Robust automated detection of microstructural white matter degeneration in Alzheimer’s disease using machine learning classification of multicenter DTI data

Diffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer’s disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6±5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naïve Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross-validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample

"The DESCRIBE-ALS-FTD study:a prospective multicenter observational study of the ALS-FTD spectrum"

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases. Consequently, there is an urgent need to improve patient stratification for the successful execution of future clinical trials. Methods/Results: We here describe the study design of the DESCRIBE-ALS/FTD study which aims to address this research gap by undertaking a systematic sampling of patients from the ALS FTD spectrum, encompassing all possible disease variants. The main objective of the study is to systematically document detailed cross-sectional phenotyping and the temporal progression of motor and neuropsychological abnormalities that occur in both ALS and FTD. Additionally, it seeks to systematically correlate these abnormalities with genetics and potentially predictive biomarkers including longitudinal biomaterial sampling, brain imaging and brain banking. Furthermore, first-degree relatives of patients with disease-causing gene variants undergo the same assessments to also sample presymptomatic risk gene carriers. Conclusion: With this prospective registry study we aim to generate datasets which will help researchers identifying different disease traits in people with sporadic and genetic ALS and FTD and to develop biomarkers to identify preclinical and prodromal disease stages. </p

Cognitive training gain transfer in cognitively healthy aging: per protocol results of the German AgeGain study

IntroductionCognitive decline is part of the normal aging process, but also a major risk factor for dementia. Cognitive training interventions aim to attenuate cognitive decline, but training gains need to be transferable to untrained cognitive abilities to influence everyday function. Furthermore, the neurobiological basis of cognitive training gain transfer remains elusive. A possible candidate is increased bilateral hemisphere usage enabled by efficient structural connectivity, especially of prefrontal regions. Therefore, the present multicentric study used a cognitive training intervention to demonstrate training transfer and identify neurobiological modulators of successful transfer.MethodsIn total 235 subjects were enrolled in AgeGain; 180 underwent a broad 4-week cognitive training intervention at three study sites. Pre- and post-training neuropsychological testing was conducted and successful transferers were identified according to preregistered definitions. Pre-training, subjects underwent diffusion and functional MRI to assess interhemispheric connectivity, measured as microstructural integrity of the corpus callosum and lateralization of functional activation patterns during a cognitive control task. Logistic regression models were estimated to predict successful transfer based on structural connectivity and bilateralization of activation patterns.ResultsOut of 180 subjects, 74 showed short-term training gain transfer that was maintained over 3 months in 19 subjects. Neither microstructural integrity of the corpus callosum, nor bilateralized activation predicted training gain transfer alone. However, their interaction was associated with long-term transfer over 3 months: subjects with higher mean diffusivity of the corpus callosum and more bilateral functional activity or conversely with lower diffusivity of the corpus callosum and more lateral functional activity were more likely successful long-term transferers.DiscussionWe demonstrated successful training gain transfer in 41.1% of subjects, among whom 25.7% maintained the transfer over 3 months. Successful long-term transfer of training gains may depend on divergent mechanisms of structural and functional connectivity, which may explain previous heterogeneous results in the literature.Trial registerGerman Clinical Trials Register (DRKS), ID: DRKS00013077. Registered on November 19th 2017

Watching TV news as a memory task -- brain activation and age effects

<p>Abstract</p> <p>Background</p> <p>Neuroimaging studies which investigate brain activity underlying declarative memory processes typically use artificial, unimodal laboratory stimuli. In contrast, we developed a paradigm which much more closely approximates real-life situations of information encoding.</p> <p>Methods</p> <p>In this study, we tested whether ecologically valid stimuli - clips of a TV news show - are apt to assess memory-related fMRI activation in healthy participants across a wide age range (22-70 years). We contrasted brain responses during natural stimulation (TV news video clips) with a control condition (scrambled versions of the same clips with reversed audio tracks). After scanning, free recall performance was assessed.</p> <p>Results</p> <p>The memory task evoked robust activation of a left-lateralized network, including primarily lateral temporal cortex, frontal cortex, as well as the left hippocampus. Further analyses revealed that - when controlling for performance effects - older age was associated with greater activation of left temporal and right frontal cortex.</p> <p>Conclusion</p> <p>We demonstrate the feasibility of assessing brain activity underlying declarative memory using a natural stimulation paradigm with high ecological validity. The preliminary result of greater brain activation with increasing age might reflect an attempt to compensate for decreasing episodic memory capacity associated with aging.</p

U–Pb Zircon geochronology of the Cambro-Ordovician metagranites and metavolcanic rocks of central and NW Iberia

