High-Dimensional ICA Analysis Detects Within-Network Functional Connectivity Damage of Default-Mode and Sensory-Motor Networks in Alzheimer’s Disease

High-dimensional independent component analysis (ICA), compared to low-dimensional ICA, allows to conduct a detailed parcellation of the resting-state networks. The purpose of this study was to give further insight into functional connectivity (FC) in Alzheimer's disease (AD) using high-dimensional ICA. For this reason, we performed both low- and high-dimensional ICA analyses of resting-state fMRI data of 20 healthy controls and 21 patients with AD, focusing on the primarily altered default-mode network (DMN) and exploring the sensory-motor network. As expected, results obtained at low dimensionality were in line with previous literature. Moreover, high-dimensional results allowed us to observe either the presence of within-network disconnections and FC damage confined to some of the resting-state subnetworks. Due to the higher sensitivity of the high-dimensional ICA analysis, our results suggest that high-dimensional decomposition in subnetworks is very promising to better localize FC alterations in AD and that FC damage is not confined to the DMN

Sympathetic skin response in multiple sclerosis : a meta-analysis of case-control studies

The study was supported by a grant of the Italian Ministry of Health, Ricerca Corrente funding program 2014–2015 [RC2014].The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22-47%; p < 0.0001) but with considerable heterogeneity across studies (I2 = 90.3%). Patients' age explained 22% of the overall variability and positive correlations were found with Expanded Disability Status Scale and disease duration. The pooled mean difference of SSR latency showed a significant increase in patients on both upper (193 ms; 95% CI 120-270 ms) and lower (350 ms; 95% CI 190-510 ms) extremities. We tested the discriminatory value of SSR latency thresholds defined as the 95% confidence interval (CI) upper bound of the healthy controls, and validated the results on a new dataset. The lower limb threshold of 1.964 s produces the best results in terms of sensitivity 0.86, specificity 0.67, positive predicted value 0.75 and negative predicted value 0.80. Despite a considerable heterogeneity of findings, there is evidence that SSR is a useful tool in MS.Publisher PDFPeer reviewe

Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population : a hint for an early identification of benign MS?

This study was supported by the Italian Ministry of Health, Ricerca Corrente funding plan to the institutional research activity of the Scientific Institute S. Maria Nascente of the Don C. Gnocchi Foundation.Background: The prognostic value of evoked potentials (EPs) in multiple sclerosis (MS) has not been fully established. The correlations between the Expanded Disability Status Scale (EDSS) at First Neurological Evaluation (FNE) and the duration of the disease, as well as between EDSS and EPs, have influenced the outcome of most previous studies. To overcome this confounding relations, we propose to test the prognostic value of EPs within an appropriate patient population which should be based on patients with low EDSS at FNE and short disease duration. Methods: We retrospectively selected a sample of 143 early relapsing remitting MS (RRMS) patients with an EDSS < 3.5 from a larger database spanning 20 years. By means of bivariate logistic regressions, the best predictors of worsening were selected among several demographic and clinical variables. The best multivariate logistic model was statistically validated and prospectively applied to 50 patients examined during 2009-2011. Results: The Evoked Potentials score (EP score) and the Time to EDSS 2.0 (TT2) were the best predictors of worsening in our sample (Odds Ratio 1.10 and 0.82 respectively, p=0.001). Low EP score (below 15-20 points), short TT2 (lower than 3-5 years) and their interaction resulted to be the most useful for the identification of worsening patterns. Moreover, in patients with an EP score at FNE below 6 points and a TT2 greater than 3 years the probability of worsening was 10% after 4-5 years and rapidly decreased thereafter. Conclusions: In an appropriate population of early RRMS patients, the EP score at FNE is a good predictor of disability at low values as well as in combination with a rapid buildup of disability. Interestingly, an EP score at FNE under the median together with a clinical stability lasting more than 3 years turned out to be a protective pattern. This finding may contribute to an early identification of benign patients, well before the term required to diagnose Benign MS (BMS).Publisher PDFPeer reviewe

Effective artifact removal in resting state fMRI data improves detection of DMN functional connectivity alteration in Alzheimer's disease

Artifact removal from resting state fMRI data is an essential step for a better identification of the resting state networks and the evaluation of their functional connectivity (FC), especially in pathological conditions. There is growing interest in the development of cleaning procedures, especially those not requiring external recordings (data-driven), which are able to remove multiple sources of artifacts. It is important that only inter-subject variability due to the artifacts is removed, preserving the between-subject variability of interest\u2014crucial in clinical applications using clinical scanners to discriminate different pathologies and monitor their staging. In Alzheimer's disease (AD) patients, decreased FC is usually observed in the posterior cingulate cortex within the default mode network (DMN), and this is becoming a possible biomarker for AD. The aim of this study was to compare four different data-driven cleaning procedures (regression of motion parameters; regression of motion parameters, mean white matter and cerebrospinal fluid signal; FMRIB's ICA-based Xnoiseifier\u2014FIX\u2014cleanup with soft and aggressive options) on data acquired at 1.5 T. The approaches were compared using data from 20 elderly healthy subjects and 21 AD patients in a mild stage, in terms of their impact on within-group consistency in FC and ability to detect the typical FC alteration of the DMN in AD patients. Despite an increased within-group consistency across subjects after applying any of the cleaning approaches, only after cleaning with FIX the expected DMN FC alteration in AD was detectable. Our study validates the efficacy of artifact removal even in a relatively small clinical population, and supports the importance of cleaning fMRI data for sensitive detection of FC alterations in a clinical environment

High-dimensional ICA analysis detects wthin-network functional connectivity damage of default-mode and sensory-motor networks in Alzheimer's disease

High-dimensional independent component analysis (ICA), compared to low-dimensional ICA, allows to conduct a detailed parcellation of the resting-state networks. The purpose of this study was to give further insight into functional connectivity (FC) in Alzheimer's disease (AD) using high-dimensional ICA. For this reason, we performed both low- and high-dimensional ICA analyses of resting-state fMRI data of 20 healthy controls and 21 patients with AD, focusing on the primarily altered default-mode network (DMN) and exploring the sensory-motor network. As expected, results obtained at low dimensionality were in line with previous literature. Moreover, high-dimensional results allowed us to observe either the presence of within-network disconnections and FC damage confined to some of the resting-state subnetworks. Due to the higher sensitivity of the high-dimensional ICA analysis, our results suggest that high-dimensional decomposition in subnetworks is very promising to better localize FC alterations in AD and that FC damage is not confined to the DMN

A Novel Approach of Groupwise fMRI-Guided Tractography Allowing to Characterize the Clinical Evolution of Alzheimer's Disease

Guiding diffusion tract-based anatomy by functional magnetic resonance imaging (fMRI), we aim to investigate the relationship between structural connectivity and functional activity in the human brain. To this purpose, we introduced a novel groupwise fMRI-guided tractographic approach, that was applied on a population ranging between prodromic and moderate stages of Alzheimer's disease (AD). The study comprised of 15 subjects affected by amnestic mild cognitive impairment (aMCI), 14 diagnosed with AD and 14 elderly healthy adults who were used as controls. By creating representative (ensemble) functionally guided tracts within each group of participants, our methodology highlighted the white matter fiber connections involved in verbal fluency functions for a specific population, and hypothesized on brain compensation mechanisms that potentially counteract or reduce cognitive impairment symptoms in prodromic AD. Our hope is that this fMRI-guided tractographic approach could have potential impact in various clinical studies, while investigating white/gray matter connectivity, in both health and disease

Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer's disease and amnestic mild cognitive impairment

This work was supported by 2012–2014 Ricerca Corrente (Italian Ministry of Health).Alzheimer's disease (AD) is a multifactorial disease with a still barely understood etiology. Herpes simplex virus 1 (HSV-1) has long been suspected to play a role in the pathogenesis of AD because of its neurotropism, high rate of infection in the general population, and life-long persistence in neuronal cells, particularly in the same brain regions that are usually altered in AD. The goal of this study was to evaluate HSV-1-specific humoral immune responses in patients with a diagnosis of either AD or amnestic mild cognitive impairment (aMCI), and to verify the possible relation between HSV-1-specific antibody (Ab) titers and cortical damage; results were compared to those obtained in a group of healthy controls (HC). HSV-1 serum IgG titers were measured in 225 subjects (83 AD, 68 aMCI, and 74 HC). HSV-specific Ab avidity and cortical gray matter volumes analyzed by magnetic resonance imaging (MRI) were evaluated as well in a subgroup of these individuals (44 AD, 23 aMCI, and 26 HC). Results showed that, whereas HSV-1 seroprevalence and IgG avidity were comparable in the three groups, increased Ab titers (p < 0.001) were detected in AD and aMCI compared to HC. Positive significant correlations were detected in AD patients alone between HSV-1 IgG titers and cortical volumes in orbitofrontal (region of interest, ROI1 RSp0.56; p = 0.0001) and bilateral temporal cortices (ROI2 RSp0.57; p < 0.0001; ROI3 RSp0.48; p = 0.001); no correlations could be detected between IgG avidity and MRI parameters. Results herein suggest that a strong HSV-1-specific humoral response could be protective toward AD-associated cortical damage.Publisher PDFPeer reviewe

Brain perfusion patterns: consistency and similarity with fMRI resting state networks and arterial vascular territories

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Relationship between cerebrovascular reactivity and age in multiple sclerosis

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Potentially inappropriate medication use in older adults with mild-moderate Alzheimer's disease:Prevalence and associations with adverse events

Aim: Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer's Disease (AD), who may represent a particularly vulnerable group. Design: Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants: 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results: Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13-1.19, P &lt; 0.001), serious adverse events (IRR 1.27; 1.17-1.37, P &lt; 0.001), unscheduled hospitalisations (IRR 1.16, 1.03-1.30, P = 0.016) and GP visits (IRR 1.22, 1.15-1.28, P &lt; 0.001). PIM use was not associated with dementia progression. Conclusions and Implications: PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted