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The care of individuals with Alzheimer's disease (AD) relies on family caregivers (FCs) who face increasing demands. This study aimed to identify trajectories of depressive symptoms in FCs.226 FCs and individuals with AD were followed up for 5 years as a part of the ALSOVA study. Depressive symptoms in FCs were measured with the Beck Depression Inventory from the time of the AD diagnosis to the 5-year follow-up. We compared the trajectory of groups regarding age, education, and sex of both FC distress and AD symptoms.We identified three trajectories of FC depressive symptoms throughout follow-up: (1) declining (7.5% of FCs), (2) minor (59.7% of FCs), and (3) increased (32.7% of FCs). These groups exhibited differences in demographic variables, FC distress, and individuals with AD neuropsychiatric symptoms.The present study showed that FC depressive symptoms existed, and one-third of caregivers experienced increasing depressive symptoms over five years.Family caregivers' health should be followed in clinical practice, and those at risk of depression could be recognized early in caregiving.

Background: Center for Epidemiological Studies-Depression scale (CES-D) is widely used self-report measure for assessing depressive symptoms. However, few studies have formally assessed whether the CES-D and its short forms can be used to compare scores in cognitively unimpaired versus cognitively impaired persons and across different age cohorts in old age. We examined the factor structures of 20-, 15-, and 8-item CES-D scales and their measurement invariance for cognitive status and age and associations with cohort, cognitive impairment, and genetic risk of depression.Methods: Participants were from a population-based older Finnish Twin Cohort study including 71–79-year-olds from the MEMTWIN II (n=1698) and 90+ year-olds from the NONAGINTA (n=134) sub-studies. Exploratory factor analyses were performed in MEMTWIN II and confirmatory factor analyses in both cohorts. Cognitive status comparisons and associations with polygenic risk score of major depressive disorder (MDD-PRS) were conducted in MEMTWIN II. Cohort comparisons were performed between MEMTWIN II and NONAGINTA.Results: Exploratory factor analyses (n=1034) suggested four- (CES-D 20) and three-factor (CES-D 8) structures and these models fit the data well in confirmatory analyses (n=664). Unidimensional models had a good (CES-D 15 & 20) or fair fit (CES-D 8). Measurement invariance testing supported scalar invariance of all CES-D versions for cognitive status and age. NONAGINTA participants had significantly more depressive symptoms than MEMTWIN II participants. Higher MDD-PRS was significantly associated with more depressive symptoms in different CES-D versions.Discussion: The measurement properties of the CES-D indicate that different versions are measuring depressive symptoms similarly across the cohorts and cognitive spectrum in old age. Thus, even the short CES-D appears to be a psychometrically adequate tool to assess depressive symptoms in old age including those over 90 years old and those with cognitive impairment. Higher MDD-PRS and older age predicted greater depressive symptoms in old age.

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore early AD-associated disease pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.

Wide-ranging functional defects in eye movements have been reported in Alzheimer's disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking.To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD.We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE = 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE = 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed.We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p 0.05). The KD error scores in the AD group differed significantly (p 0.01) from the other groups.Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.

Objectives:To investigate conditional dependence relationships of impulse dyscontrol symptoms in mild cognitive impairment (MCI) and subjective cognitive decline (SCD).Design:A prospective, observational study.Participants:Two hundred and thirty-five patients with MCI (n = 159) or SCD (n = 76) from the Prospective Study for Persons with Memory Symptoms dataset.Measurements:Items of the Mild Behavioral Impairment Checklist impulse dyscontrol subscale.Results:Stubbornness/rigidity, agitation/aggressiveness, and argumentativeness were frequent and the most central symptoms in the network. Impulsivity, the fourth most central symptom in the network, served as the bridge between these common symptoms and less central and rare symptoms.Conclusions:Impulse dyscontrol in at-risk states for dementia is characterized by closely connected symptoms of irritability, agitation, and rigidity. Compulsions and difficulties in regulating rewarding behaviors are relatively isolated symptoms.

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer’s disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.

Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved. Background: Functional defects in eye movements and reduced reading speed in neurodegenerative diseases represent a potential new biomarker to support clinical diagnosis. We investigated whether computer-based eye-tracking (ET) analysis of the King-Devick (KD) test differentiates persons with idiopathic normal pressure hydrocephalus (iNPH) from cognitively unimpaired [control (CO)] and persons with Alzheimer's disease (AD). Methods: We recruited 68 participants (37 CO, 10 iNPH, and 21 AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating interview. The KD reading test was performed using computer-based ET. We analyzed the total time used for the reading test, number of errors, durations of fixation and saccade, and saccade amplitudes. Results: The iNPH group significantly differed from the CO group in the KD test mean total time (CO 69.3 s, iNPH 87.3 s; P≤0.009) and eye-tracking recording of the mean saccade amplitude (CO 3.6 degree, iNPH 3.2 degree; P≤0.001). The AD group significantly differed from the CO group in each tested parameter. No significant differences were detected between the iNPH and AD groups. Conclusion: For the first time, we demonstrated altered reading ability and saccade amplitudes in patients with iNPH.

The Psychological Science Accelerator (PSA) is an international collaborative network of psychological scientists that facilitates rigorous and generalizable research. In this chapter, we describe how the PSA can help clinical psychologists and clinical psychological science more broadly. We first describe the PSA and outline how individual clinical psychologists can use the PSA as a helpful resource in numerous capacities: leading or contributing to clinical research or research with clinical relevance, building collaborative relationships, obtaining experience and expertise, and learning about systems and tools, particularly those related to open science practices, that they can adapt to their own research. We then describe how the PSA supports rigor and transparency at each stage of the research process. Finally, we discuss the challenges of the PSA’s large, collaborative approach to research.

Background:Neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD) are related to activities of daily living (ADLs), but longitudinal studies are sparse.Objectives:We investigated which NPSs were related to decline in instrumental ADLs (IADLs) and basic ADLs (BADLs) in a 5-year follow-up of individuals with AD.Methods:ALSOVA 5-year follow-up study data of 236 individuals with very mild or mild AD at baseline and their caregiver were analyzed. IADLs and BADLs were assessed with Alzheimer’s Disease Cooperative Study ADL inventory, and NPSs with Neuropsychiatric Inventory at annual follow-up visits. Generalized estimating equations (GEEs) were used for longitudinal data analysis, and NPS–ADL networks were estimated to demonstrate symptom interactions.Results:Apathy [rate ratio (RR) 1.23, 95% CI 1.06–1.44, p = 0.007], aberrant motor behavior (RR 1.24, 95% CI 1.07–1.44, p = 0.005), and appetite disturbances (RR 1.22, 95% CI 1.06–1.41, p = 0.005) were related to impairment in BADLs, and the same symptoms (RR 1.13, 95% CI 1.07–1.21, p < 0.001; RR 1.13, 95% CI 1.07–1.20, p < 0.001; RR 1.14; 95% CI 1.08–1.21, p < 0.001, for apathy, aberrant motor behavior, and appetite disturbances, respectively), in addition to delusions (RR 1.09, 95% CI 1.03–1.15, p = 0.004), were related to IADL impairment. Symptom networks varied at different time points.Conclusion:As AD progresses, common (apathy) and uncommon NPSs (aberrant motor behavior, appetite disturbances, delusions) seem to be related to ADLs through various symptom interactions. Previous literature suggests that frontal pathology could underlie these relationships.

Recent methodological reforms have succeeded in improving the rigor, accessibility, and transparency of psychological science, but these advances have not successfully proliferated certain subfields, including clinical psychology. Large-scale, crowdsourced collaborations offer clinical psychological scientists a way to conduct rigorous research on a scale not otherwise accessible to most researchers. The Psychological Science Accelerator (PSA) is an international collaborative network of psychological scientists that facilitates rigorous and generalizable research. In this chapter, we describe how the PSA can help clinical psychologists and clinical psychological science more broadly.

Olfactory dysfunction manifests early in several neurodegenerative disorders. Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. However, it is unclear how this tissue reflects key neurodegenerative features in Alzheimer’s disease. Here we report that Alzheimer’s disease olfactory mucosal cells obtained from live individuals secrete toxic amyloid-beta. We detail cell-type-specific gene expression patterns, unveiling 147 differentially expressed disease-associated genes compared to the cognitively healthy controls, and 5 distinct populations in globose basal cell -, myofibroblast-, and fibroblast/ stromal – like cells in vitro. Overall, coordinated alteration of RNA and protein metabolism, inflammatory processes and signal transduction were observed in multiple cell populations, suggesting a key role in pathophysiology. Our results demonstrate the potential of olfactory cell cultures in modelling Alzheimer’s disease advocate their use for diagnostic purposes. Moreover, for the first time we provide single cell data on olfactory mucosa in Alzheimer’s disease for investigating molecular and cellular mechanisms associated with the disease.

Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer’s disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients. Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA. Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h–1). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11C]-PiB-PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI. Results: When analyzed individually, in [11C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. Conclusion: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

Background Affective symptoms in Alzheimer's disease (AD) can be rated with both informant- and self-ratings. Information from these two modalities may not converge. We estimated network structures of affective symptoms in AD with both rating modalities and assessed the longitudinal stability of the networks. Methods Network analyses combining self-rated and informant-rated affective symptoms were conducted in 3198 individuals with AD at two time points (mean follow-up 387 days), drawn from the NACC database. Self-rated symptoms were assessed by Geriatric Depression Scale, and informant-rated symptoms included depression, apathy and anxiety questions from Neuropsychiatric Inventory Questionnaire. Results Informant-rated symptoms were mainly connected to symptoms expressing lack of positive affect, but not to the more central symptoms of self-rated worthlessness and helplessness. Networks did not differ in structure (p = 0.71), or connectivity (p = 0.92) between visits. Symptoms formed four clinically meaningful clusters of depressive symptoms and decline, lack of positive affect, informant-rated apathy and anxiety and informant-rated depression. Limitations The symptom dynamics in our study could have been present before AD diagnosis. The lack of positive affect cluster may represent a methodological artefact rather than a theoretically meaningful subgroup. Requiring follow-up lead to a selection of patients with less cognitive decline. Conclusions Informant rating may only capture the more visible affective symptoms, such as not being in good spirits, instead of more central and severe symptoms, such as hopelessness and worthlessness. Future research should continue to be mindful of differences between self- and informant-rated symptoms even in earlier stages of AD.

Background Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. Objectives To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. Methods We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. Results Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. Conclusion Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Over the last 80 years, brain research has gained a lot of traction, with recent advances such as the sequencing of the human genome, the development of tools for mapping neuronal connections, the improvement of neuroimaging technology, and the rise of nanoscience. This paper aims to determine how brain research has evolved over time in terms of papers and impact among countries, and how those various trends vary by areas of brain research. Our results show that over the past 30 years, the number of brain-related papers has grown at a faster pace than the number of papers from all disciplines combined with China being at the forefront of this growth. Different patterns of specializations among countries and funders have also emerged.