New U–Pb zircon data from metagranites and metavolcanic rocks of the Schist-Graywacke Complex Domain and the Schistose Domain of Galicia Tras-os-Montes Zone from central and NW Iberia contribute to constrain the timing of the Cambro-Ordovician magmatism from Central Iberian and Galicia Tras-os-Montes Zones which occurred between 498 and 462 Ma. The crystallization ages of the metagranites and metavolcanic rocks from the northern Schist-Graywacke Complex Domain are as follows: (a) in west Salamanca, 489 ± 5 Ma for Vitigudino, 486 ± 6 Ma for Fermoselle and 471 ± 7 Ma for Ledesma; (b) in northern Gredos, 498 ± 4 Ma for Castellanos, 492 ± 4 Ma for San Pelayo and 488 ± 3 Ma for Bercimuelle; (c) in Guadarrama, 490 ± 5 Ma for La Estacion I, 489 ± 9 Ma for La Canada, 484 ± 6 Ma for Vegas de Matute (leucocratic), 483 ± 6 Ma for El Cardoso, 482 ± 8 Ma for La Morcuera, 481 ± 9 Ma for Buitrago de Lozoya, 478 ± 7 Ma for La Hoya, 476 ± 5 Ma for Vegas de Matute (melanocratic), 475 ± 5 Ma for Riaza, 473 ± 8 Ma for La Estacion II and 462 ± 11 Ma for La Berzosa; and (d) in Toledo, 489 ± 7 Ma for Mohares and 480 ± 8 Ma for Polan. The crystallization ages of the metagranites from the Schistose Domain of Galicia Tras-os-Montes Zone are 497 ± 6 Ma for Laxe, 486 ± 8 Ma for San Mamede, 482 ± 7 Ma for Bangueses, 481 ± 5 Ma for Noia, 480 ± 10 for Rial de Sabucedo, 476 ± 9 Ma for Vilanova, 475 ± 6 Ma for Pontevedra, 470 ± 6 Ma for Cherpa and 462 ± 8 Ma for Bande.This magmatism is characterized by an average isotopic composition of (87Sr/86Sr)485Ma ≈ 0.712, (eNd)485Ma ≈ -4.1 and (TDM) ≈ 1.62 Ga, and a high zircon inheritance, composed of Ediacaran–Early Cambrian (65 %) and, to a lesser extent, Cryogenian, Tonian, Mesoproterozoic, Orosirian and Archean pre-magmatic cores. Combining our geochronological and isotopic data with others of similar rocks from the European Variscan Belt, it may be deduced that Cambro-Ordovician magmas from this belt were mainly generated by partial melting of Ediacaran–Early Cambrian igneous rocks

The comorbidity profiles and medication issues of patients with multiple system atrophy:a systematic cross-sectional analysis

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management.OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients.METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®.RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue.CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.</p

A Short Cognitive and Neuropsychiatric Assessment Scale for Progressive Supranuclear Palsy

Background : Patients with Progressive Supranuclear Palsy (PSP) suffer from several neuropsychological impairments. These mainly affect the frontal lobe and subcortical brain structures. However, a scale for the assessment of cognitive and neuropsychiatric disability in PSP is still missing. Objectives : To create and validate a new scale for cognitive and neuropsychiatric impairment in PSP. Methods : The Short Cognitive and Neuropsychiatric (ShoCo) scale was developed containing five items (bradyphrenia, apathy, aphasia, dysexecution and disinhibition). Each item can be categorized into 0 = no deficit, 1 = mild deficit, 2 = moderate deficit and 3 = severe deficit. The total score includes 15 points, 0 meaning no deficit and 15 severe deficits. Cross-sectional and longitudinal data from 201 baseline and 71 follow up patients were analyzed. Results : Baseline ShoCo scale results were 5.9 ± 2.9. No significant differences between patients with Richardson syndrome (PSP-RS) and variants (vPSP) could be detected in the PSP-ShoCo scale scores (PSP-RS 6.1 ± 3.0, n = 160, vPSP 5.1 ± 2.6, n = 41, P = 0.057). The scale showed good correlation with established scores (eg, Montreal cognitive assessment r = −0.535, P = 0.001). The ShoCo scale showed significant annualized change within the PSP-RS patients (baseline 6.2 ± 2.9, follow up 6.9 ± 3.1, annualized diff. 1.0 ± 3.1, n = 57, P = 0.022). Conclusions : The ShoCo scale seems a promising and valid tool to measure specific neuropsychological disabilities of PSP patients in clinical routine and research

Development and validation of the Arizona Cognitive Test Battery for Down syndrome

Neurocognitive assessment in individuals with intellectual disabilities requires a well-validated test battery. To meet this need, the Arizona Cognitive Test Battery (ACTB) has been developed specifically to assess the cognitive phenotype in Down syndrome (DS). The ACTB includes neuropsychological assessments chosen to 1) assess a range of skills, 2) be non-verbal so as to not confound the neuropsychological assessment with language demands, 3) have distributional properties appropriate for research studies to identify genetic modifiers of variation, 4) show sensitivity to within and between sample differences, 5) have specific correlates with brain function, and 6) be applicable to a wide age range and across contexts. The ACTB includes tests of general cognitive ability and prefrontal, hippocampal and cerebellar function. These tasks were drawn from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) and other established paradigms. Alongside the cognitive testing battery we administered benchmark and parent-report assessments of cognition and behavior. Individuals with DS (n = 74, ages 7–38 years) and mental age (MA) matched controls (n = 50, ages 3–8 years) were tested across 3 sites. A subsample of these groups were used for between-group comparisons, including 55 individuals with DS and 36 mental age matched controls. The ACTB allows for low floor performance levels and participant loss. Floor effects were greater in younger children. Individuals with DS were impaired on a number ACTB tests in comparison to a MA-matched sample, with some areas of spared ability, particularly on tests requiring extensive motor coordination. Battery measures correlated with parent report of behavior and development. The ACTB provided consistent results across contexts, including home vs. lab visits, cross-site, and among individuals with a wide range of socio-economic backgrounds and differences in ethnicity. The ACTB will be useful in a range of outcome studies, including clinical trials and the identification of important genetic components of cognitive disability

The comorbidity and co-medication profile of patients with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients.ObjectivesTo explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease.MethodsCross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik (R).ResultsIn total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions.ConclusionsPSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients