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OBJECTIVE Patients with moyamoya vasculopathy often experience cognitive impairments. In this prospective single-center study, the authors investigated the profile of neurocognitive impairment and its relation with the severity of ischemic brain lesions and hemodynamic compromise. METHODS Patients treated in a Dutch tertiary referral center were prospectively included. All patients underwent standardized neuropsychological evaluation, MRI, digital subtraction angiography, and [15O]H2O-PET (to measure cerebrovascular reactivity [CVR]). The authors determined z-scores for 7 cognitive domains and the proportion of patients with cognitive impairment (z-score < −1.5 SD in at least one domain). The authors explored associations between patient characteristics, imaging and CVR findings, and cognitive scores per domain by using multivariable linear regression and Bayesian regression analysis. RESULTS A total of 40 patients (22 children; 75% females) were included. The median age for children was 9 years (range 1–16 years); for adults it was 39 years (range 19–53 years). Thirty patients (75%) had an infarction, and 31 patients (78%) had impaired CVR (steal phenomenon). Six of 7 cognitive domains scored below the population norm. Twenty-nine patients (73%) had cognitive impairment. Adults performed better than children in the cognitive domain visuospatial functioning (p = 0.033, Bayes factor = 4.0), and children performed better in processing speed (p = 0.041, Bayes factor = 3.5). The authors did not find an association between infarction, white matter disease, or CVR and cognitive domains. CONCLUSIONS In this Western cohort, cognitive functioning in patients with moyamoya vasculopathy was below the population norm, and 73% had cognitive impairment in at least one domain. The cognitive profile differed between adults and children. The authors could not find an association with imaging findings.

Objectives To investigate electronic care notes to better understand reporting and management of neuropsychiatric symptoms (NPS) by residential aged care (RAC) staff. Methods We examined semi-structured care notes from electronic healthcare notes of 77 residents (67% female; aged 67-101; 79% with formal dementia diagnosis) across three RAC facilities. As part of standard clinical practice, staff documented the NPS presentation and subsequent management amongst residents. Using a mixed-method approach, we analyzed the type of NPS reported and explored care staff responses to NPS using inductive thematic analysis. Results 465 electronic care notes were recorded during the 18-month period. Agitation-related behaviors were most frequently reported across residents (48.1%), while psychosis (15.6%), affective symptoms (14.3%), and apathy (1.3%) were less often reported. Only 27.5% of the notes contained information on potential causes underlying NPS. When faced with NPS, care staff responded by either providing emotional support, meeting resident's needs, removing identified triggers, or distracting. Conclusion Results suggest that RAC staff primarily detected and responded to those NPS they perceived as distressing. Findings highlight a potential under-recognition of specific NPS types, and lack of routine examination of NPS causes or systematic assessment and management of NPS. These observations are needed to inform the development and implementation of non-pharmacological interventions and care programs targeting NPS in RAC. Supplemental data for this article is available online at https://doi.org/10.1080/13607863.2022.2032597 .

Background and ObjectivesIt is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD using normative brain volumetry software.MethodsPresymptomaticGRN,MAPT, andC9orf72pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib® ND, which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared with reference centile curves based on a large population-derived sample of nondemented individuals (n = 4,951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age.ResultsThirty-fourGRN, 8MAPT, and 14C9orf72pathogenic variant carriers were included (mean age = 52.1, standard deviation = 7.2; 66% female). The mean follow-up duration of the study was 64 ± 33 months (median = 52; range 13–108).GRNpathogenic variant carriers showed a faster decline than the reference centile curves for all brain areas, though relative volumes remained between the 5th and 75th percentiles between the ages of 45 and 70 years. InMAPTpathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45 years and showed a further decline between the ages 50 and 60 years. Temporal lobe volume started in the 50th percentile at age 45 years but showed fastest decline over time compared with other brain structures. Frontal, temporal, parietal, and cerebellar volume already started below the 5th percentile compared with the reference centile curves at age 45 years forC9orf72pathogenic variant carriers, but there was minimal decline over time until the age of 60 years.DiscussionWe provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease tracking and staging biomarkers in genetic FTD. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response.

Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer’s dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension ‘frontal-behavioural symptoms’. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.

Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white-matter abnormalities (WMA) and impaired cognition on long-term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid-attenuated inversion recovery, susceptibility-weighted images, and magnetic resonance angiography-time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late-onset Pompe disease (age range 11-56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age-adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91-111; one patient had a below-average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube-copying/clock-drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late-onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients.

Purpose: The three variants of primary progressive aphasia (PPA) differ in clinical presentation, underlying brain pathology, and clinical course, which stresses the need for early differentiation. However, brief cognitive tests that validly distinguish between all PPA variants are lacking. The Sydney Language Battery (SYDBAT) is a promising screening instrument that can be used as a first step in a comprehensive neuropsychological assessment to distinguish PPA subtypes, but evidence on its validity and reliability is to date limited. In the current study, the validation and diagnostic value of the SYDBAT are described for discriminating PPA subtypes as well as distinguishing PPA from mild cognitive impairment (MCI) or Alzheimer's dementia (AD). Method: Forty-five patients with PPA (13 with semantic PPA, 20 with logopenic PPA, and 12 with nonfluent/agrammatic PPA), 25 MCI patients, 13 AD patients, and 50 cognitively unimpaired controls were included in this study. Both patients and controls completed the SYDBAT-NL (Dutch version). Performance on and predictive ability of the four subtests (i.e., Naming, Word Comprehension, Repetition, and Semantic Association) were assessed. In addition, construct validity and internal consistency were examined. Results: Different SYDBAT performance patterns were found across PPA and non-PPA patient groups. While a discriminant function analysis based on SYDBAT subtest scores could predict PPA subtype with 78% accuracy, it was more difficult to disentangle PPA from non-PPA patients based on SYDBAT scores alone. For assisting in clinical interpretation, simple rules were set up and translated into a diagnostic decision tree for subtyping PPA, which was capable of diagnosing a large proportion of the cases. Satisfying validity and reliability measures were found. Conclusions: The SYDBAT is an easy-to-use and promising screen for assessing single-word language processes, which may contribute to the differential diagnostic process of PPA and the assessment of language impairment in MCI and AD. It can be easily implemented for initial screening of patients in a memory clinic.

The ScreeLing is a screening instrument developed to assess post-stroke aphasia, via the linguistic levels Syntax, Phonology, and Semantics. It could also be a useful test for the clinical subtypes of frontotemporal dementia (FTD) and Alzheimer’s dementia (AD), as specific and often selective disorders are expected. Its ability to differentiate between the clinical subtypes of FTD and AD is, however, still unknown. We investigated differences in ScreeLing total and subscores, linguistic-level disorders’ relationship with disease severity, and classification abilities, in patients with behavioral variant FTD (bvFTD; n = 46), patients with primary progressive aphasia (PPA; n = 105) (semantic variant primary progressive aphasia [svPPA], non-fluent variant primary progressive aphasia [nfvPPA], and logopenic variant primary progressive aphasia [lvPPA], AD [ n = 20] and controls [ n = 35]). We examined group differences in ScreeLing total and subscores, and one-, two- or three-level linguistic disorders using one-way analyses of covariance (ANCOVAs) or Quade’s rank ANCOVA. We used frequency analyses to obtain the occurrence of the linguistic-level disorders. We determined sensitivity and specificity by the area under the curve by receiver-operating characteristics analyses to investigate classification abilities. The total score was lower in patients (bvFTD: 63.8 ± 8.5, svPPA: 58.8 ± 11.3, nfvPPA: 63.5 ± 8.4, lvPPA: 61.7 ± 6.6, AD: 63.8 ± 5.5) than controls (71.3 ± 1.0) ( p < .001). Syntax subscores were lower in svPPA (19.4 ± 4.6; p < .001) and lvPPA (20.3 ± 3.2; p = .002) than controls (23.8 ± 0.4). Phonology subscores were lower in lvPPA (19.8 ± 2.6) than bvFTD (21.7 ± 2.8) ( p = .010). Semantics subscores were lowest in svPPA (17.8 ± 5.0; p < .002). A selective phonological disorder was most prevalent in lvPPA (34.9%). The higher the disease severity, the more linguistic-level disorders. The optimal cutoff for the total score was 70, and 23 for all three subscores. Good classification abilities were found for the Semantics (svPPA vs. bvFTD), Phonology (lvPPA vs. svPPA), and Syntax (nfvPPA vs. lvPPA) subscores. This easy to administer test gives information about language processing with the potential to improve differential diagnosis in memory clinics and in the future potentially also clinical trial planning.

Objective: Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics. Method: Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands. Results: The test battery included existing tests such as the Cross-Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), tests from the European Cross-Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%–100%), except for CCD Dots subtest B (58%). Although tests of the “core” TULIPA battery were administered often (median: 6 of 7, IQR: 5–7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0–3). The number of administered tests correlated with disease severity (RUDAS, ρ=.33, adjusted p

Introduction: Although qualitative studies have highlighted substantial barriers to dementia diagnosis and care in culturally diverse populations in Europe, quantitative studies examining the level of caregiver burden in these populations have been lacking thus far and are urgently needed. Methods: We compared the caregiver burden levels on the Caregiver Strain Index (CSI)-Expanded of 63 culturally diverse patient-caregiver dyads from a multicultural memory clinic with 30 native Dutch patient-caregiver dyads and examined the association between caregiver burden and determinants of burden. Results: Informal caregivers in the multicultural memory clinic cohort experienced a high level of caregiver burden (mean CSI-score multicultural cohort: 6.1 [SD: 3.3]; mean CSI-score native Dutch cohort: 4.8 [SD: 3.2]). Burden was significantly associated with impairment on proxy-rated and objective measures of cognitive functioning, such as the Informant Questionnaire on Cognitive Decline and the Rowland Universal Dementia Assessment Scale, and with instrumental activities of daily living. Burden was the highest in spousal caregivers. The positive subscale of the CSI-Expanded provided limited additional information. Conclusion: Caregivers of culturally diverse patients experience a high level of caregiver burden, in particular at more advanced disease stages. This study highlights the need to screen culturally diverse caregivers in European memory clinics on caregiver burden to identify those in need of caregiver support.

Background: While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic. Method: A total of 60 community-dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table-1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL-AD) and caregivers (Carerqol-7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI-Q & BEHAVE-AD), NPS-related distress (NPI-Q), competence managing NPS (additional NPI-Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group-level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes. Result: We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table-2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS-related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement. Conclusion: This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group-level, but suggest that particular participants might benefit from this approach. Data will be re-analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS-related knowledge and management styles of participants.

Objectives: 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. Methods: Twenty-three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearman's correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. Results: The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%–83.9%) and inconsistent correlations between NPI assessments (e.g., range r s = 0.20–0.57 for agitation, range r s = 0.29–0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (r s = 0.60, p s = 0.16, p = 0.20). Conclusions: We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.

Aims/hypothesis Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes. Methods The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48–69 mmol/mol (6.5–8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment. Results Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes. Conclusions/interpretation In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years. Funding This study was sponsored by Boehringer Ingelheim. Trial registration ClinicalTrials.gov NCT01243424. Graphical abstract

Objective: Detecting dementia in people who are illiterate or have a low level of education is complicated because many cognitive screening tests are not suitable for these persons. Caregiver or informant-based judgment of cognitive status may aid diagnosis. Our goal was to investigate the diagnostic accuracy of the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) in a population of elderly non-Western migrants with a high illiteracy rate. Second, we wanted to investigate the diagnostic accuracy of IQCODE and Rowland Universal Dementia Screening (RUDAS) combined. Method: 109 geriatric outpatients and 20 community controls were included. Geriatricians provided a research diagnosis of intact cognition (n = 27), mild cognitive impairment (MCI; n = 33) or dementia (n = 49). Diagnostic accuracy was calculated for the clinical sample (n = 109). ROC curves for prediction of group status for IQCODE, RUDAS and the combination of both were created. Results: Predictive validity was high for both IQCODE and RUDAS and was highest for the combination (Area Under the Curve.91). Sensitivity, specificity, Youden index, predictive value, and likelihood ratio for IQCODE and RUDAS are reported. Conclusions: In this study in non-Western elderly migrants, half of whom were illiterate, the IQCODE proved to be a valid instrument for dementia detection, and adding the RUDAS increased accuracy. Combining performance-based and informant-based data is recommended to enhance diagnostic precision.

The behavioral variant of Alzheimer's disease is characterized by early predominant behavioral changes, mimicking the behavioral variant of frontotemporal dementia, which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in the behavioral variant of Alzheimer's disease. 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 the behavioral variant of Alzheimer's disease with patients with the behavioral variant of frontotemporal dementia(n = 14), typical Alzheimer's disease(n = 13) and individuals with subjective cognitive decline(n = 13), using ANCOVAs and age and sex adjusted post hoc testing. Patients with the behavioral variant of Alzheimer's disease(40.1 ± 8.6) showed lower scores on the Ekman-60-faces-test compared to individuals with subjective cognitive decline(49.7 ± 5.0, p 0.001), and patients with typical Alzheimer's disease(46.2 ± 5.3, p = 0.05) and higher scores compared to patients with behavioral variant of frontotemporal dementia(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 the behavioral variant of Alzheimer's disease(18.7 ± 9.5%) and frontotemporal dementia(19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with subjective cognitive decline(30.7 ± 11.6%, p 0.01) and patients with typical Alzheimer's disease(32.7 ± 12.1%, p 0.01). Patients with the behavioral variant of Alzheimer's disease(11.3 ± 4.6) exhibited lower scores on the Interpersonal-Reactivity-Index compared with individuals with subjective cognitive decline(15.6 ± 3.1, p = 0.05) and similar scores to patients with the behavioral variant of frontotemporal dementia(8.7 ± 5.6, p = 0.19) and typical Alzheimer's disease(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 the behavioral variant of Alzheimer's disease(16.0 ± 1.6) and frontotemporal dementia(15.2 ± 2.2) showed lower scores on the Social-Norms-Questionnaire than patients with typical Alzheimer's disease(17.8 ± 2.1, p 0.05) and individuals with subjective cognitive decline(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 the behavioral variant of frontotemporal dementia(0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with subjective cognitive decline(3.4 ± 3.3 peaks per minute, p = 0.01). Concluding, patients with the behavioral variant of Alzheimer's disease showed a similar though milder social cognition profile and a similar eye-tracking signature to patients with the behavioral variant of frontotemporal dementia and greater social cognition impairments and divergent eye-movement patterns compared with patients with typical Alzheimer's disease. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.

The behavioral variant of Alzheimer’s disease (bvAD) is characterized by early and predominant behavioral changes, resembling the clinical profile of the behavioral variant of frontotemporal dementia (bvFTD). Social cognition deficits form hallmark features in bvFTD and altered biometric responses to socioemotional cues have been observed in bvFTD. However, little is known about social cognition and its biometric signature in bvAD. In this explorative study, we investigated all levels of social cognition (i.e., level-1: perception, level-2: interpretation and level-3: reasoning), using the Ekman 60 faces test (level-1), Interpersonal Reactivity Index (IRI) and empathy eliciting videos (level-2), the Social Norms Questionnaire (SNQ) and moral dilemmas (level-3), while measuring eyemovements and galvanic skin response (GSR). We compared 12 patients with bvAD with patients with bvFTD (n=14), typical AD (tAD, n=13) and controls (n=15), using ANCOVAs and post hoc testing, adjusting for age and sex. Regardingperception, bvAD (40.1±8.6) showed lower scores on the Ekman test compared to controls (50.1±4.6, p0.05), but bvAD (18.7±9.5%) and bvFTD (19.4±14.3%) spent significantly less dwell time on the mouth when viewing the faces than controls (30.4±10.6%, pempathy, bvAD (11.3±4.6) exhibited lower scores on the IRIPerspective Takingsubscale compared with controls (15±3.4, p=0.02) and similar scores to bvFTD (8.7±5.6, p=0.19) and tAD (13.0±3.2, p=0.43). The GSR to empathy eliciting videos did not differ between groups (all p>0.05). Regardingknowledge of social norms, bvAD (16.0±1.6) and bvFTD (15.2±2.2) showed lower scores on the SNQ than tAD (17.8±2.1, both pmoral reasoning, no differences among the groups were observed in responses to moral dilemmas (all p>0.05), while only bvFTD (0.9±1.1) showed a lower GSR during the personal condition compared with controls (3.2±3.3 peaks per minute, p=0.02). In conclusion, bvAD showed a similar though milder social cognition profile and a similar eyetracking signature compared with bvFTD and greater social cognition impairments and divergent eyemovement patterns compared with tAD. Our results suggest that bvAD and bvFTD show reduced attention to salient features during facial expression perception, potentially contributing to their emotion recognition deficits. These social cognition and biometric measures provide important insights into the basis of behavioral changes in bvAD, and might be valuable for its clinical diagnosis.

Background: It remains unclear whether revascularization of moyamoya vasculopathy (MMV) has a positive effect on cognitive function. In this prospective, single-center study, we investigated the effect of revascularization on cognitive function in patients with MMV. We report clinical and radiological outcome parameters and the associations between clinical determinants and change in neurocognitive functioning. Methods: We consecutively included all MMV patients at a Dutch tertiary referral hospital who underwent pre- and postoperative standardized neuropsychological evaluation, [15O]H2O-PET (including cerebrovascular reactivity (CVR)), MRI, cerebral angiography, and completed standardized questionnaires on clinical outcome and quality of life (QOL). To explore the association between patient characteristics, imaging findings, and change in the z-scores of the cognitive domains, we used multivariable linear- and Bayesian regression analysis. Results: We included 40 patients of whom 35 (27 females, 21 children) were treated surgically. One patient died after surgery, and two withdrew from the study. TIA- and headache frequency and modified Rankin scale (mRS) improved (resp. p = 0.001, 0.019, 0.039). Eleven patients (seven children) developed a new infarct during follow-up (31%), five of which were symptomatic. CVR-scores improved significantly (p < 0.0005). The language domain improved (p = 0.029); other domains remained stable. In adults, there was an improvement in QOL. We could not find an association between change in imaging and cognitive scores. Conclusion: In this cohort of Western MMV patients, TIA frequency, headache, CVR, and mRS improved significantly after revascularization. The language domain significantly improved, while others remained stable. We could not find an association between changes in CVR and cognitive scores.

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

BACKGROUND: Populations living in European countries are becoming increasingly diverse. As performance on traditional neuropsychological tests is heavily influenced by culture, language, (level and quality of) education, literacy, and other factors, neuropsychological assessment practices need to be adapted to account for this diversity. METHOD: The European Consortium for Cross-Cultural Neuropsychology (ECCroN) aims to improve assessment of culturally, educationally, and linguistically diverse individuals across Europe by 1) collaborating on the validation and implementation of cross-cultural neuropsychological tests and 2) working on initiatives geared at improving interpreter use and training programs for neuropsychologists. RESULT: The consortium was founded in late 2019 and currently consists of 16 experts based in 9 countries - some of whom work in multinational contexts. The first meetings of the network stressed several points. First, ECCroN aims to develop and/or validate cross-culturally applicable tests, as opposed to race-based norms for existing tests; for example, current projects aim to validate measures of social cognition and language (naming) in patients with migration backgrounds. Second, ECCroN emphasizes the importance of taking into account diversity across the entire spectrum, both in populations traditionally considered to be 'majority' and 'minority' groups, e.g. best practices should be developed for those with little education regardless of native-born or migrant status. Third, ECCroN aims to identify and share suitable instruments to measure factors potentially influencing the assessment, such as bilingualism, acculturation and educational quality. CONCLUSION: Joint efforts should be undertaken to develop, validate, publish, and implement cross-cultural tests across European countries to reduce misdiagnoses in diverse patient populations.

Aims: We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes. Methods: Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up. Results: CKD at baseline was more common in CARMELINA than CAROLINA (eGFR2, 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = −0.01 per doubling of UACR mg/g, 95%CI [−0.02,−0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = −0.01, 95%CI [−0.03,−0.0001] per doubling of UACR mg/g). Conclusions: eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting. ClinicalTrials.gov

Background and ObjectivesTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid–positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.MethodsIn this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (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).ResultsWe included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD 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 to −0.11, false discovery rate [FDR]–adjustedp< 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = −0.32 to 0.36, all FDR-adjustedp> 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = −0.13 to 0.44, all FDR-adjustedp> 0.05).DiscussionNPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.

Objective: Type 2 diabetes is associated with cognitive dysfunction, but the mechanisms are unknown. We assessed the relationships of biomarkers of oxidation, endothelial function and inflammation with cognition in participants of the CAROLINA® trial (CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes). Methods: Baseline circulating biomarkers of oxidation (8-iso-prostaglandin F2α), endothelial function (asymmetric dimethylarginine, endothelin-1) and inflammation (C-reactive protein, interleukin-6, tumour necrosis factor-α), based on linear regression, were related to cognition on five domains, as measured with an automated battery. Results: In 37 patients (mean age 66.7 ± 8.7 years, median HbA1c 6.9%/52 mmol/mol), 8-iso-prostaglandin F2α was associated with reduced mental flexibility and attention (standardised regression coefficients −0.47, −0.34), whereas asymmetric dimethylarginine was associated with reduced psychomotor speed and attention (standardised regression coefficients −0.39, −0.34). No significant associations were observed between biomarkers of inflammation and cognition. Conclusion: Elevated biomarkers of oxidation and endothelial function are associated and may play a role in reduced psychomotor speed, mental flexibility and attention in type 2 diabetes.

Background The emotion recognition task (ERT) was developed to overcome shortcomings of static emotion recognition paradigms, by identifying more subtle deficits in emotion recognition across different intensity levels. In this study, we used the ERT to investigate emotion recognition deficits across the frontotemporal (FTD) and Alzheimer’s Dementia (AD) spectrum. Methods With the ERT, we assessed the recognition of facial emotional expressions (anger-disgust-fear-happiness-sadness-surprise) across four intensities (40–60–80–100%) in patients with behavioural variant FTD (bvFTD; n = 32), and AD (n = 32), presymptomatic FTD mutation carriers (n = 47) and controls (n = 49). We examined group differences using multilevel linear regression with age, sex and education level as covariates, and performed post hoc analyses on presymptomatic (MAPT, GRN and C9orf72) mutation carriers. Classification abilities were investigated by means of logistic regression. Results Lowest ERT total scores were found in patients with bvFTD and AD, whereas equal highest performance was found in presymptomatic mutation carriers and controls. For all emotions, significantly lower subscores were found in patients with bvFTD than in presymptomatic mutation carriers and in controls (highest p value = 0.025). Patients with bvFTD performed lower than patients with AD on anger (p = 0.005) and a trend towards significance was found for a lower performance on happiness (p = 0.065). Task performance increased with higher emotional intensity, and classification was better at the lowest than at the highest intensity. C9orf72 mutation carriers performed worse on recognizing anger at the lowest intensity than GRN mutation carriers (p = 0.047) and controls (p = 0.038). The ERT differentiated between patients with bvFTD and controls, and between patients with AD and controls (both p Discussion Our results demonstrate emotion recognition deficits in both bvFTD and AD, and suggest the presence of subtle emotion recognition changes in presymptomatic C9orf72-FTD. This highlights the importance of incorporating emotion recognition paradigms into standard neuropsychological assessment for early differential diagnosis, and as clinical endpoints in upcoming therapeutic trials.

To investigate the relationship between the diabetes-specific dementia risk score (DSDRS) and concurrent and future cognitive impairment (CI) in type 2 diabetes (T2D).DSDRS were calculated for participants with T2D aged ≥60 years from the CARMELINA-cognition substudy (ClinicalTrials.gov Identifier: NCT01897532). Cognitive assessment included Mini-Mental State Examination (MMSE) and a composite attention and executive functioning score (AE). The relation between baseline DSDRS and probability of CI (MMSE 24) and variation in cognitive performance was assessed at baseline (n = 2241) and after 2.5 years follow-up in patients without baseline CI (n = 1312).Higher DSDRS was associated with a higher probability of CI at baseline (OR = 1.17 per point, 95% CI 1.12-1.22) and follow-up (OR = 1.24 per point, 95% CI 1.14-1.35). Moreover, in patients without baseline CI, higher DSDRS was also associated with lower baseline cognitive performance (MMSE: F(1, 1930) = 47.07, p .0001, RThe DSDRS identifies patients with T2D at risk of concurrent as well as future CI. The DSDRS may thus be a supportive tool in screening strategies for cognitive dysfunction in patients with T2D.

Objective:Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations.Method:A systematic review was performed using six databases, without restrictions on the year or language of publication.Results:Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer’s disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n = 12, of which 10 were naming tests). Many studies did not report a thorough adaptation procedure (n = 39) or blinding procedures (n = 29).Conclusions:Various formats of memory tests seem suitable for low-educated, non-Western populations. Promising tasks in other cognitive domains are the Stick Design Test, Five Digit Test, and verbal fluency test. Further research is needed regarding cross-cultural instruments measuring executive functioning and language in low-educated people.