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 &lt;.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.</p

Diversity in Alzheimer\u27s Disease Drug Trials: The Importance of Eligibility Criteria

INTRODUCTION: To generalize safety and efficacy findings, it is essential that diverse populations are well represented in Alzheimer\u27s disease (AD) drug trials. In this review, we aimed to investigate participant diversity in disease-modifying AD trials over time, and the frequencies of participant eligibility criteria. METHODS: A systematic review was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records. RESULTS: In the 101 included AD trials, participants were predominantly White (median percentage: 94.7%, interquartile range: 81.0-96.7%); and this percentage showed no significant increase or decrease over time (2001-2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific Mini-Mental State Examination scores (90.1%; no significant increase/decrease over time) may have led to a disproportionate exclusion of ethnoracially diverse individuals. DISCUSSION: Ethnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations are provided to broaden eligibility criteria

Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia

Introduction: We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD). Methods: Presymptomatic MAPT (n = 15) and GRN mutation carriers (n = 31), and healthy controls (n = 39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression. Results: MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p < 0.05). Cognitive decline in ScreeLing phonology (p = 0.046) and letter fluency (p = 0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p = 0.025) for an underlying MAPT mutation. Discussion: Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD

Cross-cultural neuropsychological assessment in Europe:Position statement of the European Consortium on Cross-Cultural Neuropsychology (ECCroN)

Objective: Over the past decades European societies have become increasingly diverse. This diversity in culture, education, and language significantly impacts neuropsychological assessment. Although several initiatives are under way to overcome these barriers – e.g. newly developed and validated test batteries – there is a need for more collaboration in the development and implementation of neuropsychological tests, such as in the domains of social cognition and language. Method: To address these gaps in cross-cultural neuropsychological assessment in Europe, the European Consortium on Cross-Cultural Neuropsychology (ECCroN) was established in 2019. Results: ECCroN recommends taking a broad range of variables into account, such as linguistic factors, literacy, education, migration history, acculturation and other cultural factors. We advocate against race-based norms as a solution to the challenging interpretation of group differences on neuropsychological tests, and instead support the development, validation, and standardization of more widely applicable/cross-culturally applicable tests that take into account interindividual variability. Last, ECCroN advocates for an improvement in the clinical training of neuropsychologists in culturally sensitive neuropsychological assessment, and the development and implementation of guidelines for interpreter-mediated neuropsychological assessment in diverse populations in Europe. Conclusions: ECCroN may impact research and clinical practice by contributing to existing theoretical frameworks and by improving the assessment of diverse individuals across Europe through collaborations on test development, collection of normative data, cross-cultural clinical training, and interpreter-mediated assessment

Assessment of Visual Association Memory in Low-Educated, Non-Western Immigrants with the Modified Visual Association Test

Background: Neuropsychological tests are influenced by culture, language, level of education, and literacy, but there are few cognitive tests of which the applicability in ethnic minority populations has been studied. Objectives: The aim of this study was to assess the reliability and validity of the Visual Association Test (VAT), a test of visual association memory, in a non-Western, low-educated memory clinic population. Additionally, a modified version of the VAT using colored photographs instead of line drawings was studied (mVAT). Method: Both the original VAT and the mVAT were administered to non-Western immigrants (n = 73) from 2 multicultural memory clinics in Rotterdam, The Netherlands, and a control sample of non-demented Turkish elderly (n = 14) with low education levels (32 and 29% illiterate, respectively). Results: Both the VAT and the mVAT were able to discriminate persons with and without dementia (area under the curve: VAT, 0.77-0.88; mVAT, 0.85-0.95). The mVAT had more homogeneous item difficulty levels than the VAT. Administration of parallel versions of the VAT and the mVAT within the same person revealed higher scores on the mVAT (Z = -3.35, p = 0.001). Conclusions: The mVAT is a reliable and valid measure of memory in non-Western immigrants. Clinicians and researchers should be aware that the memory performance of immigrants may be systematically underestimated when using tests with black-and-white line drawings, such as the original VAT

Longitudinal multimodal MRI as prognostic and diagnostic biomarker in presymptomatic familial frontotemporal dementia

Developing and validating sensitive biomarkers for the presymptomatic stage of familial frontotemporal dementia is an important step in early diagnosis and for the design of future therapeutic trials. In the longitudinal Frontotemporal Dementia Risk Cohort, presymptomatic mutation carriers and non-carriers from families with familial frontotemporal dementia due to microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations underwent a clinical assessment and multimodal MRI at baseline, 2-, and 4-year follow-up. Of the cohort of 73 participants, eight mutation carriers (three GRN, five MAPT) developed clinical features of frontotemporal dementia ('converters'). Longitudinal whole-brain measures of white matter integrity (fractional anisotropy) and grey matter volume in these converters (n = 8) were compared with healthy mutation carriers ('non-converters'; n = 35) and non-carriers (n = 30) from the same families. We also assessed the prognostic performance of decline within white matter and grey matter regions of interest by means of receiver operating characteristic analyses followed by stepwise logistic regression. Longitudinal whole-brain analyses demonstrated lower fractional anisotropy values in extensive white matter regions (genu corpus callosum, forceps minor, uncinate fasciculus, and superior longitudinal fasciculus) and smaller grey matter volumes (prefrontal, temporal, cingulate, and insular cortex) over time in converters, present from 2 years before symptom onset. White matter integrity loss of the right uncinate fasciculus and genu corpus callosum provided significant classifiers between converters, non-converters, and non-carriers. Converters' within-individual disease trajectories showed a relatively gradual onset of clinical features in MAPT, whereas GRN mutations had more rapid changes around symptom onset. MAPT converters showed more decline in the uncinate fasciculus than GRN converters, and more decline in the genu corpus callosum in GRN than MAPT converters. Our study confirm

A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations

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

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression