Quantitative EEG has been shown to reflect neurodegenerative processes in Alzheimer's disease (AD) and may provide non-invasive and widely available biomarkers to enhance the objectivization of disease assessment. To address EEG's major drawback - its low spatial resolution - many studies have employed 3D source localization. However, none have investigated whether this complex mapping into 3D space actually adds value over standard surface derivation. In fact, we found no prior study - in any disease - that quantitatively compared the results of a 3D source localization method with those achieved by surface derivation. We analyzed data from one of the largest prospective AD EEG studies ever conducted (four study centers, 188 patients, 100 female). Thousands of distinct quantitative EEG markers of slowing, complexity, and functional connectivity were computed and regressed against disease severity, with rigorous control for multiple testing. We found highly significant associations between quantitative EEG markers and disease severity. However, standardized low-resolution electromagnetic tomography (sLORETA), a widely used 3D source localization method, did not improve results. Furthermore, a surface derivation marker (auto-mutual information of the left hemisphere during the eyes-closed condition) was the best performing marker across our entire sample. While our findings strongly support that quantitative EEG markers reflect neurodegenerative processes in AD, they do not demonstrate additional benefit from sLORETA. Importantly, our results are specific to AD and sLORETA. Therefore, they should not be generalized to other neurological or psychiatric disorders or to other 3D source localization methods without further validation. Finally, these findings do not diminish the value of 3D source localization for visual EEG inspection.

Background White matter hyperintensities (WMH) have been implicated in the pathogenesis of neuropsychiatric symptoms of dementia but the functional significance of WMH in specific white matter (WM) tracts is unclear. We investigate whether WMH burden within major WM fibre classes and individual WM tracts are differentially associated with different neuropsychiatric syndromes in a large multicentre study.Method Neuroimaging and neuropsychiatric data of seven memory clinic cohorts through the Meta VCI Map consortium were harmonised. Class-based analyses of major WM fibres (association, commissural and projection) and region-of-interest-based analyses on 11 individual WM tracts were used to evaluate associations of WMH volume with severity of hyperactivity, psychosis, affective and apathy syndromes.Results Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy. Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively. Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy. No associations with affective and psychosis were observed.Conclusions Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in 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-β1-42 (Aβ42)-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 Aβ42 status in 11 memory clinic cohorts. Aβ42 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.

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.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain 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. Lesion network mapping (LNM) enables us 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 LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four 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 to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/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 connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. 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 integrity, particularly in attention-related 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.

Alzheimer’s disease (AD) imposes a major burden on affected individuals, their caregivers and health-care systems alike. Though quite many risk factors for disease progression have been identified, there is a lack of prospective studies investigating the interplay and predictive value of a wide variety of patient variables associated with cognitive deterioration (defined as key feature of AD progression). Study participants were patients with probable and possible AD, that were assessed at four time points over a period of two years (T1-T4). The main results were threefold: (i) over time, significant changes were observed regarding patients’ cognitive functioning, activities of daily living and caregiver load (but not depression, pain, neuropsychiatric symptoms); (ii) intercorrelations between caregiver load and patients’ cognitive and functional variables were high, correlation patterns remaining rather stable across time; (iii) cognitive functioning at T4 was best predicted by patients’ age, sex, atrial fibrillation and activities of daily living at T1; and (iv) across all four assessment points, cognitive functioning was best predicted by time (i.e., disease duration), age, sex, activities of daily living and depression. Overall, even in early stages of AD and during a short two-year period, functional changes were significant and tightly intertwined with caregiver load, thus stressing the need to consider caregiver load when diagnosing and treating patients with AD. A novel and clinically relevant finding is that even in early stages of AD, cognitive deterioration was best predicted by a combination of patients’ demographic, somatic and functional variables.

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.

In the newly revised guideline, the proven exploration training in treating spatial neglect has been supplemented by suggestions for the therapeutic procedure for different degrees of severity of spatial neglect, resulting in a respective reduction in time. Furthermore, the exploration training currently undergoes interesting enhancements by applying "augmented reality" and "virtual reality" procedures. Further recommendations for treating spatial neglect include training using slow smooth pursuit eye movements to the contralateral side and neck muscle vibration. Among the noninvasive transcranial brain stimulation procedures, continuous theta burst stimulation (cTBS) protocol has proved effective - if combined with at least one other neglect training procedure (e. g., exploration training). For treatment of the Pusher syndrome, different groups have successfully used visual feedback training and robot-assisted gait training. The situation is more problematic for procedures used for treating the other disorders of spatial cognition discussed in the guideline (Balint syndrome, simultanagnosia, optic ataxia, disorders of visuospatial perception, visuoconstructive disorders, topographic disorders); single-case or small-group studies dominate here. The evaluation of individual, methodologically high-quality, and well-documented therapy studies currently provides the only basis for deriving recommendations for treating this latter group of disorders of spatial cognition.

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 (β = .340; p < .001; β = .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 (β = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (β = −.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.

Zusammenfassung: In der neu überarbeiteten Leitlinie wurde das bewährte Explorationstraining bei der Behandlung des Neglects durch Vorschläge zum therapeutischen Vorgehen für verschiedene Schweregrade des Neglects und eine damit einhergehende zeitliche Reduktion ergänzt. Darüber hinaus erfährt es derzeit interessante Erweiterungen durch den Einsatz von „Augmented Reality“- und von „Virtual Reality“-Verfahren. Weiterhin empfohlen zur Behandlung des Neglects wird das Training mittels langsamer Folgebewegungen zur kontralateralen Seite und mittels Nackenmuskelvibration. Unter den nichtinvasiven transkraniellen Hirnstimulationsverfahren hat sich das kontinuierliche Theta-Burst Stimulation (cTBS) -Protokoll in Bezug auf die Neglectsymptomatik als wirksam erwiesen, wenn es mit mindestens einem weiteren Trainingsverfahren (z. B. Explorationstraining) kombiniert wurde. Zur Behandlung des Pusher-Syndroms wurden Visuelles-Feedback-Training und robotergestütztes Laufbandtraining von unterschiedlichen Gruppen erfolgreich eingesetzt. Die Situation ist problematischer bei jenen Verfahren, die zur Behandlung der weiteren in der Leitlinie besprochenen Störungen der Raumkognition (Bálint-Syndrom, Simultanagnosie, optische Ataxie, Störungen der visuell-räumlichen Wahrnehmung, visuokonstruktive Störungen, topografische Störungen) eingesetzt werden. Hier dominieren Einzelfall- bzw. Kleingruppenstudien. Die Auswertung einzelner methodisch hochwertiger und gut dokumentierter Therapiestudien bietet derzeit die einzige Grundlage zur Ableitung von Empfehlungen für die Behandlung dieser Gruppe von Störungen der Raumkognition.

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.

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.

Background: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). Objective: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. Method: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. Results: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). Conclusion: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.

BACKGROUND AND PURPOSE:Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized.METHODS:Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory-impaired and memory-intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures.RESULTS:Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left- or right-sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito-temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment.CONCLUSIONS:Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.

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.

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.

Both, decline of sensorimotor functions and cortical thickness are known processes in healthy aging. Physical activity has been suggested to enhance the execution of daily routine activities and to extend the time of functional independence in advanced age. We hypothesized that cortical thickness of motor areas in retired individuals could be related to physical demands of the profession carried out during working life. Depending on their former occupations, 69 cognitively healthy individuals (range 70–85 years) were divided into higher and lower physically complex occupations (HPCO n = 27 and LPCO n = 42) according to the international standard classification of occupations (ISCO-08). Participants underwent a high-resolution 3T T1-weighted MRI scan. Surface-based analysis revealed higher cortical thickness in the left precentral ( P = 0.001) and postcentral gyrus ( P < 0.001) and right postcentral gyrus ( P = 0.001) for the HPCO relative to the LPCO group (corrected for multiple comparisons, sex, age and leisure activities in the past 20 years). Physical leisure activities associated with exertion were positively correlated with cortical thickness in the left pre- and postcentral gyrus ( P = 0.037) of the LPCO group. Time since retirement was negatively associated with cortical thickness in the left postcentral gyrus ( P = 0.004) of the HPCO group. Executing a higher physically complex occupation before retirement was related to relative higher cortical thickness in the primary motor and somatosensory cortex in later life, supporting the hypothesis that physical activity contributes to neural reserve in these regions. However, these benefits appear to vanish when physical activity is reduced due to retirement.

Introduction and background: Care for family members suffering from neurological disorders is often demanding and increases with disease progression. Numerous patientand caregiver-related factors underlying caregiver burden have been identified. Some potential factors need to be clarified. Little is known about the effects of comorbidities and dementia complications on the burden of care for persons living with dementia. Objectives: We hypothesized that burdens of care for family members living with dementia increase with the number and severity of comorbidities and dementia complications. Methods: Multi-center prospective registry study (PRODEM) on caregiver burden in family caregivers (median age 61, 66% female) of 556 persons living with mild to moderate dementia, mainly Alzheimer’s disease (median age 77, 58% female). Results: Caregiver burden (Zarit Burden Interview) did not correlate with arterial hypertension, diabetes, hypercholesterolemia, cardioembolic/thromboembolic diagnoses, heart failure, severe arrhythmia or heart valve disease, but was worse in care recipients with symptoms of anxiety, psychotic episodes, depression and emotional, psychotic, behavioral and somatic symptom clusters (Neuropsychiatric Inventory, Geriatric Depression Scale-15 items). Moreover, caregiver burden correlated with the number of drugs taken daily. MRI evidence of cerebrovascular pathology (total volume of white matter hyperintensities on axial T2w-FLAIR sequences related to intracranial volume, measured in 301 patients) did not correlate with caregiver burden. Gerhard R, Defrancesco M, Damulina A, Hermann P, Benke T, Dal-Bianco P, et al. Much is Known about Caregiver Burden in Dementia What is Next? The Role of Comorbidities and Future Perspectives. J Exp Neurol. 2021;2(3):101-111. J Exp Neurol. 2021 Volume 2, Issue 3 102 Introduction and Background Care for patients with chronic debilitating neurological diseases is often demanding and can result in a variety of negative consequences including mental and physical morbidity. Numerous studies have been published on the burden of care for persons caring for spouses, parents, siblings or children with chronic neurological disorders, particularly for those who live with the care recipient and are directly responsible for care. Most studies address the care for dementia and stroke patients, persons with epilepsy, Parkinson’s disease and atypical parkinsonism, multiple sclerosis, motor neuron disease, Huntington’s disease, brain tumours, chronic pain syndromes, traumatic central nervous system injury, ataxias, and muscular dystrophy [1]. Little is known about caregiver burden in advanced stages of myasthenia gravis, adultonset myopathies, amyloidosis or other debilitating polyneuropathies or other rare neurological diseases. Most studies were performed in highor middle-income countries. The literature from low-income countries on family care for persons with chronic neurological diseases including dementia is sparse [2-4]. Little is known about burdens for formal caregivers caring for persons in the clients’ homes, in nursing homes or in palliative care [5-8]. Considerable differences have been found between countries concerning burdens and health-related quality of life of informal caregivers of family members living with dementia. The differences were explained by variable support, traditions and social norms, and occupational duties and other competing responsibilities [2-4]. A pattern was found with caregivers in eastern and southern European countries expressing more severe caregiver burdens than caregivers in central and western European countries. Differences in caregiver burden have been found between neurological diseases [1,9,10]. The risk of severe caregiver burden is high in persons caring for individuals with dementia [8-10]. Caregiver burden depends on objective, patient-related parameters, such as age, disease duration, disease severity, physical and mental morbidity including behavioural and neuropsychiatric impairments, daily hours and total duration of care, impairment of activities of daily living, dependency, and proximity between care recipients and caregiver. On the other hand, caregiver-related objective parameters contribute to caregiver burden, such as age, health state, incompatibility of care and occupational and family responsibilities and lack of personal, psychological and financial support. Moreover, subjective factors influence caregiver burden, such as emotional relationship between the caregiver and the care recipient, personality traits, missing agreement between involved persons, strict social norms, high expectations of the care recipient and other family members, negative social reactions, lack of choice in taking on the caregiving role, feeling of insecurity, loneliness, lack of self-esteem, self-efficacy and resilience, and poor coping strategies [2,4,7,8,11,22-28]. The Zarit Burden Interview (ZBI) is the most frequently applied inventory to estimate subjective caregiver burden [2,4,11]. Subjective caregiver burden has also been assessed in the literature using the Caregiver Strain Index (CSI) [12], the Burden Scale for Family Caregivers [13], the Multidimensional Index and the Modified Caregiver Strain Index [14,15], and other individually designed scales. The Caregiver Burden Scale [16] assesses both subjective and objective caregiver burden. In individual studies caregiver burden and caregiver strain are distinguished [14]. Different quality of life and health scales have been applied, such as the SF-36, EuroQL, Health Utility Index-3 [17-20]. Assessment tools for clinical characterisation of care recipients living with dementia depend on the type of dementia, disease severity and stage (early, advanced, late stage of dementia) and palliative care [1,2,4,6, 7,9,10,2026]. Acknowledged, objective patient-related factors underlying caregiver burden reported in the literature are summarized in Table 1. Table 2 shows objective caregiverrelated factors of caregiver burden [2,3,10,19,22-28]. However, the effect of a variety of parameters on caregiver burden is uncertain or considered controversial. The influence of caregiver age on caregiver burden is complex. In several studies an inverse relationship was found between caregiver age and caregiver burden. Caregiving children reported more severe caregiver burden than caregiving spouses [2,10,24] because of difficulties integrating caregiving into busy daily routine that include work, family life, social activities, leisure, and sports. Spousal caregivers living with a sick family member, Discussion and conclusions: Neuropsychiatric complications and the number of drugs taken daily, but not internal medicine diseases and cerebral white matter hyperintensities increased the burden of care for caregivers of family members suffering from dementia, which is in partial agreement with the literature. However, severe internal medicine comorbidities were rare in the study. Standardized and harmonized longitudinal assessment of the scope of care and caregiver burden is required including algorhythms for ageand life situation-adjusted assessment of caregiver burden. Further studies on caregiver burden and stronger male involvement in family care are needed.

Spatial neglect is a common consequence of stroke in the territory of the right middle cerebral artery. Damage to a perisylvian fronto-temporo-parietal network has been demonstrated to underlie this disorder. Less common, stroke to the posterior cerebral artery territory may also lead to spatial neglect. This study aimed to uncover the anatomical underpinnings of spatial neglect after posterior cerebral artery infarction. A sample of 50 posterior cerebral artery infarct patients was screened for spatial neglect. Neural correlates of neglect were investigated both with voxel-based lesion behaviour mapping and with region-of-interest analyses. Brain damage neither to the splenium, nor to the parahippocampal gyrus, nor to the thalamus was predictive of spatial neglect. Only damage to the perisylvian fronto-temporo-parietal network of spatial neglect was significantly associated with neglect severity. We conclude that both posterior and middle cerebral artery stroke induce spatial neglect after damage to the same perisylvian brain network. The findings contradict previous theories that postulated neural correlates of spatial neglect specifically supplied by the posterior cerebral artery. In posterior cerebral artery stroke patients, affected parts of this network are located at the border zone between the posterior and middle cerebral artery territories. Inter-individual variability in the localization of the border between both artery territories appears to mediate the occurrence of spatial neglect after posterior cerebral artery stroke.

Introduction: Previous studies have shown an association between a high health numeracy and good cognitive functioning. Objective: To investigate the moderation effect of education on this relationship and which brain structures support health numeracy. Methods: We examined 70 healthy older persons (66% females; mean ± SD: age, 75.73 ± 4.52 years; education, 12.21 ± 2.94 years). The participants underwent a T1-weighted 3-T MRI and a neuropsychological assessment including a health numeracy task. Statistical parametric mapping was applied to identify focal changes in cortical thickness throughout the entire brain and to correlate image parameters with behavioral measures. Results: Executive functions and mental calculation emerged as predictors of health numeracy (B = 0.22, p < 0.05, and B = 0.38, p < 0.01). An interaction was found between education and executive functions (B = –0.16, p = 0.01) and between education and mental calculation (B = –0.11, p < 0.05). Executive functions and mental calculation had an impact on health numeracy in participants with a low to intermediate edu­cation (≤12 years) but not in those with a higher education (>12 years). Health numeracy scores were associated with cortical thickness in the right dorsomedial prefrontal cortex and the right superior temporal gyrus (p = 0.01). Conclusions: Older people with a higher education perform better in health numeracy tasks than those with a lower education. They have access to previously acquired knowledge about ratio concepts and do not need to rely on executive functions and computational skills. This is highly relevant when decisions about health care have to be made.