Inez H. G. B. Ramakers

Background: There is an urgent need to better understand the mechanisms of dementia, particularly Alzheimer's disease (AD), the most common subtype. The BioBank Alzheimer Center Limburg (BBACL) study is an ongoing prospective cohort, including consecutive patients from the memory clinic of the Alzheimer Center Limburg, Maastricht University Medical Center+, the Netherlands. It aims to investigate the natural course of cognitive complaints and identify early clinical and biological determinants of disease progression. Objective: To describe the BBACL study design and procedures and present the baseline characteristics of the currently included participants. Methods: Patients undergo standardized assessment, including demographics, comorbidities, cognitive and functional assessments, neuropsychiatric symptoms, MRI cerebrum, and biomaterials [blood and cerebrospinal fluid (CSF) samples (subset)]. Additional blood and CSF samples are stored for future biomarkers research. Follow-up is scheduled at 1, 2, 5, and 10 years. Results: Since its start in 2009, 920 patients have been included at baseline. The mean baseline age was 68.4 (SD 11.3) years, with 41.6% being females. The mean Mini-Mental State Examination score was 27.0 (SD 2.6). At baseline, 39.6% had subjective cognitive decline, 40.0% mild cognitive impairment, and 20.4% dementia (58.0% probable/possible AD and 19.7% mixed AD/vascular dementia), reflecting the study's emphasis on early diagnostics. Cognitive, functional, and biomarker measures varied across diagnostic groups as expected. Conclusions: BBACL combines extensive biospecimens with rich multimodal phenotyping and longitudinal follow-up, creating opportunities for future integrative analyses and omics-based analyses to uncover novel biological signatures.

Objectives: Memory Clinics (MCs) have a central role in multidisciplinary diagnostics and care of cognitive disorders and dementia. This study describes current clinical practice and developments of Dutch MCs since their start in 1986. Methods: A survey was sent to all Dutch hospital-based MCs in 1998, 2004, 2009, 2017 and 2023. Topics included: organization, patient characteristics, scales and questionnaires, neuropsychological assessment, additional assessments, novel biomarkers, disclosure of diagnosis and treatment. 74 out of the total of 89 MCs completely or partially filled out the questionnaire. Results: The number of MCs increased to 89. The number of patients seen increased substantially (per MC/year: 1998: 130; 2023: 324; total: 1998: 1560; 2023: 28,848). The proportion of patients diagnosed with dementia decreased from 80% in 1998 to 47% in 2023. Most commonly available assessments were neuroimaging (100%), routine laboratory testing of blood (98%) and neuropsychological assessment (NPA; 98%). Thirty-one percent indicated infrastructure needed to be changed before prescribing monoclonal antibody treatments for Alzheimer’s disease. Conclusions: MCs showed substantial development in number, number of patients and geographical distribution within the country. Nowadays, MCs are central care facilities for the timely and multidisciplinary diagnosis and treatment of people with cognitive disorders and dementia.

Objective: We examined the user experience in different modalities (face-to-face, semi-automated phone-based, and fully automated phone-based) of cognitive testing in people with subjective cognitive decline and mild cognitive impairment. Method: A total of 67 participants from the memory clinic of the Maastricht University Medical Center+ participated in the study. The study consisted of cognitive tests in different modalities, namely, face-to-face, semi-automated phone-based guided by a researcher, and fully automated phone-based without the involvement of a researcher. After each assessment, a user experience questionnaire was administered, including questions about, for example, satisfaction, simplicity, and missing personal contact, on a seven-point Likert scale. Non-parametric tests were used to compare user experiences across different modalities. Results: In all modalities, user experiences were rated above average. The face-to-face ratings were comparable to the ratings of the semi-automated phone-based assessment, except for the satisfaction and recommendation items, which were rated higher for the face-to-face assessment. The face-to-face assessment was preferred above the fully automated phone-based assessment on all items. In general, the semi- and fully automated phone-based assessments were comparable (simplicity, conceivability, quality of sound, visiting the hospital, and missing personal contact), while on all the other items, the semi-automated phone-based assessment was preferred. Conclusions: User experience was rated high within all modalities. Simplicity, conceivability, comfortability, and participation scores were comparable in the semi-automated phone-based and face-to-face assessment. Based on these findings and earlier research on validation of the semi-automated phone-based assessment, the semi-automated assessment could be useful for screening for clinical trials, and after more research, in clinical practice.

Het neuropsychologisch onderzoek op de Nederlandse geheugenpoli: De Neuropsychologie Monitor 2023: Het neuropsychologisch onderzoek (NPO) is een belangrijke pijler in de vroegtijdige diagnostiek van cognitieve stoornissen op een Geheugenpoli (GP). Het doel van deze studie was het in kaart brengen van de kenmerken en werkwijzen omtrent het NPO binnen Nederlandse GP's. In juli 2023 werd de Neuropsychologie Monitor 2023 verspreid onder alle (neuro)psychologen van Nederlandse GP's. Deze NPO-monitor omvatte 61 inhoudelijke en procesmatige vragen over het NPO. Van de 73 gecontacteerde psychologen namen er 69 (95%) deel aan de NPO-monitor 2023. Tests voor de cognitieve domeinen geheugen, aandacht en executief functioneren bleken merendeels een standaardonderdeel te zijn van de testbatterij op de geheugenpoli. Taal (93%) en praxis (87%) werden meestal ook gemeten. Intelligentie (62%), symptoomvaliditeit (54%), perceptie (36%) en sociale cognitie (21%) maakten minder vaak deel uit van de testbatterij. Er bleek een grote variatie in de gebruikte tests en in vragenlijsten voor stemming, angst en dagelijks functioneren, als ook in de keuze voor aanvullende tests bij het vermoeden van een bepaalde onderliggende pathologie. Deze resultaten wijzen erop dat een richtlijn voor een geharmoniseerde kernbatterij van neuropsychologische tests en vragenlijsten – met daarnaast ruimte voor persoonsgerichte uitbreiding en aanpassing – wenselijk is.

Background: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer’s disease (AD) dementia. Methods: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants’ performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. Discussion: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. Trial registration: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

Background: Previous research has shown that verbal memory accurately measures cognitive decline in the early phases of neurocognitive impairment. Automatic speech recognition from the verbal learning task (VLT) can potentially be used to differentiate between people with and without cognitive impairment. Objective: Investigate whether automatic speech recognition (ASR) of the VLT is reliable and able to differentiate between subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Methods: The VLT was recorded and processed via a mobile application. Following, verbal memory features were automatically extracted. The diagnostic performance of the automatically derived features was investigated by training machine learning classifiers to distinguish between participants with SCD versus MCI/dementia. Results: The ICC for inter-rater reliability between the clinical and automatically derived features was 0.87 for the total immediate recall and 0.94 for the delayed recall. The full model including the total immediate recall, delayed recall, recognition count, and the novel verbal memory features had an AUC of 0.79 for distinguishing between participants with SCD versus MCI/dementia. The ten best differentiating VLT features correlated low to moderate with other cognitive tests such as logical memory tasks, semantic verbal fluency, and executive functioning. Conclusions: The VLT with automatically derived verbal memory features showed in general high agreement with the clinical scoring and distinguished well between SCD and MCI/dementia participants. This might be of added value in screening for cognitive impairment.

Background: Vascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.Method: Functional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.Result: Activation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.Conclusion: Brain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.

Background: Early diagnosis of Alzheimer’s disease (AD) is important to promote timely and optimal management. Currently, the diagnosis of AD involves the use of amyloid PET scan or biomarker‐based cerebrospinal fluid analyses. These tests are invasive and expensive therefore limiting their usage as a front‐line screener. Thus, there is a need for non‐invasive and cost‐effective tools to diagnose subjects in early stages of the disease. With the TearAD study, we propose using the eye as the window to the brain. The eye is closely connected to the brain through the optic nerve. Tears contain thousands of molecules and protein secretion in the lacrimal gland is regulated by (para‐)sympathetic innervation. A study performed by our group demonstrated that proteins associated with AD (Aβ38, Aβ40 and Aβ42, total‐tau and phosphor‐tau) are detectable in tear fluid (Gijs et al., 2021, Scientific reports). Tear total‐tau levels were significantly elevated in dementia patients compared to people with subjective cognitive decline (SCD). Besides changes in tear protein content, retinal abnormalities have been observed in AD patients, which include retinal nerve fiber thinning and optic nerve degeneration. This observational longitudinal multicenter study aims to evaluate diagnostic accuracy measures of tear and retinal biomarkers to discriminate individuals with and without neurodegeneration.Methods: A total of 200 subjects will be included, of which 100 with and 100 without neurodegeneration. The study includes three visits (baseline, 12 months, and 24 months). The tear fluid will be collected non‐invasively with a Schirmer strip. Retinal images will be obtained by a standard, ultra‐wide field (Optos) and hyperspectral (Optina) fundus camera. Additionally, cross‐sectional images of the retina will be obtained through optical coherence tomography. Protein levels in tear fluid will be determined using multiplex immunoassays.Results: Inclusion for baseline started in June 2022 and is expected to complete in June 2023. Currently (Jan, 2023) we included a total of 115 participants. Which consist of 50 cognitively healthy controls, 25 patients with SCD, 17 patients with mild cognitive impairment and 13 patients with dementia.Conclusion: The TearAD study will provide insight into the diagnostic accuracy of using tear and retinal biomarkers for screening and diagnosis of AD.