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Abstract Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Abstract Importance The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. Objective Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. Design, setting, and participants Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. Interventions N.A. Main outcomes and measures Cohen’s kappa, accuracy, and F1-score to assess model performance. Results Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. Conclusions and relevance Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Abstract Background Cerebrospinal fluid (CSF) analysis for detecting amyloid positivity may be as reliable as positron emission tomography (PET). We evaluated the performance of the amyloid beta (Aβ)42/40 ratio for predicting amyloid positivity by PET, compared with Aβ42 alone, and phosphorylated tau 181 (pTau181)/Aβ42 and total tau (tTau)/Aβ42 ratios, using fully automated CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) in a heterogeneous cohort of patients with a range of cognitive disorders reflecting the typical population of a memory clinic. Methods CSF samples from 103 patients with known amyloid PET status (PET positive = 54; PET negative = 49) were retrospectively selected from one site in Germany; 71 patients were undergoing treatment for mild cognitive impairment (n = 44) or mild-to-moderate dementia (n = 27) due to Alzheimer’s disease (AD), and 32 patients were undergoing treatment for non-AD-related cognitive disorders. Aβ42, pTau181, and tTau concentrations were measured in CSF samples using the respective Elecsys® CSF immunoassays modified for use on the cobas e 411 analyzer; Aβ40 concentrations were measured using a non-commercially available robust prototype assay. Sensitivities/specificities for amyloid positivity cut-offs (Youden-derived and pre-defined) were calculated, and receiver operating characteristic analyses determined area under the curve (AUC) versus amyloid PET status. Limitations include a small sample size, use of a pre-analytical protocol not in accordance with the Elecsys CSF immunoassay method sheets, and the lack of a pre-defined cut-off for Aβ42/40. Results Point estimates for sensitivity and specificity of CSF biomarkers and biomarker ratios versus amyloid PET were 0.93 and 0.57 for Aβ42, 0.96 and 0.69 for pTau181/Aβ42, 0.92 and 0.69 for tTau/Aβ42, and 0.94 and 0.82 for Aβ42/40. For AUCs, point estimates (95% confidence intervals) versus amyloid PET were 0.78 (0.68−0.88) for Aβ42, 0.88 (0.81−0.95) for pTau181/Aβ42, 0.87 (0.80−0.95) for tTau/Aβ42, and 0.90 (0.83−0.97) for Aβ42/40. Conclusions CSF Aβ42/40 ratio can predict PET amyloid positivity with high accuracy in patients with a range of cognitive disorders when evaluating Aβ pathology independent of tau and neurodegeneration for research purposes. The performance of Aβ42/40 was comparable with pTau181/Aβ42 and tTau/Aβ42 used in clinical practice and better than Aβ42 alone.

Abstract Background Cerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death, or microglial activation. Few studies have examined CSF lactate levels in dementia due to Alzheimer’s disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remain unclear. Methods We examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well-defined sample of patients with AD at the stage of mild cognitive impairment (MCI-AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD). Results Contrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI-AD compared to those with ADD and to HC in univariate analysis, as well as for MCI-AD compared to ADD when controlling for age and blood-brain barrier integrity. CSF lactate levels were associated with age and blood-brain barrier integrity but not with clinical severity or CSF biomarkers of AD. Conclusions CSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and HC or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.

Abstract Background Polypharmacy is common in people with dementia. The use of psychotropic drugs (PDs) and other, potentially inappropriate medications is high. The aims of this cross-sectional study were 1) to investigate the use of drugs in people with advanced dementia (PWAD), living at home or in long term care (LTC); 2) to focus on PD use; and 3) to identify determinants of PD use. Methods The study was performed in the context of EPYLOGE (IssuEs in Palliative care for people in advanced and terminal stages of YOD and LOD in Germany). 191 PWAD were included. All drugs that were administered at the date of the examination were recorded. Multiple logistic regression analysis identified determinants of PD use. Results 96% of PWAD received medication with a median number of four drugs. 49.7% received five or more drugs. According to the Beers Criteria 39% of PWAD ≥ 65 years received at least one potentially inappropriate medication. 79% of PWAD were treated with PDs. Older PWAD and PWAD living in LTC facilities received significantly more drugs than younger PWAD, and PWAD living at home, respectively. Dementia etiology was significantly associated with the use of antipsychotics, antidepressants and sedative substances. Place of living was associated with the use of pain medication. Behavioral disturbances were associated with the use of antipsychotics and sedative substances. Conclusions To mitigate the dangers of polypharmacy and medication related harm, critical examination is required, whether a drug is indicated or not. Also, the deprescribing of drugs should be considered on a regular basis. Trial registration Clinicaltrial.gov, NCT03364179 . Registered 6 December 2017.

Abstract Background Since people with advanced dementia are usually not able to make complex decisions, it is usually the family caregivers, as proxies, who have to decide on treatments and their termination. However, these decisions are difficult for the caregivers to make, as they are often inadequately informed and cannot properly assess the consequences; moreover, they are concerned about harming the sick person. We aimed to first develop an informative booklet about palliative care issues for caregivers of people with advanced dementia. Secondly, we aimed to investigate a change in family caregivers’ knowledge regarding palliative care issues and caregivers’ involvement in medical and care decisions before and after studying this booklet. Methods A first version of the booklet was drafted by an experienced psychiatrist and palliative care specialist based on existing booklets and guidelines; necessary cultural adaptions were taken into consideration. A nominal group process was conducted to develop the informative guide. In order to investigate the acceptance of the booklet and the possibility to implement it, 38 patient-caregiver dyads were recruited, and caregivers were interviewed both before receiving the booklet and after 3 months of receiving the booklet. Results Experts from various disciplines collaborated on a German booklet for family caregivers of people with advanced dementia as an information aid regarding issues of palliative care. The subsequent test showed that all caregivers had experienced a personal benefit from the booklet. Caregivers had a significant gain of knowledge after provision of the booklet. A large proportion of caregivers who had not previously considered and/or discussed medical topics reported that they had done so within 3 months after obtaining the booklet, or planned to do so in the near future. Conclusions The caregivers valued the comprehensible, concise and well-structured information guide on palliative care issues in advanced dementia. They agreed it increases knowledge and prompts decision making and therefore should be developed in many languages and disseminated among family caregivers of people with dementia. Trial registration clinicaltrial.gov , NCT03548142 . Retrospectively registered 7 June 2018.

Abstract Background As investigations of disease modifying drugs aim to slow down progression of Alzheimer’ disease (AD) biomarkers to reliably track disease progression gain more importance. This is especially important as clinical symptoms, including psychometric measures, are only modestly associated with the underlying disease pathology, in particular at the pre-dementia stages. The decision which biomarkers to choose in clinical trials is crucial and depends on effect size. However, longitudinal studies of multiple biomarkers in parallel that allow direct comparison on effect size are scarce. Methods We calculated effect size and minimal sample size for three common imaging biomarkers of AD, namely amyloid deposition measured with PiB-PET, neuronal dysfunction measured with FDG-PET and cortical thickness measured with MRI in a prospective 24-month follow-up study in a monocentric cohort of early AD. Results Post hoc power calculation revealed large effect sizes of Cohen’s d for PiB-PET and cortical thickness and a small effect size for FDG-PET (1.315, 0.914, and 0.341, respectively). Accordingly, sample sizes for PiB-PET and cortical thickness required significantly smaller sample sizes than FDG-PET to reliably detect statistically significant changes after 24 months in early AD (n = 7, n = 12, and n = 70, respectively). Conclusion Amyloid imaging with PET and measuring cortical thickness with MRI are suitable biomarkers to detect disease progression in early AD within a small sample.

Abstract Background Dementia of the Alzheimer’s type can impair the performance of activities of daily living and therefore severely impact independent living. Assistive technologies can support such patients when carrying out daily tasks. Methods In this crossover study, we used an augmented reality approach using a Microsoft HoloLens to support patients in a tea making task. During task execution, subjects received three-dimensional dynamic holograms of the sub-steps necessary to complete the task. Ten patients suffering from Alzheimer’s disease were tested and post-hoc semi-structured interviews were conducted to assess usability. Results The patients committed errors when executing the task with and without holographic assistance. No differences in success rates or error frequencies were observed (psuccess = .250, perrors = .887). Patients revealed prolonged trial durations (Glass’ Δ = 1.475) when wearing the augmented reality headset. A model of multiple linear regression (R2 adjusted = .958) revealed an influence of the errors in the control condition and a moderation by the errors in the experimental condition. Patients with more severe problems in the natural performance of the task showed lower increases in trial durations when wearing the HoloLens. Conclusions We assume that the application was a secondary task requesting its own resources and impairing performance on its own. The regression suggests however that the given assistance was compensating these additional costs in patients with stronger needs of support. Interview data on usability revealed an overall positive feedback towards the application although the hardware was considered uncomfortable and too large. We conclude that the approach proved feasible and the acceptability was overall high, although advances in hardware and the patient-interface are necessary to assist patients suffering from Alzheimer’s disease in daily activities. Trial registration DRKS, DRKS00014870. Registered 11 June 2018 - Retrospectively registered, TrialID = DRKS00014870.

Abstract Background Scientific research on palliative care in dementia is still underdeveloped. In particular, there are no research studies at all on palliative care issues in young onset dementia (YOD), although significant differences compared to late onset dementia (LOD) are expected. Most studies have focused on persons with dementia in long term care (LTC) facilities but have neglected persons that are cared for at home. We hypothesize that unmet care needs exist in advanced and terminal stages of YOD and LOD and that they differ between YOD and LOD. Methods/design The EPYLOGE-study (IssuEs in Palliative care for people in advanced and terminal stages of Young-onset and Late-Onset dementia in GErmany) aims to prospectively assess and survey 200 persons with YOD and LOD in advanced stages who are cared for in LTC facilities and at home. Furthermore, EPYLOGE aims to investigate the circumstances of death of 100 persons with YOD and LOD. This includes 1) describing symptoms and management, health care utilization, palliative care provision, quality of life and death, elements of advance care planning, family caregivers’ needs and satisfaction; 2) comparing YOD and LOD regarding these factors; 3) developing expert-consensus recommendations derived from the study results for the improvement and implementation of strategies and interventions for palliative care provision; 4) and communicating the recommendations nationally and internationally in order to improve and adapt guidelines, to change current practice and to give a basis and perspectives for future research projects. The results will also be communicated to patients and their families in order to counsel and support them in their decision making processes and their dialogue with professional caregivers and physicians. Discussion EPYLOGE is the first study in Germany that assesses palliative care and end-of-life issues in dementia. Furthermore, it is the first study internationally that focuses on the specific palliative care situation of persons with YOD and their families. EPYLOGE serves as a basis for the improvement of palliative care in dementia. Trial registration The study is registered in ClinicalTrials.gov (NCT03364179; Registered: 6. December 2017.

Abstract Background With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. Methods We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Results Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. Conclusion Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

Following publication of the original article [1], the authors ask to correct the surname of co-author Dennis Hedderich from from Heddderich to Hedderich.