encouraged.

Step-Counting Accuracy of a Commercial Smartwatch in Mild-to-Moderate PD Patients and Effect of Spatiotemporal Gait Parameters, Laterality of Symptoms, Pharmacological State, and Clinical Variables.

Commercial smartwatches could be useful for step counting and monitoring ambulatory activity. However, in Parkinson's disease (PD) patients, an altered gait, pharmacological condition, and symptoms lateralization may affect their accuracy and potential usefulness in research and clinical routine. Steps were counted during a 6 min walk in 47 patients with PD and 47 healthy subjects (HS) wearing a Garmin Vivosmart 4 (GV4) on each wrist. Manual step counting was used as a reference. An inertial sensor (BTS G-Walk), placed on the lower back, was used to compute spatial-temporal gait parameters. Intraclass correlation coefficient (ICC) and mean absolute percentage error (MAPE) were used for accuracy evaluation and the Spearman test was used to assess the correlations between variables. The GV4 overestimated steps in PD patients with only a poor-to-moderate agreement. The OFF pharmacological state and wearing the device on the most-affected body side led to an unacceptable accuracy. The GV4 showed an excellent agreement and MAPE in HS at a self-selected speed, but an unacceptable performance at a slow speed. In PD patients, MAPE was not associated with gait parameters and clinical variables. The accuracy of commercial smartwatches for monitoring step counting might be reduced in PD patients and further influenced by the pharmacological condition and placement of the device.

Safinamide improves executive functions in fluctuating Parkinson's disease patients: an exploratory study.

Safinamide is a monoamine-oxidase-B inhibitor with peculiar features. At the dose of 100 mg/day, safinamide stimulates dopaminergic transmission and reduces glutamatergic transmission. Here, we investigated the effects of safinamide 100 mg on executive functions at the end of levodopa dose in fluctuating Parkinson's disease (PD) patients. Thirty-two fluctuating PD patients were submitted at baseline (V1) to the UPDRS-III, the Frontal Assessment Battery (FAB) and the Stroop-Word-Color-Test (SWCT) at the end of levodopa dose. Safinamide was then added to the original therapy. After 12 weeks of treatment, patients underwent the final visit (V2), including the UPDRS-III, the FAB and the SWCT with the same daily time schedule as V1. Treatment with safinamide was associated with significant increases of the total FAB score, SWCT-interference time score and UPDRS-III score. Within FAB subdomains, add-on with safinamide significantly increased motor programming and increased mental flexibility and inhibitory control scores. The results of this exploratory study show that add-on with safinamide improves executive functions at the end of levodopa dose in fluctuating PD patients. In particular, attention and inhibition of cognitive interference were significantly ameliorated by add-on with safinamide, suggesting increased modulatory performances of prefrontal cortical pathways. If confirmed by future research on larger cohorts and under controlled conditions, the present results may represent the basis for a novel indication for the use of safinamide in fluctuating PD patients.

The tolerability, safety and efficacy of safinamide in elderly Parkinson's disease patients: a retrospective study.

Safinamide (SF) is a third-generation monoamine-oxidase-B inhibitor that proved efficacy as add-on to levodopa in fluctuating Parkinson's disease (PD) patients. Despite the high prevalence of complicated PD in older population, the data on the tolerability, safety and efficacy of SF in elderly patients are rather poor. Here we studied retrospectively the consequences of add-on with SF in PD patients older than 65 years. Fifty-three fluctuating PD patients were included (30 subjects aged between 65 and 75 years, the remaining 23 subjects aged > 75 years). Patients were treated with either 50 (n = 27) or 100 mg (n = 26) SF for at least 6 months. In all patients, fluctuations were identified by the report of a Wearing-Off-Questionnaire-19 (WOQ-19) score ≥ 3 at baseline. Add-on with SF was well tolerated and safe. Adverse events occurred in 30% of patients and led to drug discontinuation in 11% of cases. At follow-up visits, 60% of patients reported lowering of the WOQ-19 score to ≤ 2. There were no significant differences related to age or daily drug dose in tolerability, safety or efficacy. The results of this study provide evidence of the efficacy, tolerability and safety of SF in elderly PD patients.

The TANDEM investigation: efficacy and tolerability of levodopa-carbidopa intestinal gel in (LCIG) advanced Parkinson's disease patients.

The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson's disease and Movement Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in "ON" and OFF" state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in "OFF") decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4; p < 0.001) and FUV2 (40.5 ± 15.5; p < 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4; p < 0.001) and FUV2 (5.5 ± 3.2; p < 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in "OFF", complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.

Foot Pressure Wearable Sensors for Freezing of Gait Detection in Parkinson's Disease.

Freezing of Gait (FoG) is a common symptom in Parkinson's Disease (PD) occurring with significant variability and severity and is associated with increased risk of falls. FoG detection in everyday life is not trivial, particularly in patients manifesting the symptom only in specific conditions. Various wearable devices have been proposed to detect PD symptoms, primarily based on inertial sensors. We here report the results of the validation of a novel system based on a pair of pressure insoles equipped with a 3D accelerometer to detect FoG episodes. Twenty PD patients attended a motor assessment protocol organized into eight multiple video recorded sessions, both in clinical and ecological settings and both in the ON and OFF state. We compared the FoG episodes detected using the processed data gathered from the insoles with those tagged by a clinician on video recordings. The algorithm correctly detected 90% of the episodes. The false positive rate was 6% and the false negative rate 4%. The algorithm reliably detects freezing of gait in clinical settings while performing ecological tasks. This result is promising for freezing of gait detection in everyday life via wearable instrumented insoles that can be integrated into a more complex system for comprehensive motor symptom monitoring in PD.

Gender specific decrease of a set of circulating N-acylphosphatidyl ethanolamines (NAPEs) in the plasma of Parkinson's disease patients.

INTRODUCTION: Current markers of Parkinson's disease (PD) fail to detect the early progression of disease state. Conversely, current omics techniques allow the investigation of hundreds of molecules potentially altered by disease conditions. Based on evidence previously collected by our group in a mouse model of PD, we speculated that a particular set of circulating lipids might be significantly altered by the pathology. OBJECTIVES: The aim of current study was to evaluate the potential of a particular set of N-acyl-phosphatidylethanolamines (NAPEs) as potential non-invasive plasma markers of ongoing neurodegeneration from Parkinson's disease in human subjects. METHODS: A panel of seven NAPEs were quantified by LC-MS/MS in the plasma of 587 individuals (healthy controls, n = 319; Parkinson's disease, n = 268); Random Forest classification and statistical modeling was applied to compare Parkinson's disease versus controls. All p-values obtained in different tests were corrected for multiplicity by controlling the false discovery rate (FDR). RESULTS: The results indicate that this panel of NAPEs is able to distinguish female PD patients from the corresponding healthy controls. Further to this, the observed downregulation of these NAPEs is in line with the results in plasma of a mouse model of Parkinson's (6-OHDA). CONCLUSIONS: In the current study we have shown the downregulation of NAPEs in plasma of PD patients and we thus speculate that these lipids might serve as candidate biomarkers for PD. We also suggest a molecular mechanism, explaining our findings, which involves gut microbiota.

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.

Orthostatic hypotension acutely impairs executive functions in Parkinson's disease.

Orthostatic hypotension is a frequent non-motor symptom of Parkinson's disease, with negative prognostic role on cognitive functions. Here we measured the acute effects of orthostatic hypotension on executive functions in Parkinson's disease patients devoid of hypertension, carotid artery stenosis, and significant chronic cerebrovascular pathology. Measurements were carried out during regular visits in outpatient setting. Twenty-eight Parkinson's disease patients were recruited and studied along scheduled outpatient visits. They were divided into two groups (n = 14 each) based on the presence or lack of orthostatic hypotension. This was diagnosed according to international guidelines. All patients were submitted to the Stroop's test and to the phonological and semantic verbal fluency test after 10-min resting in supine position and immediately upon standing in upright position. Testing lasted less than 5 min in either position. In upright position, subjects with orthostatic hypotension displayed significantly worse performances at the Stroop's test word reading time (22.1 ± 4.1 vs. 14.9 ± 4.0 s), interference time (56.1 ± 12.3 vs. 41.4 ± 11.8 s), and number of errors at the interference section (5.8 ± 3.2 vs. 1.3 ± 2.1) as compared to those without orthostatic hypotension. These results demonstrate that worsening of attentive function upon standing can be measured in Parkinson's disease patients with orthostatic hypotension during routine outpatient visits. These findings suggest that clinically asymptomatic orthostatic hypotension in Parkinson's disease patients may acutely worsen neuropsychological performances with possible negative impact on daily functioning.

Supine hypertension in Parkinson's disease and multiple system atrophy.

