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Background and purpose: Behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), such as mood, psychotic, and autism spectrum disorders, share similar clinical characteristics of behavior and social cognition. Better understanding of clinical progression in bvFTD and PPD is essential for adequate disease monitoring and trial design. Methods: In this longitudinal study (N = 89), patients with bvFTD and PPD with at least one follow‐up assessment were included from the Social Brain Project of the Alzheimer Center Amsterdam. Behavioral change and social cognitive decline were assessed via informant‐rated questionnaires (Cambridge Behavioral Inventory–Revised, Frontal Behavioral Inventory [FBI], Stereotypy Rating Inventory, Frontotemporal Dementia Rating Scale, Revised Self‐Monitoring Scale [RSMS]‐caregiver) and patient assessment (Ekman 60‐Faces Test, RSMS‐patient, Emotional Contagion Scale). Clinical trajectories (median = 1.4 years, interquartile range = 1.0–2.2) were examined using linear mixed models. In a subsample, associations with baseline serum neurofilament light (sNfL) were examined. Results: At baseline, behavioral and social cognitive symptoms were similar between diagnosis groups, except for poorer emotion recognition in bvFTD. Over time, behavioral symptoms worsened in bvFTD, whereas most measures remained stable and the FBI improved in PPD. Regarding social cognition, emotion recognition and caregiver‐reported socioemotional sensitivity worsened in bvFTD and remained stable in PPD. Patient‐reported social cognitive measures did not change over time. Higher sNfL was associated with faster behavioral change. Conclusions: Trajectories of behavior and social cognition differentiate bvFTD from PPD, provided that social cognition is not patient‐reported. Therefore, we stress the need to optimize longitudinal social cognitive assessment in bvFTD. sNfL may be a useful prognostic marker of behavioral progression in neuropsychiatric populations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Plasma phosphorylated tau‐217 (p‐tau217) and neurofilament light (NfL) can differentiate between different dementias in selected cohorts. We aim to test the discrimination potential of these markers in a real‐world cohort. METHODS: We measured p‐tau217 (ALZpath) and NfL (Quanterix) in 415 (unselected) consecutive memory clinic patients. Biomarker levels were dichotomized as low/high to create four biomarker profiles based on p‐tau217 and NfL levels. RESULTS: p‐Tau217 levels were highest in patients with Alzheimer's disease (AD) dementia, whereas NfL levels were highest in patients with frontotemporal dementia (FTD). Low p‐tau217/low NfL was associated mostly with non‐neurological diagnoses (79%), and high p‐tau217/low NfL indicated AD pathology at any stage (84%). Low p‐tau217/high NfL indicated FTD (38%) and high p‐tau217/high NfL indicated AD dementia (87%). DISCUSSION: p‐Tau217 can identify AD pathology at any disease stage. NfL can differentiate FTD from other diagnoses (e.g., AD dementia). Plasma p‐tau217 and NfL can support clinical decision‐making, and we suggest using them as complements to standard clinical assessment. Highlights: Phosphorylated tau‐2017 (p‐tau217) can detect Alzheimer's disease (AD) across the clinical continuum.Neurofilament light (NfL) can differentiate frontotemporal dementia (FTD) from other diagnoses (AD dementia, dementia with Lewy bodies [DLB], and Psychiatry).p‐Tau217 may detect AD co‐pathology in other diseases or dementia types (e.g., DLB).p‐Tau217 and NfL show potential for clinical implementation. [ABSTRACT FROM AUTHOR]

Background: Patients displaying clinical features of behavioural variant of frontotemporal dementia (bvFTD) but lacking both neuroimaging abnormalities and clinical progression are considered to represent the phenocopy syndrome of bvFTD (phFTD). Extensive clinical overlap between early phase bvFTD and phFTD hampers diagnostic distinction. We aimed to assess the diagnostic value of clinician‐rated, self‐reported and caregiver‐reported symptoms for clinical distinction between phFTD and bvFTD. Methods: There were 33 phFTD and 95 probable bvFTD patients included in the study (total N = 128). Clinician‐rated, self‐reported tests and caregiver‐reported symptoms were compared between phFTD and bvFTD on social cognition, behaviour, mood and activities of daily living (ADL). Scores were compared between groups, followed by multiple logistic regression analysis, adjusted for age and sex. Receiver operating characteristic curves were plotted to assess diagnostic value. Results: Using clinician‐rated and self‐reported tests, phFTD patients performed better on facial emotion recognition and reported more depressive symptoms. Caregiver‐reported behavioural symptoms indicated higher behavioural and ADL impairment in phFTD compared to bvFTD. Facial emotion recognition provided highest diagnostic accuracy for distinction of phFTD from bvFTD (area under the curve (AUC) 0.813 95% CI 0.735–0.892, P < 0.001, sensitivity 81%, specificity 74%) followed by depressive symptoms (AUC 0.769 95% 0.674–0.864, P < 0.001 sensitivity 81%, specificity of 63%). Conclusion: Social cognition tests are most suitable for distinction of phFTD from bvFTD. Caregiver‐reported questionnaires and phFTD diagnosis seemed inversely correlated, showing more symptoms in phFTD. Further research is needed on phFTD aetiology and in caregivers taking into account disease burden to assess what explains this discrepancy between clinician‐rated and caregiver‐based tools. [ABSTRACT FROM AUTHOR]

