Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts.

INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease.

Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients (M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (ß = .340; p < .001; ß = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (ß = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (ß = -.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior-posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.

Serum NfL in Alzheimer Dementia: Results of the Prospective Dementia Registry Austria.

Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer's disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.

Anatomically Standardized Detection of MRI Atrophy Patterns in Early-Stage Alzheimer's Disease.

MRI studies have consistently identified atrophy patterns in Alzheimer's disease (AD) through a whole-brain voxel-based analysis, but efforts to investigate morphometric profiles using anatomically standardized and automated whole-brain ROI analyses, performed at the individual subject space, are still lacking. In this study we aimed (i) to utilize atlas-derived measurements of cortical thickness and subcortical volumes, including of the hippocampal subfields, to identify atrophy patterns in early-stage AD, and (ii) to compare cognitive profiles at baseline and during a one-year follow-up of those previously identified morphometric AD subtypes to predict disease progression. Through a prospectively recruited multi-center study, conducted at four Austrian sites, 120 patients were included with probable AD, a disease onset beyond 60 years and a clinical dementia rating of ≤1. Morphometric measures of T1-weighted images were obtained using FreeSurfer. A principal component and subsequent cluster analysis identified four morphometric subtypes, including (i) hippocampal predominant (30.8%), (ii) hippocampal-temporo-parietal (29.2%), (iii) parieto-temporal (hippocampal sparing, 20.8%) and (iv) hippocampal-temporal (19.2%) atrophy patterns that were associated with phenotypes differing predominately in the presentation and progression of verbal memory and visuospatial impairments. These morphologically distinct subtypes are based on standardized brain regions, which are anatomically defined and freely accessible so as to validate its diagnostic accuracy and enhance the prediction of disease progression.

[Position paper of the Austrian Alzheimer Association (Österreichische Alzheimer Gesellschaft, ÖAG) : Effects of the COVID-19 pandemic in Austria on people with dementia and their care environment-problem areas, recommendations, and strategies]. / Positionspapier der Österreichische Alzheimer Gesellschaft (ÖAG) : Auswirkungen der COVID-19-Pandemie in Österreich auf Menschen mit Demenz und deren Betreuungsumfeld ­ Problemfelder, Empfehlungen und Strategien.

Older adults are particularly affected by the current COVID-19 (SARS-CoV-2) pandemic. The risk of dying from COVID-19 increases with age and is often associated with pre-existing health conditions. Globally, more than 50 million-in Austria currently approximately 140,000 people-suffer from dementia. The co-occurrence of dementia as a "pandemic of old age" together with the COVID-19 pandemic has a double impact on persons living with dementia and their caregivers. The COVID-19 pandemic poses major challenges for individuals with dementia and their caregivers: (1) People with dementia have limited access to information on COVID-19, may have difficulties with protective measures such as wearing masks and in remembering safety regulations. (2) People with dementia live alone or with their family, or are institutionalized. To reduce the chance of infection among older people in nursing homes, Austrian local authorities have banned visitors to nursing homes and long-term care facilities and implemented strict social-distancing measures. As a result, older people lost face-to-face contact with their family members, became isolated and social activities stopped. Consequently, anxiety, stress and serious concerns about infections among staff in nursing homes increased and they developed signs of exhaustion and burnout during the full lockdown of the facilities. Thus, due to the emerging COVID-19 crisis, the Austrian Alzheimer Association (Österreichische Alzheimer Gesellschaft, ÖAG) and international societies developed recommendations to support people living with dementia and their caregivers on various issues of physical and mental health.

The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study.

BACKGROUND: Dementia, and in particular Alzheimer's disease (AD), is a debilitating progressive disease with high prevalence in our society. Vitamin B12 and folate deficiency are potential modifiable risk factors. However, previous studies reported inconsistent results. RESULTS: The average concentrations of all biochemical markers were within the respective reference ranges. Cross-sectional and longitudinal analyses did not reveal significant associations between biochemical markers and cognitive function, global or regional brain volume, cortical thickness or cortical surface area, neither in controls nor in AD patients. CONCLUSIONS: Variations of direct and indirect markers of B12 and folate status are not associated with cognitive dysfunction and brain atrophy. METHODS: This retrospective study explored the association between biochemical markers of B12 and folate status, cognitive function and MRI-based brain atrophy in cognitive normal elderly (controls) and AD patients. Folate, total and active vitamin B12 and MMA were measured in blood samples from 378 controls and 217 AD patients. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in 155 controls and 217 AD patients. In a subset of participants cognitive testing (n=234) and MRI (n=182) was repeated after an average median between 1.25 and 6.25 years.

Gray Matter Covariance Networks as Classifiers and Predictors of Cognitive Function in Alzheimer's Disease.

The study of shared variation in gray matter morphology may define neurodegenerative diseases beyond what can be detected from the isolated assessment of regional brain volumes. We, therefore, aimed to (1) identify SCNs (structural covariance networks) that discriminate between Alzheimer's disease (AD) patients and healthy controls (HC), (2) investigate their diagnostic accuracy in comparison and above established markers, and (3) determine if they are associated with cognitive abilities. We applied a random forest algorithm to identify discriminating networks from a set of 20 SCNs. The algorithm was trained on a main sample of 104 AD patients and 104 age-matched HC and was then validated in an independent sample of 28 AD patients and 28 controls from another center. Only two of the 20 SCNs contributed significantly to the discrimination between AD and controls. These were a temporal and a secondary somatosensory SCN. Their diagnostic accuracy was 74% in the original cohort and 80% in the independent samples. The diagnostic accuracy of SCNs was comparable with that of conventional volumetric MRI markers including whole brain volume and hippocampal volume. SCN did not significantly increase diagnostic accuracy beyond that of conventional MRI markers. We found the temporal SCN to be associated with verbal memory at baseline. No other associations with cognitive functions were seen. SCNs failed to predict the course of cognitive decline over an average of 18 months. We conclude that SCNs have diagnostic potential, but the diagnostic information gain beyond conventional MRI markers is limited.

Anatomical and functional changes in the retina in patients with Alzheimer's disease and mild cognitive impairment.

PURPOSE: There is evidence that mild cognitive impairment (MCI) or Alzheimer's disease (AD) is accompanied by alterations in the retina. The current study was performed to investigate structural and functional changes in patients with systemic neurodegenerative disease. METHODS: A total of 47 patients with either MCI or AD and 43 healthy age- and sex-matched control subjects were included. Inclusion criteria for MCI were abnormal memory function and a mini-mental state examination (MMSE) score >26 points, for patients with AD a diagnosis of probable AD of mild to moderate degree and an MMSE score in the range of 20-26. Retinal blood flow was measured using a Doppler optical coherence tomography (OCT) system. Retinal vessel diameter, oxygen saturation and flicker-induced vasodilatation were measured using a Vessel Analyzer. Retinal nerve fibre layer thickness (RNFLT) was assessed using an OCT system. RESULTS: Global RNFLT was lower in patients compared to healthy controls (93.7 ± 12.8 µm versus 99.1 ± 9.0 µm, p = 0.02). The same was found in regards to retinal arterial blood flow, which was 9.3 ± 2.4 and 12.3 ± 3.2 µl/min in the patient and control groups, respectively (p < 0.001). Mean retinal arterial diameter was reduced in patients (76.0 ± 8.9 µm versus 80.6 ± 8.0 µm, p = 0.03). Arteriovenous difference in oxygen saturation was lower in patients (20.4 ± 5.1% versus 23.5 ± 4.0%, p < 0.01). No difference in the flicker response was observed. CONCLUSION: In patients with MCI and AD, arteriovenous difference in oxygen saturation, retinal blood flow and arterial vessel diameter was reduced. No difference was found in flicker response between groups. This indicates alterations in retinal oxygen metabolism in patients with neurodegenerative disease.

Specific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer's Disease: Results of the Prospective Dementia Registry (PRODEM-Austria).

BACKGROUND: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer's disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI). OBJECTIVE: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression. METHODS: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster). RESULTS: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time. CONCLUSION: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression.

Effects of Psychotropic Medication on Cognition, Caregiver Burden, and Neuropsychiatric Symptoms in Alzheimer's Disease over 12 Months: Results from a Prospective Registry of Dementia in Austria (PRODEM).

Behavioral and psychological symptoms of dementia are common in Alzheimer's disease (AD) and associated with a more rapid decline in cognitive function. Psychotropic substances are frequently used in AD, but we lack conclusive evidence of their efficacy in this setting. SSRI and trazodone were reported to have positive effects on cognition. Based on the prospective registry of dementia in Austria (PRODEM), we investigated the effects of psychotropic substances on cognition, behavioral symptoms, and caregiver burden (CB) in patients with AD, followed up prospectively over a 12-month period. We used the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Zarit caregiver burden interview. The study cohort consisted of 309 patients. Patients taking no psychotropic drugs (NO) or those undergoing consistent monotherapy with a psychotropic drug for 12 months were analyzed further (NO 101 patients, SSRI 22, trazodone 8, atypical neuroleptics or benzodiazepines (ANL/BZD) 18). Additionally, the subgroup of patients who started taking any of the substances during the study period were analyzed further to determine the effects before versus six months after the start of medication. MMSE, NPI, and CB at baseline and during follow-up did not differ between the groups. MMSE and CB declined over 12 months in the overall group (MMSE: 21.2±4 versus 19.7±5, p = 0.001 and CB 20.3±12 versus 24.7±14.2, p = 0.007), but no statistically significant changes were registered within groups over 12 months. When trazodone was started, only NPI improved significantly after 6 months (33.4±18 versus 18.9±22.7, p < 0.01). ANL/BZD or SSRI, when started, did not alter MMSE, NPI, or CB. SSRI had no beneficial effect on cognition. We conclude that trazodone might be helpful in the treatment of behavioral symptoms.

White Matter Hyperintensities in Alzheimer's Disease: A Lesion Probability Mapping Study.

BACKGROUND/OBJECTIVE: Higher white matter hyperintensity (WMH) load has been reported in Alzheimer's disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps. METHODS: The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed. RESULTS: There were no significant between-group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients. CONCLUSION: In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location.

Associations of event-related brain potentials and Alzheimer's disease severity: A longitudinal study.

BACKGROUND: So far, no cost-efficient, widely-used biomarkers have been established to facilitate the objectivization of Alzheimer's disease (AD) diagnosis and monitoring. Research suggests that event-related potentials (ERPs) reflect neurodegenerative processes in AD and might qualify as neurophysiological AD markers. OBJECTIVES: First, to examine which ERP component correlates the most with AD severity, as measured by the Mini-Mental State Examination (MMSE). Then, to analyze the temporal change of this component as AD progresses. METHODS: Sixty-three subjects (31 with possible, 32 with probable AD diagnosis) were recruited as part of the cohort study Prospective Dementia Registry Austria (PRODEM). For a maximum of 18 months patients revisited every 6 months for follow-up assessments. ERPs were elicited using an auditory oddball paradigm. P300 and N200 latency was determined with regard to target as well as difference wave ERPs, whereas P50 amplitude was measured from standard stimuli waveforms. RESULTS: P300 latency exhibited the strongest association with AD severity (e.g., r = -0.512, p < 0.01 at Pz for target stimuli in probable AD subjects). Further, there were significant Pearson correlations for N200 latency (e.g., r = -0.407, p = 0.026 at Cz for difference waves in probable AD subjects). P50 amplitude, as measured by different detection methods and at various scalp sites, did not significantly correlate with disease severity - neither in probable AD, possible AD, nor in both subgroups of patients combined. ERP markers for the group of possible AD patients did not show any significant correlations with MMSE scores. Post-hoc pairwise comparisons between baseline and 18-months follow-up assessment revealed significant P300 latency differences (e.g., p < 0.001 at Cz for difference waves in probable AD subjects). However, there were no significant correlations between the change rates of P300 latency and MMSE score. CONCLUSIONS: P300 and N200 latency significantly correlated with disease severity in probable AD, whereas P50 amplitude did not. P300 latency, which showed the highest correlation coefficients with MMSE, significantly increased over the course of the 18 months study period in probable AD patients. The magnitude of the observed prolongation is in line with other longitudinal AD studies and substantially higher than in normal ageing, as reported in previous trials (no healthy controls were included in our study).

Neuroimaging markers of global cognition in early Alzheimer's disease: A magnetic resonance imaging-electroencephalography study.

INTRODUCTION: Magnetic resonance imaging (MRI) and electroencephalography (EEG) are a promising means to an objectified assessment of cognitive impairment in Alzheimer's disease (AD). Individually, however, these modalities tend to lack precision in both AD diagnosis and AD staging. A joint MRI-EEG approach that combines structural with functional information has the potential to overcome these limitations. MATERIALS AND METHODS: This cross-sectional study systematically investigated the link between MRI and EEG markers and the global cognitive status in early AD. We hypothesized that the joint modalities would identify cognitive deficits with higher accuracy than the individual modalities. In a cohort of 111 AD patients, we combined MRI measures of cortical thickness and regional brain volume with EEG measures of rhythmic activity, information processing and functional coupling in a generalized multiple regression model. Machine learning classification was used to evaluate the markers' utility in accurately separating the subjects according to their cognitive score. RESULTS: We found that joint measures of temporal volume, cortical thickness, and EEG slowing were well associated with the cognitive status and explained 38.2% of ifs variation. The inclusion of the covariates age, sex, and education considerably improved the model. The joint markers separated the subjects with an accuracy of 84.7%, which was considerably higher than by using individual modalities. CONCLUSIONS: These results suggest that including joint MRI-EEG markers may be beneficial in the diagnostic workup, thus allowing for adequate treatment. Further studies in larger populations, with a longitudinal design and validated against functional-metabolic imaging are warranted to confirm the results.

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease.

BACKGROUND: Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. METHODS: We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry. RESULTS: The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment. CONCLUSIONS: AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1. TRIAL REGISTRATION: The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.

Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society.

BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients. METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.

A flexible method for the automated offline-detection of artifacts in multi-channel electroencephalogram recordings.

Electroencephalogram (EEG) signal quality is often compromised by artifacts that corrupt quantitative EEG measurements used in clinical applications and EEG-related studies. Techniques such as filtering, regression analysis and blind source separation are often used to remove these artifacts. However, these preprocessing steps do not allow for complete artifact correction. We propose a method for the automated offline-detection of remaining artifacts after preprocessing in multi-channel EEG recordings. In contrast to existing methods it requires neither adaptive parameters varying between recordings nor a topography template. It is suited for short EEG segments and is flexible with regard to target applications. The algorithm was developed and tested on 60 clinical EEG samples of 20 seconds each that were recorded both in resting state and during cognitive activation to gain a realistic artifact set. Five EEG features were used to quantify temporal and spatial signal variations. Two distance measures for the single-channel and multi-channel variations of these features were defined. The global thresholds were determined by three-fold cross-validation and Youden's J statistic in conjunction with receiver operating characteristics (ROC curves). We observed high sensitivity of 95.5%±4.8 and specificity of 88.8%±2.1. The method has thus shown great potential and is promising as a possible tool for both EEG-based clinical applications and EEG-related research.