OBJECTIVE: Supine hypertension (SH) is a feature of cardiovascular autonomic failure that often accompanies orthostatic hypotension and may represent a negative prognostic factor in parkinsonian syndromes. Here we investigated the frequency rate as well as the clinical and tilt test correlates of SH in Parkinson's disease (PD) and multiple system atrophy (MSA). METHODS: 197 PD (33 demented) and 78 MSA (24 MSA-Cerebellar, 54 MSA-Parkinsonian) patients who had undergone a tilt test examination were retrospectively included. Clinical-demographic characteristics were collected from clinical records at the time of the tilt test examination. RESULTS: SH (>140 mmHg systolic, >90 mmHg diastolic) occurred in 34 % of PD patients (n = 66, mild in 71 % of patients, moderate in 27 %, severe in 2 %) and 37 % of MSA ones (n = 29, mild in 55 % of patients, moderate in 17 %, severe in 28 %). No difference was observed in SH frequency between demented versus gender-, age- and disease duration-matched non-demented PD patients, or between patients with the parkinsonian (MSA-P) versus the cerebellar (MSA-C) variant of MSA. In PD, SH was associated with presence of cardiovascular comorbidities (p = 0.002) and greater systolic (p = 0.007) and diastolic (p = 0.002) orthostatic blood pressure fall. Orthostatic hypotension (p = 0.002), and to a lesser degree, lower daily dopaminergic intake (p = 0.01) and use of anti-hypertensive medications (p = 0.04) were associated with SH in MSA. INTERPRETATION: One-third of PD and MSA patients suffer from mild to severe SH, independently of age, disease duration or stage. In PD, cardiovascular comorbidities significantly contribute to the development of SH, while in MSA, SH appears to reflect cardiovascular autonomic failure.

Metabotropic Glutamate Receptors Type 3 and 5 Feature the "NeuroTransmitter-type" of Glioblastoma: A Bioinformatic Approach.

BACKGROUND: Glioblastoma (GBM) represents an aggressive and common tumor of the central nervous system. The prognosis of GBM is poor, and despite a refined genetic and molecular characterization, pharmacological treatment is largely suboptimal. OBJECTIVE: Contribute to defining a therapeutic line in GBM targeting the mGlu3 receptor in line with the principles of precision medicine. METHODS: Here, we performed a computational analysis focused on the expression of type 3 and 5 metabotropic glutamate receptor subtypes (mGlu3 and mGlu5, respectively) in high- and low-grade gliomas. RESULTS: The analysis allowed the identification of a particular high-grade glioma type, characterized by a high expression level of both receptor subtypes and by other markers of excitatory and inhibitory neurotransmission. This so-called neurotransmitter-GBM (NT-GBM) also shows a distinct immunological, metabolic, and vascularization gene signature. CONCLUSION: Our findings might lay the groundwork for a targeted therapy to be specifically applied to this putative novel type of GBM.

Unveiling the Unpredictable in Parkinson's Disease: Sensor-Based Monitoring of Dyskinesias and Freezing of Gait in Daily Life.

BACKGROUND: Dyskinesias and freezing of gait are episodic disorders in Parkinson's disease, characterized by a fluctuating and unpredictable nature. This cross-sectional study aims to objectively monitor Parkinsonian patients experiencing dyskinesias and/or freezing of gait during activities of daily living and assess possible changes in spatiotemporal gait parameters. METHODS: Seventy-one patients with Parkinson's disease (40 with dyskinesias and 33 with freezing of gait) were continuously monitored at home for a minimum of 5 days using a single wearable sensor. Dedicated machine-learning algorithms were used to categorize patients based on the occurrence of dyskinesias and freezing of gait. Additionally, specific spatiotemporal gait parameters were compared among patients with and without dyskinesias and/or freezing of gait. RESULTS: The wearable sensor algorithms accurately classified patients with and without dyskinesias as well as those with and without freezing of gait based on the recorded dyskinesias and freezing of gait episodes. Standard spatiotemporal gait parameters did not differ significantly between patients with and without dyskinesias or freezing of gait. Both the time spent with dyskinesias and the number of freezing of gait episodes positively correlated with the disease severity and medication dosage. CONCLUSIONS: A single inertial wearable sensor shows promise in monitoring complex, episodic movement patterns, such as dyskinesias and freezing of gait, during daily activities. This approach may help implement targeted therapeutic and preventive strategies for Parkinson's disease.

The Story behind the Mask: A Narrative Review on Hypomimia in Parkinson's Disease.

Facial movements are crucial for social and emotional interaction and well-being. Reduced facial expressions (i.e., hypomimia) is a common feature in patients with Parkinson's disease (PD) and previous studies linked this manifestation to both motor symptoms of the disease and altered emotion recognition and processing. Nevertheless, research on facial motor impairment in PD has been rather scarce and only a limited number of clinical evaluation tools are available, often suffering from poor validation processes and high inter- and intra-rater variability. In recent years, the availability of technology-enhanced quantification methods of facial movements, such as automated video analysis and machine learning application, led to increasing interest in studying hypomimia in PD. In this narrative review, we summarize the current knowledge on pathophysiological hypotheses at the basis of hypomimia in PD, with particular focus on the association between reduced facial expressions and emotional processing and analyze the current evaluation tools and management strategies for this symptom, as well as future research perspectives.