The use of wearable/portable digital sensors in Huntington’s disease: a systematic review

In chronic neurological conditions, wearable/portable devices have potential as innovative tools to detect subtle early disease manifestations and disease fluctuations for the purpose of clinical diagnosis, care and therapeutic development. Huntington’s disease (HD) has a unique combination of motor and non-motor features which, combined with recent and anticipated therapeutic progress, gives great potential for such devices to prove useful. The present work aims to provide a comprehensive account of the use of wearable/portable devices in HD and of what they have contributed so far. We conducted a systematic review searching MEDLINE, Embase, and IEEE Xplore. Thirty references were identified. Our results revealed large variability in the types of sensors used, study design, and the measured outcomes. Digital technologies show considerable promise for therapeutic research and clinical management of HD. However, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable/portable devices in HD

Sex Differences in Long-Term Mortality and Functional Outcome After Rehabilitation in Patients With Severe Stroke

Objective: We sought to determine sex differences in outcomes in patients with severe stroke who had been admitted to inpatient rehabilitation. Methods: We studied 1,316 patients aged 18 to 99 (mean 72) classified as case-mix groups 0108, 0109, and 0110 of the Medicare case-mix classification system. These groups encompass the most severe strokes. Three outcomes were analyzed: (1) 3-year mortality from admission to rehabilitation; (2) combined outcome of transfer to acute care or death within 90 days from admission to rehabilitation; (3) functional outcome, including proportional recovery in motor functioning and good functional outcome as defined by achievement of a Functional Independence Measure (FIM)-motor score ≥65 points at discharge. Multivariable regression analyses were used to assess sex-difference in each outcome between women and men. The covariates examined included age, marital status, comorbidities, time from stroke onset to rehabilitation admission <30 days, ischemic stroke, dysphagia, neglect, motor FIM score at admission, and cognitive FIM score at admission. Results: Kaplan-Meier estimated 3-year mortality rate was 20.7% in women and 22.0% in men. The crude hazard ratio (HR) of death for women compared with men was 0.94 (95% CI 0.74–1.20). After adjustment for significant covariates, the HR of 3-year mortality was 0.73 (95% CIs 0.56–0.96; p = 0.025). Comorbidity, including diabetes, anemia, coronary artery disease, atrial fibrillation, and chronic obstructive pulmonary disease, significantly increased mortality risk by 49–88%. The incidence of the combined outcome was 8.3% in women and 8.4% in men. The crude HR of the combined end-point for women compared with men was 1.05 (95% CI 0.72–1.53). After adjustment for significant covariates, the HR was 0.95 (95% CIs 0.65–1.40; p = 0.810). Likewise, no significant difference in proportional recovery or in the rate of achievement of a good functional outcome between women and men was observed. Conclusion: Among patients admitted to inpatient rehabilitation after severe stroke, women and men had comparable crude mortality rates at 3 years. After multivariable adjustment, however, women had lower mortality risk. No sex-differences in the risk of being transferred to acute care or dying within 90 days from admission to rehabilitation or in responsiveness to rehabilitation were observed

The Modified Five-Point Test (MFPT): normative data for a sample of Italian elderly

INTRODUCTION: Non-verbal figural fluency is related to executive functions and specifically to the ability to create as many unique designs as possible, while minimizing their repetitions. An Italian version of figural fluency is the Modified Five-Point Test (MFPT), which is highly employed in the clinical practice of neuropsychologists. To date, reference data of Italian population are limited to a sample aged between 16 and 60 years old. Thus, the current study aims to provide normative data of the MFPT in the context of a population-based setting, conducted in Southern Italy. MATERIAL AND METHODS: We collected N = 340 Italian healthy subjects, aged over 65 years old (range: 65-91), pooled across subgroups for age, sex, and education. Multiple regression analyses were performed to estimate the effect of age, education, and sex on the participant's performance. Equivalent scores and cut-off scores were also defined for the number of unique designs (UDs) and the number of strategies (CSs). RESULTS: Multiple regression analyses revealed that UDs increase with decreasing age and increasing educational level. CSs are influenced by higher educational levels but neither by age nor sex. A significant inverse correlation between the UDs and percentage of errors occurred, suggesting that a higher number of UDs are associated with a fewer number of errors and higher CSs employed. CONCLUSION: The MFPT provides a measure of cognitive functioning in terms of the ability to initiate and realize designs, affording useful hints for clinical settings. The MFPT may represent a handy and useful tool with a specific focus in the differentiation of healthy versus pathological aging

Plasma Inflammatory Cytokines Are Elevated in ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which leads to death in a median time of 2–3 years. Inflammation has been claimed important to the ALS pathogenesis, but its role is still not well-characterized. In the present study, a panel of five cytokines (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha)measured in plasma has been investigated in ALS. These biomarkers of inflammation were measured in a population-based cohort of 79 patients with ALS and 79 age- and sex-matched healthy controls using the Bio-Plex technology (Bio-Rad). All the five cytokines were significantly increased in plasma samples of patients compared with controls (p < 0.0001), with IL-6 having the highest median concentration (10.11 pg/ml) in the ALS group. Furthermore, IL-6 was the plasma cytokine with the highest discrimination ability between patients and controls according to the receiver operating characteristic analysis (area under the curve = 0.93). At a cut-off point of 5.71 pg/ml, it was able to classify patients and controls with 91% of sensitivity and 87% of specificity. In the ALS group, plasma IL-6 concentration correlated with demographic (age: rs = 0.25, p = 0.025) and clinical (revised ALS Functional Rating Scale at evaluation: rs = −0.32, p = 0.007; Manual Muscle Testing: rs =−0.33, p=0.004; progression: rs=0.29, p=0.0395) parameters. In line with previous studies, our results confirm that inflammatory cytokines are elevated in ALS, supporting a possible role of inflammation in disease mechanism and progression. However, the precise role of inflammation in ALS needs to be further investigated on larger samples and with more mechanistic studies

Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease. © 2013 Mezzapesa et al

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington’s disease

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF

Episodic memory and learning rates in amyotrophic lateral sclerosis without dementia

In amyotrophic lateral sclerosis (ALS), memory deficits may be primary or secondary to executive dysfunction. We assessed episodic memory and executive function of nondemented ALS patients, comparing episodic memory profiles and learning rates of ALS patients with those of mild cognitive impairment (MCI) subjects and cognitively healthy controls (HC). In a multidisciplinary tertiary centre for motor neuron disease, 72 nondemented ALS patients, 57 amnestic MCI (aMCI), 89 single non amnestic MCI with compromised executive functions (dysexecutive MCI), and 190 HC were enrolled. They were screened using the Frontal Assessment Battery and Mini Mental State Examination. Episodic memory performances and learning rates were tested using the Rey Auditory Verbal Learning Test (RAVLT). Episodic memory dysfunction (immediate recall) was found in 14 ALS patients (19.4%). The ALS group had lower performance than HC on immediate recall, without differences in learning rate, and better performance than aMCI subjects on all RAVLT measures. Compared to dysexecutive MCI subjects, ALS patients had only better verbal learning abilities. ALS patients with executive dysfunction had a lower score on immediate and delayed recalls, verbal learning, and primacy effect than ALS patients without executive dysfunction. The immediate recall among couples of diagnostic groups differed in a statistically significant way except for the ALS/dysexecutive MCI groups. In ALS patients, episodic memory performances and learning rates appeared to be better than in aMCI subjects and similar to those with dysexecutive MCI, suggesting also a secondary functional damage due to executive impairment

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) were quantified using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. BDNF in CSF and plasma is unlikely to be a biomarker of HD progression, and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF

Age-Related Central Auditory Processing Disorder, MCI, and Dementia in an Older Population of Southern Italy

Objective: We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study). / Study Design: Cross-sectional data from a population-based study. / Setting: Castellana Grotte, Bari, Italy. / Subjects and Methods: Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and 65 years. / Results: The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers. / Conclusion: The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients

Urinary Extracellular Domain of Neurotrophin Receptor p75 as a Biomarker for Amyotrophic Lateral Sclerosis in a Chinese cohort

To comprehensively assess whether p75ECD in urine could be a candidate biomarker for ALS evaluation. Urine samples were collected from 101 ALS patients, 108 patients with other neurological disease (OND) and 97 healthy controls. 61 ALS patients were followed up with clinical data including ALSFRS-r every 6 to 12 months, 23 ALS patients died and 17 ALS patients lost touch during follow up period. Enzyme-linked immunoassay was employed to determine urine p75ECD concentration. The ALSFRS-r was employed to assess the severity of ALS. The concentration of p75ECD in ALS was significantly higher than that of OND and CTRL (p < 0.001). Additionally, urine p75ECD concentrations in ALS-definite grade patients were significantly higher than that in ALS-probable grade and ALS-possible grade patients (p < 0.001). Higher urine p75ECD concentrations were correlated with increased clinical stage (p = 0.0309); urine p75ECD concentrations and ALSFRS-r were negatively correlated (p = 0.022); and urine p75ECD concentration in the fast-progressing ALS group was significantly higher than that in slow-progression (p = 0.0026). Our finding indicates that urine p75ECD concentration provides additional evidence for patients with clinically suspected ALS, and can be employed to evaluate ALS-severity