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With the advent of the first generation of disease-modifying treatments for Alzheimer's disease, it is clearer now more than ever that the field needs to move toward personalized medicine. Pooling data from past trials may help identify subgroups most likely to benefit from specific treatments and thus inform future trial design. In this perspective, we report on our effort to pool data from past Alzheimer's disease trials to identify patients most likely to respond to different treatments. We delineate challenges and hurdles, from our proof-of-principle study, for which we requested access to trial datasets from various pharmaceutical companies and encountered obstacles in the process of arranging data-sharing agreements through legal departments. Six phase I-III trials from three sponsors provided access to their data (total n = 3170), which included demographic information, vital signs, primary and secondary endpoints, and in a small subset, cerebrospinal fluid amyloid (n = 165, 5.2%) and tau (n = 212, 6.7%). Data could be analyzed only within specific data access platforms, limiting potential harmonization with data provided through other platforms. Limited overlap in terms of outcome measures, clinical and biological information hindered analyses. Thus, while it is a commendable advancement that (some) trials now allow researchers to study their data, we conclude that gaining access to past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals. We provide a plea to promote harmonization and open access to data, by urging trial sponsors and the academic research community alike to remove barriers to data access and improve collaboration through practicing open science and harmonizing outcome measures, to allow investigators to learn all there is to learn from past failures and successes. HIGHLIGHTS: Pooling data from past Alzheimer's disease clinical trials may help identify subgroups most likely to benefit from specific treatments and may help inform future trial design.Accessing past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals.We urge trial sponsors and the academic research community to remove data access barriers and improve collaboration through practicing open science and harmonizing outcome measures.
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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.
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Traumatic brain injury (TBI) and Alzheimer's disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1-42 (Aß42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Lesões Encefálicas Traumáticas , Cognição , Proteínas tau , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/complicações , Biomarcadores/líquido cefalorraquidiano , Masculino , Feminino , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Idoso de 80 Anos ou mais , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Proteína C-Reativa/líquido cefalorraquidiano , Proteínas do Tecido NervosoRESUMO
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by diverse and prominent changes in behavior and personality. One of the greatest challenges in bvFTD is to capture, measure and predict its disease progression, due to clinical, pathological and genetic heterogeneity. Availability of reliable outcome measures is pivotal for future clinical trials and disease monitoring. Detection of change should be objective, clinically meaningful and easily assessed, preferably associated with a biological process. The purpose of this scoping review is to examine the status of longitudinal studies in bvFTD, evaluate current assessment tools and propose potential progression markers. A systematic literature search (in PubMed and Embase.com) was performed. Literature on disease trajectories and longitudinal validity of frequently-used measures was organized in five domains: global functioning, behavior, (social) cognition, neuroimaging and fluid biomarkers. Evaluating current longitudinal data, we propose an adaptive battery, combining a set of sensitive clinical, neuroimaging and fluid markers, adjusted for genetic and sporadic variants, for adequate detection of disease progression in bvFTD.
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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.
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Demência Frontotemporal , Testes Neuropsicológicos , Cognição Social , Humanos , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/psicologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Cuidadores/psicologia , Atividades Cotidianas/psicologia , Diagnóstico Diferencial , Autorrelato , FenótipoRESUMO
BACKGROUND: Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development. METHODS: We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01-01-2017 and 01-01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type. RESULTS: We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aß (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers. CONCLUSIONS: As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.
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Doença de Alzheimer , Biomarcadores , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Ensaios Clínicos como Assunto/métodos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangueRESUMO
BACKGROUND AND OBJECTIVES: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. METHODS: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (ßtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. RESULTS: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (ßtime range -0.30 to -0.71), followed by delayed word list recognition (ßtime range -0.18 to -0.50). Functional decline (ßtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (ßtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. DISCUSSION: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
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Doença de Alzheimer , Feminino , Humanos , Masculino , Doença de Alzheimer/diagnóstico por imagem , Apolipoproteína E4/genética , Proteínas Amiloidogênicas , Biomarcadores , CogniçãoRESUMO
BACKGROUND: Behavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning. RESULTS: Compared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca's area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001). CONCLUSIONS: Our findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.
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In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer's disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers.
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Doença de Alzheimer , Encefalopatia Traumática Crônica , Futebol , Esportes , Masculino , Humanos , Encéfalo/diagnóstico por imagemRESUMO
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.
