female sex has been associated with faster tau accumulation over time and greater resilience in Alzheimer’s disease. However, relatively few studies have examined regional tau accumulation rates and cognitive resilience in a large amyloid-positive cohort. We included n=761 amyloid-positive (A+) participants from the Swedish BioFINDER-2 study who had undergone (longitudinal) tau PET and cognitive testing, of whom n=253 were cognitively unimpaired (CU A+) and n=508 were cognitively impaired (CI A+). [ 18 F]RO948-tau-PET SUVR within entorhinal, medial temporal, neocortical temporal, medial parietal, lateral parietal, occipital, frontal, anterior cingulate, insula and cortical composite regions was quantified. Cognition was assessed with the modified preclinical Alzheimer’s disease cognitive composite (mPACC5). Linear mixed models were fitted to assess the effect of the interaction between sex and baseline tau on cognition over time, adjusting for age, education and APOE e4 status. Demographic characteristics are shown in Table 1. Models assessing the effect of the interaction between baseline tau and sex on cognitive decline showed significant positive associations between multiple tau regions in CU A+ and longitudinal mPACC5 (medial parietal: 0.39±0.10, p=0.0005, lateral parietal: 0.31±0.08, p=0.0005, occipital: 0.26±0.07, p=0.0005, lateral temporal: 0.23±0.07, p=0.006, inferior middle temporal: 0.18±0.07, p=0.03, insula: 0.17±0.07, p=0.04, Figure 1), while models showed significant negative associations between some tau regions in CI A+ and longitudinal mPACC5 (lateral temporal: -0.38±0.11, p=0.007, inferior middle temporal: -0.35±0.11, p=0.01, anterior cingulate: -0.35±0.13, p=0.03, Figure 1). Assessing cognitive trajectories by sex per quartiles of baseline tau burden revealed that females show similar cognitive trajectories to males in the 1 st -3 rd quartiles of tau burden, but seem to show less cognitive decline in the 4 th quartile of tau burden in CU, while in CI, females show a steeper decline than males (Figure 2). Our results suggest that cognitively unimpaired A+ females exhibit greater cognitive resilience, while cognitively impaired A+ females exhibit steeper cognitive decline than males in the face of tau pathology, and that these effects occur particularly at high levels of tau pathology.

Human musicality might have co-evolved with social cognition abilities, but common neuroanatomical substrates remain largely unclear. In behavioural variant frontotemporal dementia, social cognitive abilities are profoundly impaired, whereas these are typically spared in Alzheimer's disease. If musicality indeed shares a neuroanatomical basis with social cognition, it could be hypothesized that clinical and neuroanatomical associations of musicality and social cognition should differ between these causes of dementia. We recruited 73 participants from the Amsterdam Dementia Cohort (n = 30 female; aged 50-78), of whom 23 had behavioural variant frontotemporal dementia, 22 Alzheimer's disease and 28 were healthy controls. Musicality was assessed using a music-emotion recognition test, melody, tempo, accent and tuning subscores, a musicality summed score, the identification of auditory hedonic phenotypes and music emotion induction using skin conductance responses. Social cognition was assessed across multiple levels, including emotion recognition, theory of mind, socio-emotional sensitivity and understanding of social norms. We used ANCOVA to investigate subgroup differences in musicality and social cognition and linear regressions to investigate associations between musicality and social cognition. All analyses were adjusted for age, sex, musical training and mini mental state examination. Finally, we performed voxel-based morphometry analyses on T1-weighted MRI to study whether regions for musicality and social cognition overlapped anatomically. We found that patients with behavioural variant frontotemporal dementia performed worse on music-emotion recognition (all P < 0.001) and tempo recognition (all P < 0.05) compared with Alzheimer's disease and on musicality summed score (all P = 0.02) compared to controls only. Furthermore, patients with behavioural variant frontotemporal dementia had lower mean skin conductance responses during emotion-inducing music, compared to Alzheimer's disease (all P < 0.045). Worse music emotion recognition scores were associated with worse facial emotion recognition (P < 0.0001), worse theory of mind (P = 0.0005) and worse understanding of social norms (P = 0.01). Melody and tempo recognition were associated with facial emotion recognition and theory of mind, and accent recognition was associated with the theory of mind. Music emotion recognition and tempo recognition were also associated with executive functions. Worse music emotion recognition, melody recognition, tempo recognition, facial emotion recognition and theory of mind scores were all related to atrophy in the anterior temporal regions and the fusiform gyri, which play a role in multisensory integration, and worse tempo recognition was associated with atrophy of the anterior cingulate cortex. These results support the idea that musicality and social cognition may share a neurobiological basis, which may be vulnerable in behavioural variant frontotemporal dementia.

The behavioural variant of Alzheimer's disease (bvAD) is characterized by early predominant behavioural changes, mimicking the behavioural variant of frontotemporal dementia (bvFTD), which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in bvAD. We investigated multiple social cognition components (i.e. emotion recognition, empathy, social norms and moral reasoning), using the Ekman 60 faces test, Interpersonal Reactivity Index, empathy eliciting videos, Social Norms Questionnaire and moral dilemmas, while measuring eye movements and galvanic skin response. We compared 12 patients with bvAD with patients with bvFTD (n = 14), typical Alzheimer's disease (tAD, n = 13) and individuals with subjective cognitive decline (SCD, n = 13), using ANCOVAs and age- and sex-adjusted post hoc testing. Patients with bvAD (40.1 ± 8.6) showed lower scores on the Ekman 60 faces test compared to individuals with SCD (49.7 ± 5.0, P < 0.001), and patients with tAD (46.2 ± 5.3, P = 0.05) and higher scores compared to patients with bvFTD (32.4 ± 7.3, P = 0.002). Eye-tracking during the Ekman 60 faces test revealed no differences in dwell time on the eyes (all P > 0.05), but patients with bvAD (18.7 ± 9.5%) and bvFTD (19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with SCD (30.7 ± 11.6%, P < 0.01) and patients with tAD (32.7 ± 12.1%, P < 0.01). Patients with bvAD (11.3 ± 4.6) exhibited lower scores on the Interpersonal Reactivity Index compared with individuals with SCD (15.6 ± 3.1, P = 0.05) and similar scores to patients with bvFTD (8.7 ± 5.6, P = 0.19) and tAD (13.0 ± 3.2, P = 0.43). The galvanic skin response to empathy eliciting videos did not differ between groups (all P > 0.05). Patients with bvAD (16.0 ± 1.6) and bvFTD (15.2 ± 2.2) showed lower scores on the Social Norms Questionnaire than patients with tAD (17.8 ± 2.1, P < 0.05) and individuals with SCD (18.3 ± 1.4, P < 0.05). No group differences were observed in scores on moral dilemmas (all P > 0.05), while only patients with bvFTD (0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with SCD (3.4 ± 3.3 peaks per min, P = 0.01). Concluding, patients with bvAD showed a similar although milder social cognition profile and a similar eye-tracking signature to patients with bvFTD and greater social cognition impairments and divergent eye movement patterns compared with patients with tAD. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.

BACKGROUND AND PURPOSE:Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD.METHODS:The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons.RESULTS:Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76).CONCLUSIONS:In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.

BACKGROUND:Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented. OBJECTIVE:To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic. METHODS:We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n = 36) and the second wave underwent the DICE method (n = 24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n = 12). RESULTS:The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs. CONCLUSION:The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.

Tau pathology is strongly associated with clinical symptoms, possibly (partly) through the manifestation of neurodegeneration. However, independent pathways between tau pathology and clinical symptoms have been suggested. Longitudinal studies investigating the role of tau vs neurodegeneration on cognitive and behavioral changes across the AD clinical spectrum are relatively lacking. We included n = 482 individuals from the Swedish-BioFINDER-2-study who had undergone longitudinal neuropsychological assessments and [18F]RO948-tau-PET and 3T-MRI, of whom n = 157 were amyloid-beta positive (A+) cognitively unimpaired (CU), and n = 326 A+ cognitively impaired (CI) individuals, and calculated SUVRs and cortical thickness in multiple regions(i.e. medial-temporal, lateral-temporal, medial-parietal, lateral-parietal, frontal, occipital, whole-brain). Mean follow-up time was 1.63(1.29) years. Linear-Mixed-Effects-models with random-intercepts and fixed-slopes were performed, adjusting for age, sex, and education, applying FDR-correction, with both baseline and rate-of-change in tau-PET or MRI (the annualized difference between baseline and 2 year follow-up) as predictors and MMSE, mPACC5 or the Mild Behavioral Inventory (MBI) as outcomes. Post-hoc analyses included corrections for the other modality and serial mediation analyses (n = 1000 bootstrap iterations). Linear-Mixed-Effects-models with baseline tau-PET or MRI as predictors showed stronger associations between tau-PET and cognitive and behavioral changes over time than cortical thickness, which were more pronounced in CI than CU individuals (Figure 1). Analyses with rate-of-change in tau-PET or MRI as predictors showed stronger associations for tau-PET in CU individuals, but superiority of MRI in CI individuals, which was confirmed when correcting for the other modality, i.e. assessing independent effects (Figure 2). No significant associations were found between rate-of-change in tau-PET or MRI and longitudinal MBI (all p>0.05; data not shown). Serial mediation analyses revealed no mediating effect of rate-of-change in tau-PET or MRI between baseline tau-PET and cognition over time in CU, while in CI, rate-of-change in MRI did show a significant mediating effect (p = 0.002; Figure 3). Tau-PET showed stronger associations with cognitive and behavioral changes over time than cortical thickness at baseline across the AD clinical spectrum. However, assessing rate-of-change, MRI showed superiority over tau-PET in CI individuals, suggesting differential contributions of tau pathology vs neurodegeneration in different disease stages.

Background Neuropsychiatric symptoms (NPS) are prevalent in the early clinical stages of Alzheimer’s disease (AD) according to proxy-based instruments. Little is known about which NPS clinicians report and whether their judgment aligns with proxy-based instruments. We used natural language processing (NLP) to classify NPS in electronic health records (EHRs) to estimate the reporting of NPS in symptomatic AD at the memory clinic according to clinicians. Next, we compared NPS as reported in EHRs and NPS reported by caregivers on the Neuropsychiatric Inventory (NPI). Methods Two academic memory clinic cohorts were used: the Amsterdam UMC ( n = 3001) and the Erasmus MC ( n = 646). Patients included in these cohorts had MCI, AD dementia, or mixed AD/VaD dementia. Ten trained clinicians annotated 13 types of NPS in a randomly selected training set of n = 500 EHRs from the Amsterdam UMC cohort and in a test set of n = 250 EHRs from the Erasmus MC cohort. For each NPS, a generalized linear classifier was trained and internally and externally validated. Prevalence estimates of NPS were adjusted for the imperfect sensitivity and specificity of each classifier. Intra-individual comparison of the NPS classified in EHRs and NPS reported on the NPI were conducted in a subsample (59%). Results Internal validation performance of the classifiers was excellent (AUC range: 0.81–0.91), but external validation performance decreased (AUC range: 0.51–0.93). NPS were prevalent in EHRs from the Amsterdam UMC, especially apathy (adjusted prevalence = 69.4%), anxiety (adjusted prevalence = 53.7%), aberrant motor behavior (adjusted prevalence = 47.5%), irritability (adjusted prevalence = 42.6%), and depression (adjusted prevalence = 38.5%). The ranking of NPS was similar for EHRs from the Erasmus MC, although not all classifiers obtained valid prevalence estimates due to low specificity. In both cohorts, there was minimal agreement between NPS classified in the EHRs and NPS reported on the NPI (all kappa coefficients < 0.28), with substantially more reports of NPS in EHRs than on NPI assessments. Conclusions NLP classifiers performed well in detecting a wide range of NPS in EHRs of patients with symptomatic AD visiting the memory clinic and showed that clinicians frequently reported NPS in these EHRs. Clinicians generally reported more NPS in EHRs than caregivers reported on the NPI.

Abstract Background The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. Methods VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. Results The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. Discussion VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

OBJECTIVES:Frontotemporal dementia (FTD) can present with changes in music appreciation. Research has suggested a relationship of altered music appreciation phenotypes with typical socio-emotional changes. We aimed to determine the prevalence and severity of music appreciation phenotypes in FTD and study the relationship with emotion recognition capacities in order to examine whether they could serve as a proxy for changes in socio-emotional functioning.METHODS/DESIGN:Based on reported musical changes in the literature, we developed an informant-based questionnaire to assess musical changes and a music test to assess music emotion recognition. Social cognition was assessed with the Ekman 60 faces test in a subgroup of patients (n = 23). Relationships between measures were assessed with linear regressions.RESULTS:We included 47 patients (44.7% female, mean age 65.0 ± 8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), and six progressive nonfluent aphasia (PNFA)). Thirty-six caregivers were included in the music emotion recognition test as controls. Altered music appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was present in a third of bvFTD patients, and only in up to 10% in language FTD variants. Changes in music appreciation were not associated with decreased music emotion recognition or visual emotion recognition. Compared to controls, bvFTD performed worse on the music emotion recognition task (p < 0.003), and no differences were found with SD (p = 0.06) and PNFA patients (p = 0.8).CONCLUSIONS:Music appreciation phenotypes are highly prevalent in FTD patients. Future studies should further investigate the potential diagnostic value of changes in music processing.

This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period.

ABSTRACTObjectiveTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of amyloid-β positive individuals across the Alzheimer’s disease (AD) clinical spectrum.MethodsWe included 1,524 amyloid-β positive individuals from the Amsterdam Dementia Cohort with subjective cognitive decline (SCD, n=113), mild cognitive impairment (MCI, n=321), or dementia (n=1,090). We measured NPS with the neuropsychiatric inventory (NPI), examining total scores and the presence of specific NPI-items. Cognition was assessed across five cognitive domains and with the MMSE. We examined trajectories including model based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time-points (subsample n=520, Mean=1.8 [SD=0.7] years follow-up).ResultsNPS were prevalent across all clinical AD stages (NPI total score ≥1 81.4% in SCD, 81.2% in MCI, 88.7% in dementia). Cognitive functioning showed an uniform gradual decline; while in contrast, large intra-individual heterogeneity of NPS was observed over time across all groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β:-0.18–0.11, FDR-adjusted p<0.05), while there were no cross-sectional relationships in SCD and MCI (β:-0.32– 0.36, FDR-adjusted p>0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (β:-0.13–0.44, FDR-adjusted p>0.05).ConclusionNPS and cognitive symptoms are both prevalent across the AD continuum, but show a different evolution during the course of the disease.

Frontotemporal dementia (FTD) can present with changes in music appreciation. The aim of the present study was to determine the prevalence and nature of music appreciation phenotypes among FTD syndromes in a memory clinic population.

to examine the relative role of the frontal cortex in neuropsychiatric symptoms in Alzheimer’s disease (AD), we assessed associations between latent atrophy factors and neuropsychiatric symptoms in AD. We employed a data-driven Bayesian modelling framework based on Latent Dirichlet Allocation (LDA) to identify latent atrophy factors in a cohort of 1135 Aβ-positive MCI and AD patients from the Amsterdam Dementia Cohort (age: 66.4±7.44, 50% male, MMSE: 22.3±0.1). The model uses standardized gray matter density images as input, adjusted for age, sex, intracranial volume and scanner field strength, and yields voxelwise probabilistic maps for a predetermined number of atrophy factors, providing data–driven factor expression loadings per individual. These factor expressions were correlated to scores on the Neuropsychiatric Inventory (NPI) using general linear models, adjusting for sex, age, education and MMSE scores. the LDA model revealed a frontal (dorsolateral and insular), a medial temporal lobe (hippocampal and entorhinal), a temporoparietal and a late-stage (sensorimotor and occipital) factor (Figure 1). The highest percentage of individual expressions was found in the late-stage factor (34.0±0.6), followed by the MTL (27.3±0.6), TPC (22.0±0.5) and frontal (16.7±0.5) factors (Figure 2). Higher frontal expression relative to both the MTL and late-stage factors was associated with a higher odds for apathy (MTL; OR =1.012, p =0.010, late-stage; OR =1.011, p =0.046; Figure 3). Negative associations, however, were found between relative frontal atrophy and disinhibition, anxiety and nighttime behaviors (Figure 3); a higher frontal load relative to each reference factor related to a lower odds for disinhibition (frontal-MTL: OR =0.978, p =0.035; frontal-TPC: OR =0.969, p =0.042; frontal-‘late-stage’: OR =0.976, p =0.029), a higher frontal load relative to MTL and late-stage factors were associated with a lower odd for anxiety (frontal-MTL: OR =0.984, p =0.015; frontal-‘late-stage’: OR =0.983, p =0.003) and night-time behaviors (frontal-MTL: OR =0.982, p =0.023; frontal-‘late-stage’: OR =0.980, p =0.005). Relative frontal atrophy was related to more frequent apathy and less frequent disinhibition, anxiety and night-time behaviors and may point towards more AD-typical regions as determining neurobiological regions for disinhibition, anxiety and night-time behaviors than frontal regions in AD. Alternatively, disinhibition may be more dependent on the right frontal pole, less prominently involved in the current frontal factor.

OBJECTIVE:The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination. METHODS:For the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7). RESULTS:Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05). CONCLUSIONS:Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

This systematic review and meta-analysis reviews literature on the behavioral variant of Alzheimer disease and uses the outcomes to propose research criteria for this syndrome.

Neuropsychiatric symptoms (NPS) are highly prevalent in early Alzheimer’s disease (AD) and are associated with poor clinical outcomes. Although non‐pharmacological interventions are considered first‐line treatment for NPS in AD, they are rarely implemented into the memory clinic. Here, we present the protocol of our intervention study aimed to structure and standardize the detection and treatment of NPS in AD in the memory clinic, and provide preliminary data from our control group to obtain more insight in the current memory clinic care as usual (CAU) of NPS in AD.

AbstractBackgroundA distinct subset of patients with Alzheimer’s disease (AD) experience early and predominant behavioral and personality changes, while the neurobiological origins of these symptoms are largely unknown. In this study, we examined the distribution of tau pathology using PET imaging or post‐mortem evaluation in patients with the behavioral variant of AD (bvAD).MethodFor the PET study, seven amyloid‐β positive clinically diagnosed patients with bvAD from the Amsterdam Dementia Cohort (ADC, n=2), University of California San Francisco (UCSF, n=3) and the Swedish BioFINDER study (n=2) underwent [18F]flortaucipir or [18F]RO948 (tau) PET (Table 1). Regional standardized uptake value ratios (SUVR) in entorhinal, temporoparietal, frontal, and insular cortex as well as mean cortical SUVR and frontal‐to‐parietal SUVR ratios were contrasted against patients with typical (memory‐predominant) AD (tAD; n=55, n=60 and n=90, respectively). For the post‐mortem component of the study, the percentages of AT8 (tau)‐positive areas in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between 9 cases with bvAD and 7 with tAD.ResultVisual inspection of subject‐specific tau PET patterns revealed more pronounced frontal involvement in 6/7 bvAD patients compared to patients with tAD (Figure 1). Regional SUVR analyses revealed higher‐than‐average tau uptake in 3/7 bvAD cases in the temporoparietal cortex, 5/7 in the frontal cortex, and 3/7 in the insular cortex compared to patients with tAD (Figure 2). Furthermore, 4/7 cases showed higher‐than‐average mean cortical SUVR and 6/7 cases had higher‐than‐average frontal‐to‐parietal SUVR ratios (Figure 2 & Table 2). Postmortem evaluation revealed that bvAD cases had a lower tau load in the CA1 region of the hippocampus compared to patients with tAD (p<.05); no differences were found, however, in temporal, parietal, frontal or insular regions (all p>.05, Figure 3 & Table 3).ConclusionThis multicenter case series with tau PET and neuropathological examination demonstrates a heterogeneous distribution of tau pathology across patients with bvAD, ranging from pronounced anterior involvement to a more temporoparietal pattern. Further work is needed to explore alternative pathophysiological mechanisms underlying the bvAD phenotype.

We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD

The anterior cingulate (ACC) and frontoinsular cortex (FI) are key regions implicated in behavior and social cognition. These regions harbor a novel cortical neuronal group, characterized by expression of the GABA subunit theta (GABRQ) and inclusion of Von Economo Neurons (VENs). This neuronal group is selectively vulnerable in the behavioral variant of frontotemporal dementia (bvFTD), but not in typical Alzheimer’s disease (typAD)(1). Currently, it is unknown whether this neuronal population is affected in the behavioral variant of AD (bvAD) compared to controls and typAD and whether there is a difference in local pathological burden and morphology between bvAD and typAD.