Objective: Methylation of plasma cell‐free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. Methods: cfDNA was isolated from cross‐sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome‐wide methylation of cfDNA was determined using a high‐resolution sequencing technique (MeD‐seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). Results: Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription‐start‐site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin‐dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. Interpretation: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated whether mortality in memory clinic patients changed due to coronavirus disease 2019 (COVID‐19) pandemic. METHODS: We included patients from the Amsterdam Dementia Cohort: (1) n = 923 pandemic patients (baseline visit: 2017–2018, follow‐up: until 2021), and (2) n = 830 historical control patients (baseline visit: 2015–2016, follow‐up: until 2019). Groups were well‐balanced. We compared mortality during pandemic with historical control patients using Cox regression. Differences in cause of death between groups were explored using Fisher's exact test. RESULTS: Pandemic patients had a higher risk of mortality than historical control patients (hazard ratio [HR] [95% confidence interval {CI}] = 1.34 [1.05–1.70]). Stratified for syndrome diagnosis, the effect remained significant in dementia patients (HR [95% CI] = 1.35 [1.03–1.78]). Excluding patients who died of COVID‐19‐infection, the higher mortality risk in pandemic patients attenuated (HR [95% CI] = 1.24 [0.97–1.58]). Only the difference in cause of death between pandemic patients and historical control patients for death to COVID‐19‐infection (p = 0.001) was observed. CONCLUSION: Memory clinic patients had increased mortality risk during COVID‐19 compared to historical control patients, attributable to dementia patients. Highlights: We investigated if mortality rates in memory clinic patients changed due to COVID‐19 pandemic.We included patients along the cognitive continuum, including SCD, MCI, and dementia.We used a well‐balanced historical control group.Memory clinic patients had higher risk for mortality during COVID‐19 lockdown.Our results indicate that excess mortality is mainly caused by death to COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Introduction: We conducted a systematic literature review and meta‐analysis of empirical evidence on expected and experienced implications of sharing Alzheimer's disease (AD) biomarker results with individuals without dementia. Methods: PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Results from included studies were synthesized, and quantitative data on psychosocial impact were meta‐analyzed using a random‐effects model. Results: We included 35 publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta‐analysis of five studies including 2012 participants (elevated amyloid = 1324 [66%], asymptomatic = 1855 [92%]) showed short‐term psychological impact was not significant (random‐effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional stakeholders valued biomarker testing, although attitudes and practices varied considerably. Discussion: Interest in AD biomarker testing was high and sharing their results did not cause psychological harm. Highlights: Most personal stakeholders expressed interest in Alzheimer's disease biomarker assessment.Personal motivations included gaining insight, improving lifestyle, or preparing for the future.There was no short‐term psychological impact of sharing biomarker status, implying it can be safe.Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risk.Harmonized guidelines on biomarker testing and sharing results are required. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The history of frontotemporal dementia (FTD) is both old and new. This study explores its historical roots, dating back to the 19th century, while recognizes it as a distinct neurological entity only a few decades ago. METHODS: This qualitative study and literature review provides an overview of FTD's historical background, birth, evolution, and future directions. RESULTS: Recognition of FTD was hindered by rigid perceptions of dementia, the division between neurology and psychiatry, reliance on IQ‐based assessment, limited neuroimaging capabilities, and lack of pathological proof. Overcoming these barriers involved revisiting early pioneers' approaches, focusing on focal impairment, establishing non‐Alzheimer's disease cohorts, fostering collaboration, and developing diagnostic criteria. Current gaps include the need for biology‐oriented psychiatry education, biological biomarkers, and culturally sensitive, objective clinical instruments predicting underlying pathology. DISCUSSION: Independent multidisciplinary centers are essential. The future of FTD lies in disease‐modifying therapies, presenting new opportunities for healthcare professionals and researchers. [ABSTRACT FROM AUTHOR]

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

The disease trajectory and healthcare requirements of patients with young‐onset dementia (YOD) differ from those of older patients. Accurate data about YOD is crucial to improve diagnosis and optimize care. PRECODE‐GP aims to set up a prospective national database of patients with YOD to gain insight into the occurrence and characteristics of patients with YOD in memory clinics in the Netherlands. The national database includes data from dementia patients aged <70 years at diagnosis, collected by local memory clinics (MCs). Data included demographic information, clinical variables, and (etiological) diagnoses. Between July 2019 and December 2022, 781 patients with a mean age of 62±6y at diagnosis (range 37 to 69y) were included from 39 MCs. Most (n = 547,70%) were diagnosed with dementia due to Alzheimer's disease (AD). Patients with Frontotemporal lobe dementia (FTD, n = 87, 11%) were youngest (61±6.0y). Over half (55%) of patients were experiencing symptoms for ≥2 years. We initiated a Dutch national YOD database to improve diagnosis and care for this underrepresented and vulnerable patient group. The database provides a basis for future in‐depth studies on YOD. [ABSTRACT FROM AUTHOR]

Background: The prevalence of Alzheimer's Disease (AD) increases with age, yet a small fraction of the population reaches ages beyond 100 years maintaining cognitive abilities, so‐called cognitively‐healthy‐centenarians. We aimed to uncover the genetic factors associated with such protection against AD, and to highlight the effects of AD‐associated variants during advanced aging. Method: Previous Genome‐Wide‐Association‐Studies (GWAS) identified 86 single‐nucleotide‐polymorphisms (SNPs) associated with AD‐risk. We investigated the frequency of each SNP in 346 cognitively‐healthy‐centenarians (mean age 101.05±2.51), compared to 2,281 AD cases (mean age 67.96±9.84), 3,165 middle‐aged healthy controls (mean age 62.57±8.66), and we combined the SNPs into Polygenic Risk Scores (PRS) for each individual. Finally, we characterized the functional properties of the SNPs enriched/depleted the most in the centenarians. Result: At the SNP level, centenarians were depleted with risk‐increasing SNPs and enriched with protective SNPs. The AD‐related PRS (excluding APOE SNPs) was significantly lower in centenarians; not only compared to AD (OR = 1.96, p = 4.07×10−26), but also to middle‐aged controls (OR = 1.29, p = 2.61×10−5). When including APOE SNPs these effects were even stronger (OR = 5.07, p = 6.15×10−71, and OR = 1.87, p = 4.67×10−17, for comparisons with AD and normal controls, respectively). The most depleted/enriched SNPs in centenarians functionally mapped to activation/regulation of immune response and endocytosis/phagocytosis. These SNPs were located near ANKH, TMEM106B, CLNK, EPDR1, WDR12, PLCG2, RIN3, CD2AP, MS4A, TREM2, ABCA7 and MAF. Conclusion: The ability to reach advanced age without cognitive decline is influenced by AD‐associated genetic variants. An advantageous regulation of the brain's immune system, intracellular protein trafficking, and endocytosis/phagocytosis may confer the strongest protection against AD and potentially other age‐related diseases. [ABSTRACT FROM AUTHOR]

Interpretation of axonal damage biomarker Neurofilament Light chain (NfL) concentrations is difficult due to the lack of age‐specific and disease‐specific reference values. We here developed an interactive interface to support interpretation of NfL results in human body fluids. We used NfL values of 1698 individuals without a neurological disorder, aged 19–85 years, and patients with MS and dementias. Percentile regression estimates per diagnosis populate interactive graphs, alongside NfL background information (available on: https://mybiomarkers.shinyapps.io/Neurofilament). This accessible interface provides reference for interpretation of the individual patient results for clinicians. It showcases an adaptable method to support interpretation of age‐dependent biomarkers in neurology. [ABSTRACT FROM AUTHOR]

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

Aims: The loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social–emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ‐expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms. Methods: We quantified VENs and GABRQ‐immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD‐TDP) (n = 34), tau (FTLD‐tau) (n = 24) or FUS (FTLD‐FUS) (n = 8) pathology, neurologically healthy controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we quantified VENs and the GABRQ‐expressing population in relation to presence of behavioural symptoms in the first years of disease onset. Results: The number of VENs and GABRQ‐expressing neurons and the ratio of VENs and GABRQ‐expressing neurons over total Layer 5 neuronal population decreased in FTLD‐TDP and FTLD‐FUS, but not in FTLD‐tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count. Conclusion: We show that in FTD, a loss of VENs together with GABRQ‐expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD‐tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD‐tau sample size. Overall, we show the GABRQ‐expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD. [ABSTRACT FROM AUTHOR]

Objective: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features.Methods: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors.Results: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002).Interpretation: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950-961. [ABSTRACT FROM AUTHOR]

Objective: To identify novel CSF biomarkers in GRN‐associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high‐resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor‐type tyrosine‐protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin‐A (CHGA), and V‐set and transmembrane domain‐containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN‐associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We aimed to investigate mutation‐specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT, and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72, MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers. Results: Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC. Interpretation: This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network‐based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease‐tracking and ‐staging in presymptomatic to early‐stage familial FTD. [ABSTRACT FROM AUTHOR]

Follow-up studies on predictive testing for hereditary neurodegenerative diseases mainly focussed on psychological outcomes. We investigated whether the social and personal life of mutation carriers differ negatively from non-carriers and untested at-risk individuals. Asymptomatic individuals (≥ 35 years) who received a genetic test result for Huntington’s disease, frontotemporal dementia or Alzheimer’s disease more than 2 years before the onset of the study and untested subjects at 50% risk were invited to complete a questionnaire and an additional questionnaire with extra or adjusted items. Of the 283 selected individuals, 115 returned a positive informed consent (response rate 39.6%). Of these, 17 carriers, 30 non-carriers and 27 untested persons (n = 74) fulfilled the criteria and completed both questionnaires. We found no significant differences in employment, financial situation and lifestyle or anxiety and depression between carriers and non-carriers or untested individuals at risk. Carriers were more often single and childless, though these differences were not significant. The findings of this study suggest that the result of predictive testing on adult-onset neurodegenerative diseases does not have a large negative effect on social and personal life, although these observations should be interpreted with caution because of the small number of participants and low response rate. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Disease-specific patterns of gray matter atrophy in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) overlap with distinct structural covariance networks (SCNs) in cognitively healthy controls. This suggests that both types of dementia target specific structural networks. Here, we study SCNs in AD and bvFTD. We used structural magnetic resonance imaging data of 31 AD patients, 24 bvFTD patients, and 30 controls from two centers specialized in dementia. Ten SCNs were defined based on structural covariance of gray matter density using independent component analysis. We studied group differences in SCNs using F-tests, with Bonferroni corrected t-tests, adjusted for age, gender, and study center. Associations with cognitive performance were studied using linear regression analyses. Cross-sectional group differences were found in three SCNs (all P < 0.0025). In bvFTD, we observed decreased anterior cingulate network integrity compared with AD and controls. Patients with AD showed decreased precuneal network integrity compared with bvFTD and controls, and decreased hippocampal network and anterior cingulate network integrity compared with controls. In AD, we found an association between precuneal network integrity and global cognitive performance ( P = 0.0043). Our findings show that AD and bvFTD target different SCNs. The comparison of both types of dementia showed decreased precuneal (i.e., default mode) network integrity in AD and decreased anterior cingulate (i.e., salience) network integrity in bvFTD. This confirms the hypothesis that AD and bvFTD have distinct anatomical networks of degeneration and shows that structural covariance gives valuable insights in the understanding of network pathology in dementia. Hum Brain Mapp 37:978-988, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background The neuropathology of behavioural and psychological symptoms is much less understood than the neuropathology of cognitive impairment in AD. On MRI, medial temporal lobe atrophy (MTA) is presumed to reflect Alzheimer- type pathology. White matter hyperintensities (WMH) are considered markers of vascular pathology. Aim We investigated differences in prevalence of behavioural and psychological symptoms in AD according to the presence of MTA and WMH on MRI. Methods Behavioural and psychological symptoms of 111 consecutive AD patients were assessed using the Neuropsychatric Inventory (NPI). Symptoms were considered present when the score was ≥1. On MRI, MTA was rated using the five-point Scheltens-scale and WMH using the four-point Fazekas-scale. Both MRI measures were dichotomised (MTA: absent 0/1, present 2–4; WMH absent 0/1, present 2/3). Results Of the 111 AD patients, 60(55%) had MTA, and 32(29%) had WMH. The presence of MTA was associated with the presence of WMH (χ2 = 11.8, p < 0.001). The prevalence of behavioural and psychological symptoms––defined as a NPI score of ≥1 on at least one symptom––was 74%.The median NPI score of the total study population was 6(0–41). There was no difference in prevalence according to MTA (p = 0.53) or WMH (p = 0.18). On inspection of individual NPI items, neither MTA, nor WMH was related to any of the symptoms. Conclusions There were no differences in prevalence of behavioural and psychological symptoms according to MTA or WMH, as rated on MRI. This suggests that the occurrence of those symptoms depends on other determinants, such as coping style or genetic make-up. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Instrumental Activities of Daily Living in the Screening of Dementia in Population Studies: Comment on Castilla-Rilo," in a 2007 issue of the journal.