Neuropsychiatric symptoms are associated with exacerbated cognitive impairment in covert cerebral small vessel disease.

OBJECTIVES: Neuropsychiatric symptoms are related to disease progression and cognitive decline over time in cerebral small vessel disease (SVD) but their significance is poorly understood in covert SVD. We investigated neuropsychiatric symptoms and their relationships between cognitive and functional abilities in subjects with varying degrees of white matter hyperintensities (WMH), but without clinical diagnosis of stroke, dementia or significant disability. METHODS: The Helsinki Small Vessel Disease Study consisted of 152 subjects, who underwent brain magnetic resonance imaging (MRI) and comprehensive neuropsychological evaluation of global cognition, processing speed, executive functions, and memory. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory Questionnaire (NPI-Q, n = 134) and functional abilities with the Amsterdam Instrumental Activities of Daily Living questionnaire (A-IADL, n = 132), both filled in by a close informant. RESULTS: NPI-Q total score correlated significantly with WMH volume (rs = 0.20, p = 0.019) and inversely with A-IADL score (rs = -0.41, p < 0.001). In total, 38% of the subjects had one or more informant-evaluated neuropsychiatric symptom. Linear regressions adjusted for age, sex, and education revealed no direct associations between neuropsychiatric symptoms and cognitive performance. However, there were significant synergistic interactions between neuropsychiatric symptoms and WMH volume on cognitive outcomes. Neuropsychiatric symptoms were also associated with A-IADL score irrespective of WMH volume. CONCLUSIONS: Neuropsychiatric symptoms are associated with an accelerated relationship between WMH and cognitive impairment. Furthermore, the presence of neuropsychiatric symptoms is related to worse functional abilities. Neuropsychiatric symptoms should be routinely assessed in covert SVD as they are related to worse cognitive and functional outcomes.

Synergistic associations of cognitive and motor impairments with functional outcome in covert cerebral small vessel disease.

BACKGROUND: Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their combined effects on functional outcome have not been elucidated. This study investigated the interactions and mediating effects of cognitive and motor functions on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH). METHODS: Participants of the Helsinki Small Vessel Disease Study (n = 152) were assessed according to an extensive clinical, physical, neuropsychological and MRI protocol. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. RESULTS: Cognitive (global cognition, executive functions, processing speed, memory) and motor functions (gait speed, single-leg stance, timed up-and-go) had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on informant-evaluated IADL, but not on self-evaluated quality of life. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance. CONCLUSION: The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than their individual effects. Patients with both impairments are at disproportionate risk for poor outcome. WMH and brain atrophy contribute to disability through cognitive and motor impairment.

Associations of cognitive reserve and psychological resilience with cognitive functioning in subjects with cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is characterized by progressive white matter hyperintensities (WMH) and cognitive decline. However, variability exists in how individuals maintain cognitive capabilities despite significant neuropathology. The relationships between individual cognitive reserve, psychological resilience and cognitive functioning were examined in subjects with varying degrees of WMH. METHODS: In the Helsinki Small Vessel Disease Study, 152 subjects (aged 65-75 years) underwent a comprehensive neuropsychological assessment, evaluation of subjective cognitive complaints and brain magnetic resonance imaging with volumetric WMH evaluation. Cognitive reserve was determined by education (years) and the modified Cognitive Reserve Scale (mCRS). Psychological resilience was evaluated with the Resilience Scale 14. RESULTS: The mCRS total score correlated significantly with years of education (r = 0.23, p < 0.01), but it was not related to age, sex or WMH volume. Together, mCRS score and education were associated with performance in a wide range of cognitive domains including processing speed, executive functions, working memory, verbal memory, visuospatial perception and verbal reasoning. Independently of education, the mCRS score had incremental predictive value on delayed verbal recall and subjective cognitive complaints. Psychological resilience was not significantly related to age, education, sex, WMH severity or cognitive test scores, but it was associated with subjective cognitive complaints. CONCLUSIONS: Cognitive reserve has strong and consistent associations with cognitive functioning in subjects with WMH. Education is widely associated with objective cognitive functioning, whereas lifetime engagement in cognitively stimulating leisure activities (mCRS) has independent predictive value on memory performance and subjective cognitive complaints. Psychological resilience is strongly associated with subjective, but not objective, cognitive functioning.

A novel CT-based automated analysis method provides comparable results with MRI in measuring brain atrophy and white matter lesions.

PURPOSE: Automated analysis of neuroimaging data is commonly based on magnetic resonance imaging (MRI), but sometimes the availability is limited or a patient might have contradictions to MRI. Therefore, automated analyses of computed tomography (CT) images would be beneficial. METHODS: We developed an automated method to evaluate medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and the severity of white matter lesions (WMLs) from a CT scan and compared the results to those obtained from MRI in a cohort of 214 subjects gathered from Kuopio and Helsinki University Hospital registers from 2005 - 2016. RESULTS: The correlation coefficients of computational measures between CT and MRI were 0.9 (MTA), 0.82 (GCA), and 0.86 (Fazekas). CT-based measures were identical to MRI-based measures in 60% (MTA), 62% (GCA) and 60% (Fazekas) of cases when the measures were rounded to the nearest full grade variable. However, the difference in measures was 1 or less in 97-98% of cases. Similar results were obtained for cortical atrophy ratings, especially in the frontal and temporal lobes, when assessing the brain lobes separately. Bland-Altman plots and weighted kappa values demonstrated high agreement regarding measures based on CT and MRI. CONCLUSIONS: MTA, GCA, and Fazekas grades can also be assessed reliably from a CT scan with our method. Even though the measures obtained with the different imaging modalities were not identical in a relatively extensive cohort, the differences were minor. This expands the possibility of using this automated analysis method when MRI is inaccessible or contraindicated.

Global Burden of Small Vessel Disease-Related Brain Changes on MRI Predicts Cognitive and Functional Decline.

Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P<0.001 for global cognitive function, processing speed, executive functions, and memory and P<0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes (P<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.

Evaluating severity of white matter lesions from computed tomography images with convolutional neural network.

PURPOSE: Severity of white matter lesion (WML) is typically evaluated on magnetic resonance images (MRI), yet the more accessible, faster, and less expensive method is computed tomography (CT). Our objective was to study whether WML can be automatically segmented from CT images using a convolutional neural network (CNN). The second aim was to compare CT segmentation with MRI segmentation. METHODS: The brain images from the Helsinki University Hospital clinical image archive were systematically screened to make CT-MRI image pairs. Selection criteria for the study were that both CT and MRI images were acquired within 6 weeks. In total, 147 image pairs were included. We used CNN to segment WML from CT images. Training and testing of CNN for CT was performed using 10-fold cross-validation, and the segmentation results were compared with the corresponding segmentations from MRI. RESULTS: A Pearson correlation of 0.94 was obtained between the automatic WML volumes of MRI and CT segmentations. The average Dice similarity index validating the overlap between CT and FLAIR segmentations was 0.68 for the Fazekas 3 group. CONCLUSION: CNN-based segmentation of CT images may provide a means to evaluate the severity of WML and establish a link between CT WML patterns and the current standard MRI-based visual rating scale.

Automatically computed rating scales from MRI for patients with cognitive disorders.

OBJECTIVES: The aims of this study were to examine whether visual MRI rating scales used in diagnostics of cognitive disorders can be estimated computationally and to compare the visual rating scales with their computed counterparts in differential diagnostics. METHODS: A set of volumetry and voxel-based morphometry imaging biomarkers was extracted from T1-weighted and FLAIR images. A regression model was developed for estimating visual rating scale values from a combination of imaging biomarkers. We studied three visual rating scales: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and white matter hyperintensities (WMHs) measured by the Fazekas scale. Images and visual ratings from the Amsterdam Dementia Cohort (ADC) (N = 513) were used to develop the models and cross-validate them. The PredictND (N = 672) and ADNI (N = 752) cohorts were used for independent validation to test generalizability. RESULTS: The correlation coefficients between visual and computed rating scale values were 0.83/0.78 (MTA-left), 0.83/0.79 (MTA-right), 0.64/0.64 (GCA), and 0.76/0.75 (Fazekas) in ADC/PredictND cohorts. When performance in differential diagnostics was studied for the main types of dementia, the highest balanced accuracy, 0.75-0.86, was observed for separating different dementias from cognitively normal subjects using computed GCA. The lowest accuracy of about 0.5 for all the visual and computed scales was observed for the differentiation between Alzheimer's disease and frontotemporal lobar degeneration. Computed scales produced higher balanced accuracies than visual scales for MTA and GCA (statistically significant). CONCLUSIONS: MTA, GCA, and WMHs can be reliably estimated automatically helping to provide consistent imaging biomarkers for diagnosing cognitive disorders, even among less experienced readers. KEY POINTS: • Visual rating scales used in diagnostics of cognitive disorders can be estimated computationally from MRI images with intraclass correlations ranging from 0.64 (GCA) to 0.84 (MTA). • Computed scales provided high diagnostic accuracy with single-subject data (area under the receiver operating curve range, 0.84-0.94).

Association between Deep Gray Matter Changes and Neurocognitive Function in Mild Cognitive Impairment and Alzheimer's Disease: A Tensor-Based Morphometric MRI Study.

BACKGROUND: Atrophy of the deep gray matter (DGM) has been associated with a risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the degree of cognitive impairment. However, specific knowledge of the associations between degenerative DGM changes and neurocognitive functions remains limited. OBJECTIVE: To examine degenerative DGM changes and evaluate their association with neurocognitive functions. METHOD: We examined DGM volume changes with tensor-based morphometry (TBM) and analyzed the relationships between DGM changes and neurocognitive functions in control (n = 58), MCI (n = 38), and AD (n = 58) groups with multiple linear regression analyses. RESULTS: In all DGM areas, the AD group had the largest changes in TBM volume. The differences in TBM volume changes were larger between the control group and the AD group than between the other pairs of groups. In the AD group, volume changes of the right thalamus were significantly associated with episodic memory, learning, and semantic processing. Significant or trend-level associations were identified between bilateral caudate nucleus changes and episodic memory as well as semantic processing. In the control and MCI groups, very few significant associations emerged. CONCLUSIONS: Atrophy of the DGM structures, especially the thalamus and caudate nucleus, is related to cognitive impairment in AD. DGM atrophy is associated with tests reflecting both subcortical and cortical cognitive functions.

White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study.

BACKGROUND: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD. OBJECTIVE: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data. METHODS: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86). RESULTS: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically. CONCLUSIONS: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.

Longitudinal changes in the brain in mild cognitive impairment: a magnetic resonance imaging study using the visual rating method and tensor-based morphometry.

Background Brain atrophy is associated with mild cognitive impairment (MCI), and by using volumetric and visual analyzing methods, it is possible to differentiate between individuals with progressive MCI (MCIp) and stable MCI (MCIs). Automated analysis methods detect degenerative changes in the brain earlier and more reliably than visual methods. Purpose To detect and evaluate structural brain changes between and within the MCIs, MCIp, and control groups during a two-year follow-up period. Material and Methods Brain magnetic resonance imaging (MRI) scans of 11 participants with MCIs, 18 participants with MCIp, and 84 controls were analyzed by the visual rating method (VRM) and tensor-based morphometry (TBM). Results At baseline, both VRM and TBM differentiated the whole MCI group (combined MCIs and MCIp) and the MCIp group from the control group, but they did not differentiate the MCIs group from the control group. At follow-up, both methods differentiated the MCIp group from the control group, but minor differences between the MCIs and control groups were only seen by TBM. Neuropsychological tests did not find differences between the MCIs and control groups at follow-up. Neither method revealed relevant signs of brain atrophy progression within or between MCI subgroups during the follow-up time. Conclusion Both methods are equally good in the evaluation of structural brain changes in MCI if the groups are sufficiently large and the disease progresses to AD. Only TBM disclosed minor atrophic changes in the MCIs group compared to controls at follow-up. The results need to be confirmed with a large patient group and longer follow-up time.

Visual rating method and tensor-based morphometry in the diagnosis of mild cognitive impairment and Alzheimer's disease: a comparative magnetic resonance imaging study.

BACKGROUND: Atrophy of the medial temporal lobe (MTL) is the main structural magnetic resonance imaging (MRI) finding in the brain of patients with Alzheimer's disease (AD). However, evaluating the degree of atrophy is still demanding. PURPOSE: The visual rating method (VRM) was compared with multi-template tensor-based morphometry (TBM), in terms of its efficacy in diagnosing of mild cognitive impairment (MCI) and AD. MATERIAL AND METHODS: Forty-seven patients with MCI, 80 patients with AD and 84 controls were studied. RESULTS: TBM seems to be more sensitive than VRM at the early stage of dementia in the areas of MTL and ventricles. The methods were equally good in distinguishing controls and the MCI group from the AD group. At the frontal areas TBM was better than VRM in all comparisons. CONCLUSION: A user-friendly VRM is still useful for the clinical evaluation of MCI patients, but multi-template TBM is more sensitive for diagnosing the early stages of dementia. However, TBM is currently too demanding to use for daily clinical work.

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus.

OBJECTIVES: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. METHODS: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. RESULTS: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58). CONCLUSIONS: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

Comparing predictors of conversion to Alzheimer's disease using the disease state index.

BACKGROUND: The Disease State Index (DSI) is a method which interprets data originating from multiple different sources, assisting the clinician in the diagnosis and follow-up of dementia diseases. OBJECTIVE: We compared the differences in accuracy in differentiating stable mild cognitive impairment (S-MCI) and progressive MCI (P-MCI) obtained from different data combinations using the DSI. METHODS: We investigated 212 cases with S-MCI and 165 cases with P-MCI from the Alzheimer's Disease Neuroimaging Initiative cohort. Data from neuropsychological tests, cerebrospinal fluid, apolipoprotein E (APOE) genotype, magnetic resonance imaging (MRI) and positron emission tomography (PET) were included. RESULTS: The combination of all parameters gave the highest accuracy (accuracy 0.70, sensitivity 0.71, specificity 0.68). In the different categories, neuropsychological tests (0.65, 0.65, 0.65) and hippocampal volumetry (0.66, 0.66, 0.66) achieved the highest accuracy. CONCLUSION: In addition to neuropsychological testing, MRI is recommended to be included for differentiating S-MCI from P-MCI. APOE genotype, CSF and PET may provide some additional information.

cCOG Web-Based Cognitive Assessment Tool.

Cognitive testing is an essential part of clinical diagnostics and clinical trials in Alzheimer's disease. Digital cognitive tests hold a great opportunity to provide more versatile and cost-efficient patient pathways through flexible testing including at home. In this work, we describe a web-based cognitive test, cCOG, that can be used in screening, differential diagnosis, and monitoring the progression of neurodegenerative diseases.

Frontal white and gray matter abnormality in gambling disorder: A multimodal MRI study.

Background: Changes in brain structural connections appear to be important in the pathophysiology of substance use disorders, but their role in behavioral addictions, such as gambling disorder (GD), is unclear. GD also offers a model to study addiction mechanisms without pharmacological confounding factors. Here, we used multimodal MRI data to examine the integrity of white matter connections in individuals with GD. We hypothesized that the affected areas would be in the fronto-striatal-thalamic circuit. Methods: Twenty individuals with GD (mean age: 64 years, GD duration: 15.7 years) and 40 age- and sex-matched healthy controls (HCs) underwent detailed clinical examinations together with brain 3T MRI scans (T1, T2, FLAIR and DWI). White matter (WM) analysis involved fractional anisotropy and lesion load, while gray matter (GM) analysis included voxel- and surface-based morphometry. These measures were compared between groups, and correlations with GD-related behavioral characteristics were examined. Results: Individuals with GD showed reduced WM integrity in the left and right frontal parts of the corona radiata and corpus callosum (pFWE < 0.05). WM gambling symptom severity (SOGS score) was negatively associated to WM integrity in these areas within the left hemisphere (p < 0.05). Individuals with GD also exhibited higher WM lesion load in the left anterior corona radiata (pFWE < 0.05). GM volume in the left thalamus and GM thickness in the left orbitofrontal cortex were reduced in the GD group (pFWE < 0.05). Conclusions: Similar to substance addictions, the fronto-striatal-thalamic circuit is also affected in GD, suggesting that this circuitry may have a crucial role in addictions, independent of pharmacological substances.

Computerized decision support is an effective approach to select memory clinic patients for amyloid-PET.

BACKGROUND: The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET. METHODS: We included 286 subjects (135 controls, 108 Alzheimer's disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients. RESULTS: The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%). CONCLUSION: Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aß deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aß-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aß pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Use of a digital tool to support the diagnostic process in memory clinics-a usability study.

BACKGROUND: Both memory clinic professionals and patients see value in digital tools, yet these hardly find their way to clinical practice. We explored the usability of a digital tool to support the diagnostic work-up in daily memory clinic practice. We evaluated four modules that integrate multi-modal patient data (1.cognitive test; cCOG, and 2. MRI quantification; cMRI) into useful diagnostic information for clinicians (3. cDSI) and understandable and personalized information for patients (4. patient report). METHODS: We conducted a mixed-methods study in five Dutch memory clinics. Fourteen clinicians (11 geriatric specialists/residents, two neurologists, one nurse practitioner) were invited to integrate the tool into routine care with 43 new memory clinic patients. We evaluated usability and user experiences through quantitative data from questionnaires (patients, care partners, clinicians), enriched with thematically analyzed qualitative data from interviews (clinicians). RESULTS: We observed wide variation in tool use among clinicians. Our core findings were that clinicians: 1) were mainly positive about the patient report, since it contributes to patient-centered and personalized communication. This was endorsed by patients and care partners, who indicated that the patient report was useful and understandable and helped them to better understand their diagnosis, 2) considered the tool acceptable in addition to their own clinical competence, 3) indicated that the usefulness of the tool depended on the patient population and purpose of the diagnostic process, 4) addressed facilitators (ease of use, practice makes perfect) and barriers (high workload, lack of experience, data unavailability). CONCLUSION: This multicenter usability study revealed a willingness to adopt a digital tool to support the diagnostic process in memory clinics. Clinicians, patients, and care partners appreciated the personalized diagnostic report. More attention to education and training of clinicians is needed to utilize the full functionality of the tool and foster implementation in actual daily practice. These findings provide an important step towards a lasting adoption of digital tools in memory clinic practice.

The Cognitive Function at Work Questionnaire (CFWQ): A new scale for measuring cognitive complaints in occupational population.

Cognitive functioning is a relevant work and health related topic, however, validated methods to assess subjective cognitive complaints (SCC) at work are lacking. We introduce the Cognitive Function at Work Questionnaire (CFWQ) for measuring SCC in occupational settings. 1-year follow-up data of 418 employees from a Finnish public media service company was analyzed. Participants completed web-based CFWQ, cognitive tests and a broad set of questionnaires for evaluating depression, anxiety, insomnia, daytime sleepiness, burnout, stress, mental job burden, work ability, cognitive errors, and perceived health. The factor analysis yielded a model with the CFWQ subdomains: Memory, Language, Executive Function, Speed of Processing, Cognitive Control and Name Memory. The internal consistency (Cronbach's alpha = .87) and the test-retest constancy (ICC = .84) reflected good reliability. Correlation between the CFWQ and cognitive errors at work ranged from .25 to .64 indicating adequate concurrent validity. Employees with depression, insomnia and burnout symptoms had higher (p < .001) CFWQ scores than participants without these symptoms. Depression and burnout symptom severity as well as accumulation of mood, sleep, and psychosocial stressors were associated with higher CFWQ scores (p < .001 in all). The CFWQ appears psychometrically sound measure for the assessment of SCC in occupational population.

Subjective vs informant-reported cognitive complaints have differential clinical significance in covert cerebral small vessel disease.

Objective: Subjective cognitive complaints are common in patients with cerebral small vessel disease (cSVD), yet their relationship with informant evaluations, objective cognitive functions and severity of brain changes are poorly understood. We studied the associations of subjective and informant reports with findings from comprehensive neuropsychological assessment and brain MRI. Method: In the Helsinki SVD Study, 152 older adults with varying degrees of white matter hyperintensities (WMH) but without stroke or dementia were classified as having normal cognition or mild cognitive impairment (MCI) based on neuropsychological criteria. The measures also included continuous domain scores for memory and executive functions. Cognitive complaints were evaluated with the subjective and informant versions of the Prospective and Retrospective Memory Questionnaire (PRMQ) and Dysexecutive Questionnaire (DEX); functional abilities with the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL); and depressive symptoms with the Geriatric Depression Scale (GDS-15). Results: Subjective cognitive complaints correlated significantly with informant reports (r=0.40-0.50, p<0.001). After controlling for demographics, subjective and informant DEX and PRMQ were not related to MCI, memory or executive functions. Instead, subjective DEX and PRMQ significantly associated with GDS-15 and informant DEX and PRMQ with WMH volume and A-IADL. Conclusions: Neither subjective nor informant-reported cognitive complaints associated with objective cognitive performance. Informant-evaluations were related to functional impairment and more severe WMH, whereas subjective complaints only associated with mild depressive symptoms. These findings suggest that awareness of cognitive impairment may be limited in early-stage cSVD and highlight the value of informant assessments in the identification of patients with functional impairment.