Dementia in Rare Genetic Neurodevelopmental Disorders: A Systematic Literature Review.

BACKGROUND AND OBJECTIVES: Knowledge of young-onset Alzheimer disease in adults with Down syndrome has greatly improved clinical care. However, little is known about dementia in rare genetic neurodevelopmental disorders (RGNDs). In this review, a comprehensive overview is provided of reports on dementia and cognitive/adaptive trajectories in adults with RGNDs. METHODS: A systematic literature review was conducted in Embase, Medline ALL, and PsycINFO on December 6, 2022. The protocol was registered in PROSPERO (CRD42021223041). Search terms for dementia, cognitive and adaptive functioning, and RGNDs were combined using generic terms and the Orphanet database. Study characteristics and descriptive data on genetic diagnosis, clinical and neuropathologic features, comorbidities, and diagnostic methods were extracted using a modified version of the Cochrane Data Extraction Template. RESULTS: The literature search yielded 40 publications (17 cohorts, 23 case studies) describing dementia and/or cognitive or adaptive trajectories in adults with 14 different RGNDs. Dementia was reported in 49 individuals (5 cohorts, 20 cases) with a mean age at onset of 44.4 years. Diagnostics were not disclosed for half of the reported individuals (n = 25/49, 51.0%). A total of 44 different psychodiagnostic instruments were used. MRI was the most reported additional investigation (n = 12/49, 24.5%). Comorbid disorders most frequently associated with cognitive/adaptive decline were epilepsy, psychotic disorders, and movement disorders. DISCUSSION: Currently available literature shows limited information on aging in RGNDs, with relatively many reports of young-onset dementia. Longitudinal data may provide insights into converging neurodevelopmental degenerative pathways. We provide recommendations to optimize dementia screening, diagnosis, and research.

Occupational differences in a Dutch sample of patients with primary progressive aphasia, behavioral variant frontotemporal dementia, and Alzheimer's dementia.

BACKGROUND: Cognitive reserve is a potential mechanism to cope with brain damage as a result of dementia, which can be defined by indirect proxies, including education level, leisure time activities, and occupational attainment. In this study we explored the association between dementia diagnosis and type of occupation in a retrospective Dutch outpatient memory clinic sample of patients with primary progressive aphasia (PPA), behavioral variant frontotemporal dementia (bvFTD), and Alzheimer's Dementia (AD). METHODS: We included data from 427 patients (bvFTD n = 87, PPA n = 148, AD n = 192) and compared the frequency of occupations (11 categories) between patients and data from the Dutch census using Pearson Χ2 tests and we calculated odds ratios (OR) by means of multinomial logistic regression analyses. We also investigated patient group differences in age, sex, education, disease duration, and global cognition. RESULTS: The frequency of teachers in patients with PPA was significantly higher than the frequency of teachers in patients with bvFTD [OR = 4.79, p = .007] and AD [OR = 2.04, p = .041]. The frequency of teachers in patients with PPA (16%) was also significantly higher than the frequency of teachers in the Dutch census [5.3%; OR = 3.27, p < .001]. The frequency of teachers in both bvFTD and AD groups were not significantly different from the frequency of teachers in the Dutch census (p = .078 and p = .513, respectively). CONCLUSIONS: A potential explanation for our results is the so called "wear and tear" hypothesis, suggesting that teachers have a communication-wise demanding occupation - and therefore are at higher risk to develop PPA. Alternatively, teaching requires continuous communication, hence teachers are more sensitive to subtle changes in their speech and language abilities. Our findings broaden our understanding of the relationship between occupational activity and cognitive reserve in the development of dementia.

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

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

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

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

Differential contribution of language and executive functioning to verbal fluency performance in glioma patients.

Glioma patients often suffer from deficits in language and executive functioning. Performance in verbal fluency (generating words within one minute according to a semantic category-category fluency, or given letter-letter fluency) is typically impaired in this patient group. While both language and executive functioning play a role in verbal fluency, the relative contribution of both domains remains unclear. We aim to retrospectively investigate glioma patients' performance on verbal and nonverbal fluency and to explore the influence of language and executive functioning on verbal fluency. Sixty-nine adults with gliomas in eloquent areas underwent a neuropsychological test battery (verbal fluency, nonverbal fluency, language, and executive functioning tests) before surgery (T1) and a subgroup of 31 patients also at three (T2) and twelve months (T3) after surgery. Preoperatively, patients were impaired in all verbal fluency tasks and dissociations were found based on tumour location. In contrast, nonverbal fluency was intact. Different language and executive functioning tests predicted performance on category fluency animals and letter fluency, while no significant predictors for category fluency professions were found. The longitudinal results indicated that category fluency professions deteriorated after surgery (T1-T2, T1-T3) and that nonverbal fluency improved after surgery (T1-T3, T2-T3). Verbal fluency performance can provide information on different possible underlying deficits in language and executive functioning in glioma patients, depending on verbal fluency task selection. Efficient task (order) selection can be based on complexity. Category fluency professions can be selected to detect more permanent long-term deficits.

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

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

New horizons in cognitive and functional impairment as a consequence of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a frequent finding in imaging of the brain in older adults, especially in the concomitance of cardiovascular disease risk factors. Despite the well-established link between cSVD and (vascular) cognitive impairment (VCI), it remains uncertain how and when these vascular alterations lead to cognitive decline. The extent of acknowledged markers of cSVD is at best modestly associated with the severity of clinical symptoms, but technological advances increasingly allow to identify and quantify the extent and perhaps also the functional impact of cSVD more accurately. This will facilitate a more accurate diagnosis of VCI, against the backdrop of concomitant other neurodegenerative pathology, and help to identify persons with the greatest risk of cognitive and functional deterioration. In this study, we discuss how better assessment of cSVD using refined neuropsychological and comprehensive geriatric assessment as well as modern image analysis techniques may improve diagnosis and possibly the prognosis of VCI. Finally, we discuss new avenues in the treatment of cSVD and outline how these contemporary insights into cSVD can contribute to optimise screening and treatment strategies in older adults with cognitive impairment and multimorbidity.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

BACKGROUND: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. METHODS: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. RESULTS: The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. CONCLUSIONS: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer's disease: a natural language processing study.

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.

Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer's Disease at the Memory Clinic: The BEAT-IT Study.

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.

The ScreeLing: Detecting Semantic, Phonological, and Syntactic Deficits in the Clinical Subtypes of Frontotemporal and Alzheimer's Dementia.

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.

Addition of the FTD Module to the Neuropsychiatric Inventory improves classification of frontotemporal dementia spectrum disorders.

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.

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

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

Social cognition deficits and biometric signatures in the behavioural variant of Alzheimer's disease.

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.

Neuropsychological assessment in the multicultural memory clinic: Development and feasibility of the TULIPA battery.

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.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.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 < .001), but not with other patient characteristics. Complicating factors were observed frequently, e.g. suboptimal effort (29%-50%), fatigue (29%), depression (37%-57%).The TULIPA test battery is a promising new battery to assess culturally diverse populations in a feasible way, provided that complicating factors are taken into account.Supplemental data for this article is available online at https://doi.org/10.1080/13854046.2022.2043447 .

Residential aged care staff perceptions and responses towards neuropsychiatric symptoms: a mixed methods analysis of electronic healthcare records.

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 .

The profile of cognitive impairment and hemodynamic compromise in moyamoya: a single-center prospective cohort study.

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.

Clinical Outcome, Cognition, and Cerebrovascular Reactivity after Surgical Treatment for Moyamoya Vasculopathy: A Dutch Prospective, Single-Center Cohort Study.

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.

Longitudinal Brain Atrophy Rates in Presymptomatic Carriers of Genetic Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: It 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. METHODS: Presymptomatic GRN, MAPT, and C9orf72 pathogenic 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 to reference centile curves based on a large population-derived sample of non-demented individuals (n=4951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age. RESULTS: 34 GRN, eight MAPT, and 14 C9orf72 pathogenic variant carriers were included (mean age=52.1, standard deviation=7.2; 66% female). Mean follow-up duration of the study was 64±33 months (median=52; range 13-108). GRN pathogenic variant carriers showed faster decline than the reference centile curves for all brain areas, though relative volumes remained between 5th and 75th percentile between the ages of 45-70. In MAPT pathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45, and showed further decline between the ages 50-60. Temporal lobe volume started in the 50th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5th percentile compared to the reference centile curves at age 45 for C9orf72 pathogenic variant carriers, but there was minimal decline over time until the age of 60. DISCUSSION: We 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.