Summary Alzheimer's disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. ...Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimer's disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimer's disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimer's disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.
Abstract The pathway leading from beta-amyloid deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer’s disease (AD). However, what drives amyloid ...build-up in sporadic non-genetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (i) GMB taxa with pro- and anti-inflammatory activity, and (ii) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa ( Escherichia/Shigella, Pseudomonas aeruginosa , Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii and Bacteroides fragilis ) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, IL-1β, IL-6, IL-18, IL-8, NLRP3, TNF-α; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n=40, Amy+) and with no brain amyloidosis (n=33, Amy-), and also in a group of controls (n=10, no brain amyloidosis and no cognitive impairment, HC). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3 and IL-1β) compared to both controls and to Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of Eubacterium rectale and higher abundance of Escherichia/Shigella as compared to both HC (Fold Change, FC=-9.6, p<0.001 and FC=+12.8, p<0.001, respectively ) and to Amy- (FC=-7.7, p<0.001 and FC=+7.4, p=0.003 ). A positive correlation was observed between pro-inflammatory cytokines IL-1β, NLRP3 and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho=0.60, p<0.001; rho=0.57, p<0.001; and rho=0.30, p=0.007, respectively) and a negative correlation with the anti-inflammatory Eubacterium rectale ( rho=-0.48, p<0.001; rho=-0.25, p=0.024; rho=-0.49, p<0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella , and a reduction in the abundance of an anti-inflammatory taxon, Eubacterium rectale , are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.
In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be ...combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.
Summary Despite advances towards understanding the molecular pathophysiology of the neurodegenerative dementias, the mechanisms linking molecular changes to neuropathology and neuropathological ...changes to clinical symptoms remain largely obscure. Connectivity is a distinctive feature of the brain and the integrity of functional network dynamics is crucial for normal functioning. A better understanding of network disruption in the neurodegenerative dementias might help bridge the gap between molecular changes, pathological changes, and symptoms. Recent findings on functional network disruption as assessed with resting-state or intrinsic connectivity functional MRI and electroencephalography and magnetoencephalography have shown distinct patterns of network disruption across the major neurodegenerative diseases. These network abnormalities are somewhat specific to the clinical syndromes and, in Alzheimer's disease and frontotemporal dementia, network disruption tracks the pattern of pathological changes. These findings might have practical implications for diagnostic accuracy, allowing earlier detection of neurodegenerative diseases even at the presymptomatic stage, and tracking of disease progression.
Summary In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging–Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's ...disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
To assess the impact of clinical instability (CI) and delirium on admission to a rehabilitation unit on clinical and functional outcomes (death, transfer to acute care, poor functional recovery) at ...discharge, in a population of elderly patients.
Observational study.
Rehabilitation and Aged Care Unit (RACU).
Participants were 583 consecutively and firstly admitted elderly patients.
On admission, all patients underwent a comprehensive geriatric assessment including sociodemographics, cognitive and depressive symptoms, nutritional status, physical health, and functional status. CI was recorded for all patients on admission, assessing 5 vital signs (temperature, heart rate, systolic blood pressure, respiratory rate, and oxygen saturation). Delirium was assessed daily with the Confusion Assessment Method.
Patients were on average old (mean age: 77.8 +/- 9.8), predominantly female (68.6%), with mild cognitive deterioration (MMSE: 22.1 +/- 6.3) and depressive symptoms (GDS: 5.9 +/- 3.5). They had moderate comorbidity (means CIRS: 3.1 +/- 1.9), and functional impairment both before (Barthel Index pre-admission: 84.5 +/- 19.2; IADL: 3.3 +/- 3.0) and on admission (Barthel Index: 55.8 +/- 27.5). On admission, 136 (23.3%) patients were classified as clinically unstable: 76 (13%) had either CI or delirium, and 60 (10.3%) had CI associated to delirium. At discharge, 26 patients were transferred to acute care hospitals, and 14 died. Transfer to acute care occurred in more than 10% of patients with almost one altered condition (CI or delirium), and in one fifth of patients with the association of CI and delirium. In-RACU death was observed only in this latter group. Functional recovery at discharge was significantly higher in stable patients than in patients with CI and/or delirium.
CI and delirium are useful prognostic markers of adverse clinical and functional outcomes in a population of elderly subjects admitted to a rehabilitative unit.
Abstract Guerini F, Frisoni GB, Marrè A, Turco R, Bellelli G, Trabucchi M. Subcortical vascular lesions predict falls at 12 months in elderly patients discharged from a rehabilitation ward. Objective ...To test whether subcortical vascular lesions are associated with falls in elderly patients with gait disorder discharged from a rehabilitation ward. Design Secondary 12-month follow-up analysis of an observational survey focusing on the prevalence of subcortical vascular lesions in a population of elderly patients discharged from rehabilitation hospitals. Setting A rehabilitation and aged care unit. Participants Consecutively admitted elderly patients (N=214) with gait disorder. Interventions Not applicable. Main Outcome Measures On admission, all patients underwent comprehensive geriatric assessment including sociodemographics, cognitive and depressive symptoms, nutritional status, physical health, and functional status. Subcortical vascular lesions were assessed on computed tomography films with a validated rating scale. All patients received a standardized rehabilitative program. Twelve months after discharge, all patients were interviewed by telephone, mainly focusing on the occurrence of falls during the follow-up period. Potential predictors of falls were assessed in univariate and multivariate analyses. Results Univariate predictors of falls were age, sex, Mini-Mental State Examination, Barthel Index on admission, and subcortical vascular lesions. In multivariate analyses, subcortical vascular lesions were the only significant predictor of risk of falling; patients with moderate and severe subcortical vascular lesions scores had a greater risk of falling (odds ratio OR=3.0; 95% confidence interval CI, 1.3–7.1; P =.012; OR=3.9; 95% CI, 1.6–9.2; P =.002, respectively) than those with no subcortical vascular lesions. Conclusions Subcortical vascular lesions are associated with falls at 12 months in elderly patients with gait disorder discharged from a rehabilitative ward. Future research is needed to confirm our results.
Summary Background Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in ...vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. Methods We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study–Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov ( NCT01689246 ) and the European Union Clinical Trials Registry (2012-002866-11). Findings Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control n=354, 6·32, 95% CI 5·31−7·34: 75 mg LMTM twice a day n=257 −0·02, −1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day n=250 −0·43, −2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control −8·22, 95% CI −9·63 to −6·82: 75 mg LMTM twice a day −0·93, −3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day −0·34, −2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. Interpretation The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. Funding TauRx Therapeutics.
LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.
To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in ...an 18-month Phase III trial in mild AD.
Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.
The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.
The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual ...outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset.
70 MS patients (median EDSS of 2.0 range 0.0–6.5) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on ‘unseen’ center.
Compared to the reference mean lesion volume (4.85 ± 7.29 mL), the methods displayed a mean difference of 1.60 ± 4.83 (Cascade), 2.31 ± 7.66 (LGA), 0.44 ± 4.68 (LPA), 1.76 ± 4.17 (Lesion-TOADS) and −1.39 ± 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 ± 0.23), Lesion-TOADS (SI = 0.35 ± 0.18) and kNN-TTP (SI = 0.44 ± 0.14) than for Cascade (SI = 0.26 ± 0.17) or LGA (SI = 0.31 ± 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization.
The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods.
•Much-needed study on quantitative evaluation and objective comparison of WM lesion segmentation methods.•Using different scanners and different MR protocols in a real-life setting similar to phase-III trials and everyday clinical practice.•The methods perform almost equally well whether parameter tuning is performed using data from the same center or not.
PDF