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Doença de Alzheimer , Demência Frontotemporal , Humanos , Demência Frontotemporal/psicologia , Testes Neuropsicológicos , Reconhecimento Psicológico , Emoções , Cognição , Doença de Alzheimer/diagnósticoRESUMO
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.
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Doença de Alzheimer , Apatia , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Registros Eletrônicos de Saúde , Processamento de Linguagem Natural , Testes NeuropsicológicosRESUMO
INTRODUCTION: In the context of the development of pharmaceutical interventions, expectations and experiences of participants are essential. Their insights may be particularly helpful to address the challenges of recruiting and retaining participants for Alzheimer's disease (AD) clinical trials. We examined clinical trial participants' experiences to optimize trial design in Alzheimer's disease (AD). METHOD: In this mixed-methods study, we included adults who participated in sponsor-initiated AD trials at Brain Research Center, a clinical trial organization in the Netherlands. Participants (N = 71, age 69 ± 6.5, 54%F, 19 cognitively normal (CN), 19 mild cognitive impairment (MCI), and 33 AD dementia) first completed an online survey. Diagnostic group differences were investigated using chi-square tests or one-way ANOVAs. Next, a subsample (N = 12; 8 = CN, 4 = MCI) participated in focus groups to gain in-depth insight into their opinions on optimizing trial design from a participants' point of view. Audio recordings from focus group interviews were transcribed verbatim and analyzed by thematic content analysis by two independent researchers. RESULTS: Most reported motives for enrolment included "to benefit future generations" (89%), followed by "for science" (66%) and "better monitoring" (42%). Frequent suggestions for increasing willingness to participate included a smaller chance to receive placebo (n = 38, 54%), shorter travel times (n = 27, 38%), and sharing individual results of different assessments (n = 57, 80%), as well as receiving trial results (n = 52, 73). Highest visual analogue burden scores (0-100) were found for the lumbar puncture (M = 47.2, SD = 38.2) and cognitive assessments (M = 27.2, SD = 25.7). Results did not differ between diagnostic groups, nor between patient and caregiver participants (all p-values>.05). Two additional themes emerged from the focus groups: "trial design," such as follow-up visit(s) after participating, and "trial center," including the relevance of a professional and empathic staff. CONCLUSION: Relevant factors include expectation management and careful planning of high-burden assessments, provision of individual feedback, and prioritizing professionalism and empathy throughout conduct of the trial. Our findings provide insight into participants' priorities to increase willingness to participate and can be used to optimize trial success.
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Doença de Alzheimer , Ensaios Clínicos como Assunto , Disfunção Cognitiva , Idoso , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/diagnóstico , Encéfalo , Disfunção Cognitiva/psicologia , Países Baixos , Projetos de PesquisaRESUMO
The clinical overlap of frontotemporal dementia and primary psychiatric diseases hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. Neurofilament light chain has shown great potential in CSF and blood for the distinction of frontotemporal dementia from primary psychiatric diseases. Measurement of neurofilament light chain in urine would be even more patient-friendly. We aimed to test the performance of neurofilament light chain urine measurements for diagnostics in frontotemporal dementia and to assess their correlation with serum levels. Fifty-five subjects (n = 19 frontotemporal dementia, n = 19 primary psychiatric diseases and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analysed with the ultrasensitive single molecule array neurofilament light chain assay. Neurofilament light chain group comparisons were performed adjusted for age, sex and geriatric depression scale. In the majority of the cohort, neurofilament light chain concentrations were not detectable in urine (n = 6 samples above lower limit of detection (0.038â pg/ml): n = 5 frontotemporal dementia, n = 1 primary psychiatric disease). The frequency of a detectable neurofilament light chain level in urine in the frontotemporal dementia group did not differ from psychiatric disorders (Fisher Exact-test P = 0.180). In the individuals with detectable urine neurofilament light chain values, there was no correlation between the urine and serum neurofilament light chain levels. As expected, serum neurofilament light chain levels were higher in frontotemporal dementia compared to primary psychiatric diseases and controls (P < 0.001), adjusted for age, sex and geriatric depression scale. Receiver operating characteristic curve analysis of serum neurofilament light chain of frontotemporal dementia versus primary psychiatric diseases showed an area under the curve of 0.978 95% confidence interval 0.941-1.000, P < 0.001. Urine is not suitable as a matrix for neurofilament light chain analysis and serum neurofilament light chain is still the most patient-friendly matrix for differentiation between frontotemporal dementia and primary psychiatric diseases.
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Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989 .
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Doença de Alzheimer , Proteínas tau , Humanos , Proteínas tau/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Oligonucleotídeos Antissenso/uso terapêutico , Resultado do Tratamento , Método Duplo-CegoRESUMO
BACKGROUND: Adequate detection of symptoms and disease progression in behavioural variant frontotemporal dementia (bvFTD) is complex. Dementia cohorts usually utilize cognitive and functional measures, which fail to detect dominant behavioural and social cognitive deficits in bvFTD. Moreover, since patients typically have a loss of insight, caregivers are important informants. This is the first qualitative study to investigate caregiver relevant symptoms during the disease course of bvFTD, aiming to improve tools for diagnosis, progression, and future clinical trials. METHODS: Informal caregivers of patients in different disease stages of bvFTD (N = 20) were recruited from the neurology outpatient clinic of the Amsterdam UMC and a patient organization for peer support in the Netherlands. Their perspectives on clinical relevance were thoroughly explored during individual semi-structured interviews. Inductive content analysis with open coding was performed by two researchers independently to establish overarching themes and patterns. RESULTS: Caregivers reported a variety of symptoms, in which (i) loss of emotional connection, (ii) preoccupation and restlessness, and (iii) apathy and dependency compose major themes of relevance for diagnosis and treatment. Within heterogeneous disease trajectories, symptom presence differed between stages and among individuals, which is relevant in the context of progression and outcome measures. Significant socio-emotional changes dominated in early stages, while severe cognitive, behavioural, and physical deterioration shifted focus from predominant personality change to quality of life in later stages. CONCLUSIONS: Caregiver perspectives on target symptoms in bvFTD differ according to clinical stage and patient-caregiver characteristics, with significant socio-emotional changes characterizing early stages. These findings call for more appropriate tools and symptomatic treatments, as well as a personalized approach in treatment of bvFTD and a focus on early stage interventions in clinical trial design.
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Cuidadores , Demência Frontotemporal , Humanos , Cuidadores/psicologia , Gerenciamento Clínico , Demência Frontotemporal/psicologia , Demência Frontotemporal/terapia , Ensaios Clínicos como Assunto , Projetos de PesquisaRESUMO
Introduction: Traumatic brain injury (TBI) has been associated with a greater risk of developing Alzheimer's disease (AD). Less is known about the clinical features of AD patients with TBI history. The objective of this study was to examine whether a history of TBI and specific injury characteristics are associated with differences in age of disease onset, cognitive features, and neuropsychiatric symptoms (NPSs) in AD patients. Methods: Biomarker-proven AD patients (CSF or amyloid PET) were selected from the Amsterdam Dementia Cohort. TBI events were classified by age at injury (TBI <25 or ≥25 years) and TBI severity (loss of consciousness, multiple events). Cognitive composite scores were calculated from results of a neuropsychological test battery. NPSs were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). Linear regression analyses were utilized to examine associations between TBI, TBI characteristics, and clinical outcome measures. Results: Among the 1,755 selected AD patients (mean age = 65.2 years), 166 (9.5%) had documented ≥1 TBI in their medical history. Overall, TBI history was not related to differences in age of disease onset, but age at injury <25 years old was associated with 2.3 years earlier age at symptom onset (B = -2.34, p = 0.031). No significant associations were found between TBI history or TBI characteristics and differences in cognition or NPSs. Conclusion: Our results underscore previous findings on the vulnerability of the brain during critical maturation phases and suggest that an early TBI may contribute to lower resilience to neurodegenerative changes.
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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.
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Axônios , Filamentos Intermediários , Humanos , Valores de Referência , BiomarcadoresRESUMO
BACKGROUND: Repetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study. METHODS: NEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw. RESULTS: To date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023. CONCLUSIONS: The NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.
Assuntos
Lesões Encefálicas Traumáticas , Lesão Encefálica Crônica , Encefalopatia Traumática Crônica , Biomarcadores , Encéfalo/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesão Encefálica Crônica/diagnóstico , Lesão Encefálica Crônica/etiologia , Encefalopatia Traumática Crônica/diagnóstico por imagem , Encefalopatia Traumática Crônica/etiologia , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid ß deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. METHODS: We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. RESULTS: We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid ß and tau. Interestingly, the percentage of amyloid ß targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. CONCLUSIONS: Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials.