Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment: the Ability-TelerehABILITation study protocol for a randomized controlled trial.

BACKGROUND: According to the World Alzheimer Report (Prince, The Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends, 2015), 46.8 million people worldwide are nowadays living with dementia. And this number is estimated to approximate 131.5 million by 2050, with an increasing burden on society and families. The lack of medical treatments able to stop or slow down the course of the disease has moved the focus of interest toward the nonpharmacological approach and psychosocial therapies for people with/at risk of dementia, as in the Mild Cognitive Impairment (MCI) condition. The purpose of the present study is to test an individualized home-based multidimensional program aimed at enhancing the continuum of care for MCI and outpatients with dementia in early stage using technology. METHODS: The proposed study is a single blind randomized controlled trial (RCT) involving 30 subjects with MCI and Alzheimer's disease (AD) randomly assigned to the intervention group (Ability group), who will receive the "Ability Program", or to the active control group (ACG), who will receive "Treatment As Usual" (TAU). The protocol provides for three steps of assessment: at the baseline (T_0), after treatment, (T_1) and at follow-up (T_2) with a multidimensional evaluation battery including cognitive functioning, behavioral, functional, and quality of life measures. The Ability Program lasts 6 weeks, comprises tablet-delivered cognitive (5 days/week) and physical activities (7 days/week) combined with a set of devices for the measurement and monitoring from remote of vital and physical health parameters. The TAU equally lasts 6 weeks and includes paper and pencil cognitive activities (5 days/week), with clinician's prescription to perform physical exercise every day and to monitor selected vital parameters. DISCUSSION: Results of this study will inform on the efficacy of a technology-enhanced home care service to preserve cognitive and motor levels of functioning in MCI and AD, in order to slow down their loss of autonomy in daily life. The expected outcome is to ensure the continuity of care from clinical practice to the patient's home, enabling also cost effectiveness and the empowerment of patient and caregiver in the care process, positively impacting on their quality of life. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02746484 (registration date: 12/apr/2016 - retrospectively registered).

Individual Thresholding of Voxel-based Functional Connectivity Maps. Estimation of Random Errors by Means of Surrogate Time Series.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". BACKGROUND: Voxel-based functional connectivity analysis is a common method for resting state fMRI data. However, correlations between the seed and other brain voxels are corrupted by random estimate errors yielding false connections within the functional connectivity map (FCmap). These errors must be taken into account for a correct interpretation of single-subject results. OBJECTIVES: We estimated the statistical range of random errors and propose two methods for an individual setting of correlation threshold for FCmaps. METHODS: We assessed the amount of random errors by means of surrogate time series and described its distribution within the brain. On the basis of these results, the FCmaps of the posterior cingulate cortex (PCC) from 15 healthy subjects were thresholded with two innovative methods: the first one consisted in the computation of a unique (global) threshold value to be applied to all brain voxels, while the second method is to set a different (local) threshold of each voxel of the FCmap. RESULTS: The distribution of random errors within the brain was observed to be homogeneous and, after thresholding with both methods, the default mode network areas were well identifiable. The two methods yielded similar results, however the application of a global threshold to all brain voxels requires a reduced computational load. The inter-subject variability of the global threshold was observed to be very low and not correlated with age. Global threshold values are also almost independent from the number of surrogates used for their computation, so the analyses can be optimized using a reduced number of surrogate time series. CONCLUSIONS: We demonstrated the efficacy of FCmaps thresholding based on random error estimation. This method can be used for a reliable single-subject analysis and could also be applied in clinical setting, to compute individual measures of disease progression or quantitative response to pharmacological or rehabilitation treatments.

Growth hormone and disease severity in early stage of multiple sclerosis.

Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS). GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n = 64), healthy controls (HC, n = 62), and patients affected by other neurological diseases (OND, n = 46) were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS = 0.87 ± 1.32 ng/mL; OND = 1.66 ± 3.7; and HC = 1.69 ± 3.35; P = 0.858) when considering gender, disease duration, and disease course. However, GH was lower (P = 0.007) in patients with more severe disease (expanded disability scale score, EDSS ≥ 4.0) compared with milder forms (EDSS < 4). IGF-I l did not differ across the 3 groups (P = 0.160), as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

The evoked potentials score improves the identification of benign MS without cognitive impairment.

BACKGROUND AND PURPOSE: The presence of cognitive impairments (CI) among Benign MS (BMS) patients has challenged actual BMS criteria. We hypothesized that a low evoked potentials score (EP-score) at first neurological evaluation would help identify BMS patients without CI. METHODS: The EP-score was retrospectively computed in 29 putative BMS patients who were then tested for CI during 2012. The difference in the prevalence of CI between low EP-score patients and the recent literature was assessed using resampling methods. RESULTS: Among 23 low EP-score patients, only 3 (13%) had CI. This percentage was significantly reduced (P-values 0.05-0.005) compared to recent literature (39-46%). CONCLUSION: We conclude that a low EP-score at first neurological evaluation successfully helps to identify BMS patients without CI.

Oxidative imbalance in different neurodegenerative diseases with memory impairment.

BACKGROUND: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. METHODS: Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. RESULTS: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 µg/l; HC: 9.1 ± 4.9 µg/l; p = 1.7 × 10(-6)), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10(-5)), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10(-7)) and PAO (MD: 1,066.5 ± 247.7 µmol; HC: 954.9 ± 200.4 µmol; p = 0.8 × 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. CONCLUSION: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

Functional living skills assessment: a standardized measure of high-order activities of daily living in patients with dementia.

AIM: Performance measures are tools aimed to directly evaluate social function in older adults. The authors present the standardization of a new direct performance measure for patients with dementia, the functional living skills assessment (FLSA). METHODS: FLSA was conceived to detect functional impairment in very mild to moderate patients and to pick up functional modification due to intervention. The patient is asked to perform an activity, and the performance is scored according to completeness and level of assistance required. Eight areas of interest are evaluated (Resources, Consumer Skills, Public Transportation, Time Management, Money management, Leisure, Telephone Skills, Self-Care and Health). Subjects included 54 patients with dementia and 36 normal controls. RESULTS: Total and partial FLSA scores significantly differed for the two groups (P<0.0001). Performance on FLSA could divide clinical dementia rating (CDR) 0 from CDR 1, CDR 2 e CDR 3 groups. Both sensitivity and specificity were 94%; inter-rater and test-retest reliability was good (P>0.9). Correction scores for education were calculated, while age influence was only marginally significant. Mini Mental State Examination (MMSE) and CDR highly influenced FLSA score (P< 0.0001); FLSA was highly correlated with another performance measure (the Direct Assessment of Functional Status; P=0.821), and with the Instrumental Activity of Daily Living (IADL) scale (P=-0.612), while no significant correlation was present with the Geriatric Depression Scale. CONCLUSION: FLSA evidences construct, concurrent and discriminative validity. We suggest that this tool could be possibly useful when a high sensibility to different levels of functional impairment is needed, as evaluation of treatment efficacy (both non-pharmacological and pharmacological) identification of relatively intact functional areas to plan cognitive rehabilitation, and confirmation of dementia in the initial phase when there are doubts about functional decline.

HLA-A*01 is associated with late onset of Alzheimer's disease in Italian patients.

In this study, the distribution of HLA-A alleles was analyzed in Italian Alzheimer's Disease (AD)patients. Interaction between HLA alleles, APOE genotypes, age of onset, and gender were also analyzed. The results were compared to those obtained in healthy controls (HC). One hundred-seventy-three AD patients and 258 age-and-sex-matched healthy controls were enrolled in the study. AD patients were classified according to age at the onset of disease using quartiles of the distribution. HLA-A genotyping was performed by PCR-SSP; APOE genotyping was performed by RFLP. A correlation between late disease onset and HLA-A*01 was observed. Thus, HLA-A*01, calculated as number of alleles, was significantly more present in patients with age of onset > 74.0 years than in HC (20% vs 10.5%; p=0.014); the distribution of this allele was skewed also in patients 68.1-74 years of age (16.3%), even if the difference did not reach statistical significance. The relative risk ratio (RRR) of AD onset calculated by a multinomial logistic regression adjusted for sex and presence of APOE-4 confirmed a significant association of HLA-A*01 with AD onset > 74.0 years of age (RRR=2.2; 95%CI: 1.1-4.6; p=0.033). A high RRR (2.04) was also present in patients 68.1-74 years (p=0.064). Lower age of disease onset did not correlate with HLA-A*01. Data herein suggest that the presence of HLA-A*01 results in delayed AD development, even in patients carrying APOE-4. These results could offer new insights into the etiopathogenesis of Alzheimer's disease.

Humoral and cellular immune responses to myelin protein peptides in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVES: Evidence that chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease was sought, by studying cellular and humoral immune responses to peripheral nerve myelin proteins. METHODS: 40 CIDP, 36 healthy control subjects (HC) and subjects with non-immune mediated neuropathies (other neuropathies, ON) for antibodies were studied by ELISA and cellular responses by cytokine ELISPOT (INF gamma, IL10) and ELISA (IL17) to synthetic peptides representing P0, P2 and PMP22. RESULTS: Antibodies to P0, P2 or PMP22 peptides were detected in only a minority of CIDP, both not treated (nT-CIDP) and treated (T-CIDP). IgG antibodies to P2(80-105) were significantly more frequent in CIDP than in HC (4/30 vs 0/32; p<0.05) but the difference from ON (1/25) was not significant. In ELISPOT assays, IFN gamma was detected at a low frequency in CIDP and did not differ from HC or ON. In contrast, IL10 responses against P2(1-85) were more frequent in nT and T-CIDP (7/24 and 3/16) than HC (0/36; p<0.001 and p<0.05, respectively). The production of IL17 in cell-culture supernatants was not increased. CONCLUSIONS: Antibodies to non-conformational antigenic epitopes of myelin proteins rarely occur in CIDP. None of the myelin protein peptides elicited IFN gamma responses, but P2 elicited IL10 responses significantly more often in CIDP patients than in controls. This reactivity may be part of an antigen-specific Th2 type pathogenetic or regulatory mechanism or represent a transitory epiphenomenon due to nerve damage. In our study, P2 was the protein antigen most likely to be involved in the aberrant immune responses in CIDP.

HLA-DRB1 polymorphisms distribution in chronic dysimmune polyneuropathy.

The frequency of HLA-DRB1*15 polymorphism, which is strongly associated to multiple sclerosis, was investigated in 84 adult patients with chronic dysimmune polyneuropathy and 272 healthy controls. No significant differences were detected between cases and controls and, among patients, according to gender, peripheral nerve antigen antibody seropositivity, and electrophysiological features. A trend towards an increase of HLA-DRB1*11 in anti-MAG neuropathy was detected.

A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Voxel-wise analysis of diffusion tensor MRI improves the confidence of diagnosis of corticobasal degeneration non-invasively.

Corticobasal degeneration (CBD) presents with symptoms that often overlap with other neurological conditions. In many cases, diagnosis, prognosis and consequent clinical management remain uncertain. Structural and functional asymmetric brain changes represent the most consistent imaging findings that may assist in CBD diagnosis. Diffusion Tensor MRI (DT-MRI) is a quantitative technique that allows microscopic tissue abnormalities to be non-invasively assessed in vivo. A single case of clinically suspected CBD with symmetric diffuse brain atrophy on conventional-MRI scans was studied using DT-MRI by voxel-wise comparison with eight healthy subjects. The lateralized distribution of DT-MRI abnormalities was consistent with clinical features providing a substantial support to the diagnosis.

The association between impaired turning and normal straight walking in Parkinson's disease.

Turning whilst walking was investigated by gait analysis in a group of Parkinson's Disease (PD) patients with mild clinical impairment and no significant abnormalities in stride parameters and kinematics of steady-state, linear walking. Comparison with age-matched controls demonstrated that patients approached turns with a slower step and completed turning with a greater number of steps. Moreover, the normal cranio-caudal sequence, whereby rotation of the head toward the intended direction of travel is followed by rotation of the trunk, was replaced by nearly simultaneous rotation of head and trunk and decreased relative head excursion after the second turning step. The evidence of abnormal inter-segmental coordination during turning in mildly affected, normally walking patients suggests that task-specific pathophysiological mechanisms, not necessary related to basic locomotor deficits, underlie disturbed directional changes in PD. Furthermore, turning-related neural systems may be more vulnerable to functional impairments associated with PD, as compared with linear walking. Hierarchically higher control levels involved in the turning ability may explain the observed unexpected association.

Evaluating two group programmes of cognitive training in mild-to-moderate AD: is there any difference between a 'global' stimulation and a 'cognitive-specific' one?

This study evaluated the efficacy of two different group procedures of non-pharmacological treatment in mild-to-moderate Alzheimer's disease (AD). Thirty-two patients entered the study and were divided in groups of four subjects. We compared recreational activities ('global' stimulation) with a combination of procedural memory training on activities of daily living and neuropsychological rehabilitation of 'residual' functions ('cognitive-specific'). All patients and caregivers were ensured psychological support. Both group treatments were delivered for six weeks. Multidimensional efficacy assessment of functional, behavioural and neuropsychological aspects was performed. Patients receiving 'global' stimulation showed a substantial reduction in behavioural disturbances (Neuropsychiatric Inventory [NPI]: frequency p = 0.034; severity p = 0.012); Revised Memory Behaviour Problems Checklist (frequency p = 0.008; reaction p = 0.027), and better performance in the Functional Living Skills Assessment (FLSA), a standardized direct measure of performance in everyday life (p = 0.021) and Verbal Fluency for Letters (p = 0.000). Patients receiving 'cognitive-specific' treatment improved only on the scale evaluating functional competence in daily living (Nurses' Observation Scale for Geriatric Patients [NOSGER] p = 0.018). At follow-up (six months later), compared with baseline, patients following the 'global' stimulation treatment showed an improvement at caregiver distress on NPI (p = 0.04). No other significant difference was detected. Our results support the contention that a 'global' treatment can lead to a significant improvement in AD patients, both for behavioural and functional aspects. The 'cognitive-specific' treatment we used in this research did not show better efficacy.

Locomotor disorders in patients at early stages of Parkinson's disease: a quantitative analysis.

Several studies have been performed with automatic motion analysis techniques to investigated the locomotor disorders of patients with severe Parkinson's disease (PD). These are mainly related to steady-state walking. Aim of the present study was to investigate the presence and the degree of these disorders in patients at early stages of PD. For this purpose a group of patients with mild PD (H&Y < or =2) and a group of age-matched controls were assessed by means of multifactorial analysis of kinematic and kinetic variables, during the execution of the following motor tasks: steady-state walking, gait initiation and turning around an obstacle. Results showed that PD patients did not differ from controls in steady-state walking, while significant differences emerged in gait initiation and turning strategies. Main differences consisted in a limitation of the amplitude of the imbalance phase and of the first step, and, for the turning task, in a delayed initiation of the turning movement, with an altered head-trunk rotational strategy. It is concluded that patients in early stages of PD do not reveal, during steady state walking, consistent impairments of kinematic and kinetic patterns typical of severe PD patients. Nevertheless, they present significant alterations in transient conditions such as gait initiation and change of walking direction. The above results suggest that a quantitative analysis of locomotor tasks which imply the transition from one condition to another, could provide parameters useful for the characterization of early stage PD patients and, potentially, markers for a precox differential diagnosis respect other neurodegenerative diseases characterized by parkinsonisms.

Procedure for the quantitative evaluation of motor disturbances in cerebellar ataxic patients.

Cerebellar ataxia is a complex motor disturbance that involves the planning and execution of movements and reduces movement accuracy and co-ordination. The quantification of ataxic signs is commonly realised through visual examination of motor tasks performed by the patient and assignment of scores to specific items composing the international co-operative ataxia rating scale (ICARS). The present work studied an experimental procedure to characterise specific aspects of motor disturbances in ataxia objectively. Four tests belonging to the ICARS were considered: walking, knee-tibia test, finger-to-nose and finger-to-finger test. Through a kinematic analysis performed during the above tests, specific indices were defined to quantify velocity, linearity, asymmetry, tremor, instability and smoothness of movement or posture. The procedure was applied to five patients with cerebellar ataxia and to ten healthy adult subjects. Results demonstrated that the patients moved significantly more slowly than the healthy subjects (0.67 against 0.97m s(-1) and 0.81 against 1.02 m s(-1), respectively, for straight walk and finger-to-nose tests) and showed poorer linearity and smoothness behaviour. Velocity, linearity, tremor, smoothness and instability indices showed moderate to good correlation with the corresponding ICARS score. Some of these indices can separately evaluate aspects that are combined in single ICARS subscores. It is concluded that the combination of clinical assessments and instrumental evaluations allows a better insight into ataxic patients' motor disturbances and is a useful tool for the definition and follow-up of rehabilitation programmes.

Brain tissue damage in dementia with Lewy bodies: an in vivo diffusion tensor MRI study.

The aim of the present study was to apply diffusion tensor MRI (DT-MRI), a quantitative MRI measure which reflects tissue organization, to dementia with Lewy bodies (DLB). DT-MRI scans were obtained from 15 patients with probable DLB and 10 sex- and age-matched healthy controls. Abnormalities were found in the corpus callosum, pericallosal areas and the frontal, parietal, occipital and, less prominently, temporal white matter of patients compared with controls. Abnormalities were also found in the caudate nucleus and the putamen. The average grey matter volume was lower in patients than in controls. These findings of concomitant grey matter atrophy and white matter abnormalities (as detected by DT-MRI) in regions with a high prevalence of long connecting fibre tracts might suggest the presence of neurodegeneration involving associative cortices. The modest involvement of the temporal lobe fits with the relative preservation of global neuropsychological measures and memory tasks in the early stage of DLB. The selective involvement of parietal, frontal and occipital lobes might explain some of the clinical and neuropsychological features of DLB, providing a possible distinctive marker for this disease. The abnormalities found in the subcortical grey matter may indicate that DLB and Parkinson's disease share a similar nigrostriatal involvement caused by common pathophysiological mechanisms.

Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies.

The authors report the presence of high titer antibodies to glutamic acid decarboxylase (anti-GAD65) until age 24 months in two asymptomatic newborns of a woman with stiff-person syndrome (SPS). No signs of SPS were detectable in the two children at ages 6 and 8 years. This observation indicates that other cofactors are involved in the pathogenesis of SPS.