A Novel Computerized Flexible Attention Test in Detecting Executive Dysfunction of Patients with Early-Onset Cognitive Impairment and Dementia.

OBJECTIVE: The number of computer-based cognitive tests has increased in recent years, but there is a need for tests focusing on the assessment of executive function (EF), as it can be crucial for the identification of early-onset neurodegenerative disorders. This study aims to examine the ability of the Flexible Attention Test (FAT), a new computer-based test battery for detecting executive dysfunction of early-onset cognitive impairment and dementia patients. METHOD: We analyzed the FAT subtask results in memory clinic patients with cognitive symptom onset at ≤65 years. The patients were divided into four groups: early onset dementia (EOD, n = 48), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes (MCI-o, n = 99), and subjective cognitive decline (SCD, n = 14). The test accuracy to distinguish EOD patients from other groups was examined, as well as correlations with pen-and-paper EF tests. We also reported the 12-months follow-up results. RESULTS: The EOD and MCI-n patients performed significantly poorer (p ≤ .002) than those in the MCI-o and SCD groups in most of the FAT subtasks. The accuracies of the FAT subtasks to detect EOD from other causes were mainly moderate (0.34 ≤ area under the curve < 0.74). The FAT subtasks correlated logically with corresponding pen-and-paper EF tests (.15 ≤ r ≤ .75). No systematic learning effects were detected in the FAT performance at follow-up. CONCLUSIONS: The FAT appears to be a promising method for the precise evaluation of EF and applicable distinguishing early-onset neurodegenerative disorders from patients with other causes of cognitive problems.

Exposure to urban particulate matter alters responses of olfactory mucosal cells to SARS-CoV-2 infection.

Respiratory viruses have a significant impact on health, as highlighted by the COVID-19 pandemic. Exposure to air pollution can contribute to viral susceptibility and be associated with severe outcomes, as suggested by recent epidemiological studies. Furthermore, exposure to particulate matter (PM), an important constituent of air pollution, is linked to adverse effects on the brain, including cognitive decline and Alzheimer's disease (AD). The olfactory mucosa (OM), a tissue located at the rooftop of the nasal cavity, is directly exposed to inhaled air and in direct contact with the brain. Increasing evidence of OM dysfunction related to neuropathogenesis and viral infection demonstrates the importance of elucidating the interplay between viruses and air pollutants at the OM. This study examined the effects of subacute exposure to urban PM 0.2 and PM 10-2.5 on SARS-CoV-2 infection using primary human OM cells obtained from cognitively healthy individuals and individuals diagnosed with AD. OM cells were exposed to PM and subsequently infected with the SARS-CoV-2 virus in the presence of pollutants. SARS-CoV-2 entry receptors and replication, toxicological endpoints, cytokine release, oxidative stress markers, and amyloid beta levels were measured. Exposure to PM did not enhance the expression of viral entry receptors or cellular viral load in human OM cells. However, PM-exposed and SARS-CoV-2-infected cells showed alterations in cellular and immune responses when compared to cells infected only with the virus or pollutants. These changes are highly pronounced in AD OM cells. These results suggest that exposure of human OM cells to PM does not increase susceptibility to SARS-CoV-2 infection in vitro, but it can alter cellular immune responses to the virus, particularly in AD. Understanding the interplay of air pollutants and COVID-19 can provide important insight for the development of public health policies and interventions to reduce the negative influences of air pollution exposure.

Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study.

Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting. Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset). Methods: The patients' (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14). Results: The most prevalent diagnoses were Alzheimer's disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05). Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

Human-derived air-liquid interface cultures decipher Alzheimer's disease-SARS-CoV-2 crosstalk in the olfactory mucosa.

BACKGROUND: The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD. METHODS: To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing. RESULTS: Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation. CONCLUSIONS: The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.

Utility of the INECO Frontal Screening and the Frontal Assessment Battery in detecting executive dysfunction in early-onset cognitive impairment and dementia.

OBJECTIVE: The INECO Frontal Screening (IFS) and the Frontal Assessment Battery (FAB) are executive dysfunction (ED) screening tools that can distinguish patients with neurodegenerative disorders from healthy controls and, to some extent, between dementia subtypes. This paper aims to examine the suitability of these tests in assessing early-onset cognitive impairment and dementia patients. METHOD: In a memory clinic patient cohort (age mean = 57.4 years) with symptom onset at ≤65 years, we analyzed the IFS and the FAB results of four groups: early-onset dementia (EOD, n = 49), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes such as depression (MCI-o, n = 99) and subjective cognitive decline (SCD, n = 14). Data were gathered at baseline and at 6 and 12 months. We also studied the tests' accuracy in distinguishing EOD from SCD patients and ED patients from those with intact executive functioning. Correlations with neuropsychological measures were also studied. RESULTS: The EOD group had significantly (p < .05) lower IFS and FAB total scores than the MCI-o and SCD groups. Compared with the FAB, the IFS showed more statistically significant (p < .05) differences between diagnostic groups, greater accuracy (IFS AUC = .80, FAB AUC = .75, p = .036) in detecting ED and marginally stronger correlations with neuropsychological measures. We found no statistically significant differences in the EOD group scores from baseline up to 6- or 12-months follow-up. CONCLUSIONS: While both tests can detect EOD among memory clinic patients, the IFS may be more reliable in detecting ED than the FAB.

Emissions from modern engines induce distinct effects in human olfactory mucosa cells, depending on fuel and aftertreatment.

Ultrafine particles (UFP) with a diameter of ≤0.1 µm, are contributors to ambient air pollution and derived mainly from traffic emissions, yet their health effects remain poorly characterized. The olfactory mucosa (OM) is located at the rooftop of the nasal cavity and directly exposed to both the environment and the brain. Mounting evidence suggests that pollutant particles affect the brain through the olfactory tract, however, the exact cellular mechanisms of how the OM responds to air pollutants remain poorly known. Here we show that the responses of primary human OM cells are altered upon exposure to UFPs and that different fuels and engines elicit different adverse effects. We used UFPs collected from exhausts of a heavy-duty-engine run with renewable diesel (A0) and fossil diesel (A20), and from a modern diesel vehicle run with renewable diesel (Euro6) and compared their health effects on the OM cells by assessing cellular processes on the functional and transcriptomic levels. Quantification revealed all samples as UFPs with the majority of particles being ≤0.1 µm by an aerodynamic diameter. Exposure to A0 and A20 induced substantial alterations in processes associated with inflammatory response, xenobiotic metabolism, olfactory signaling, and epithelial integrity. Euro6 caused only negligible changes, demonstrating the efficacy of aftertreatment devices. Furthermore, when compared to A20, A0 elicited less pronounced effects on OM cells, suggesting renewable diesel induces less adverse effects in OM cells. Prior studies and these results suggest that PAHs may disturb the inflammatory process and xenobiotic metabolism in the OM and that UFPs might mediate harmful effects on the brain through the olfactory route. This study provides important information on the adverse effects of UFPs in a human-based in vitro model, therefore providing new insight to form the basis for mitigation and preventive actions against the possible toxicological impairments caused by UFP exposure.

Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

The Cognitive Function at Work Questionnaire in memory clinic setting: a validation study.

INTRODUCTION: As there is a trend toward more people seeking medical help due to cognitive symptoms, validated and targeted questionnaires are increasingly important in the clinical evaluation process. The Cognitive Function at Work Questionnaire (CFWQ) was developed to identify and rate subjective cognitive symptoms of individuals active in working life. However, its psychometric characteristics have not been previously studied in a memory clinic setting. METHOD: The factorial structure, internal consistency, test-retest reliability, and convergent validity of the CFWQ were studied in a memory clinic setting (N = 113). We also investigated the instrument's ability to identify cognitive symptoms in a cohort of early-onset dementia (EOD, N = 22), mild cognitive impairment-neurological (MCI-n, N = 18), MCI due to mood, sleep, or other physical health problems (MCI-o, N = 59), and subjective cognitive decline (SCD, N = 14) patients. RESULTS: Based on factor analysis, eight cognitive subscales were identified covering main cognitive domains: Memory, Language, Executive Function, Speed of Processing, Cognitive Control, Name Memory, Visuospatial/Praxis and Attention. The internal consistency (α = .93) and the test-retest reliability (ICC = .91) were high. Several correlations (r = .19 - .33, p < .05) were documented between neuropsychological impairment level and CFWQ scores. EOD, MCI-n, MCI-o, and SCD groups did not differ statistically significantly in the levels of cognitive symptoms as measured by the CFWQ Total score. EOD group scored higher (p = .009) than other patient groups on the Visuospatial/Praxis subscale, but the difference between EOD and MCI-o groups turned insignificant after correcting for multiple testing. CONCLUSIONS: The results of the study support the validity and reliability characteristics of the CFWQ in a memory clinic setting. The instrument is easy-to-use and has clinical utility in capturing the subjective cognitive symptoms of patients active in working life and who need a referral to a more detailed evaluation.

Cerebrospinal Fluid Diagnostics of Alzheimer's Disease in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. OBJECTIVE: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. METHODS: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n = 33) and patients with diagnosed AD and no iNPH (n = 39).*-31ptResults:Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aß1 - 42, 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aß1 - 42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). CONCLUSION: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181/Aß1 - 42 ratio showed some utility in the diagnosis of AD in iNPH patients.

Development of Lyophilised Eudragit® Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration.

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400-500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-ß-CD as a cryoprotectant. It ensured the preservation of the NPs' size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.

Intelligent digital tools for screening of brain connectivity and dementia risk estimation in people affected by mild cognitive impairment: the AI-Mind clinical study protocol.

More than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual's risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AI-Mind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind's innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contributions.

An Alzheimer's Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition.

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 changes of early AD-associated 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.

Computer-based Eye-tracking Analysis of King-Devick Test Differentiates Persons With Idiopathic Normal Pressure Hydrocephalus From Cognitively Unimpaired.

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.

Different Trajectories of Depressive Symptoms in Alzheimer's Disease Caregivers - 5-Year Follow-Up.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The present study showed that FC depressive symptoms existed, and one-third of caregivers experienced increasing depressive symptoms over five years. CLINICAL IMPLICATIONS: Family caregivers' health should be followed in clinical practice, and those at risk of depression could be recognized early in caregiving.

Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer's Disease.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Treatment initiation for parkinson's disease in Australia 2013-2018: a nation-wide study.

BACKGROUND: Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from 2013-2018, and to determine factors predicting choice of initial treatment. METHODS: Cohort of new-users (N = 4,887) of anti-Parkinson medication aged ≥ 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex. RESULTS: Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged ≥ 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged < 65 years, rates of treatment initiation with DAs (37%) and levodopa (37%) were similar in 2013/2014 but initiation with DA exceeded levodopa thereafter. Among men aged < 65 years, treatment initiation with levodopa (44%-49%) remained more frequent than initiation with DAs (29%-32%) throughout the study period. CONCLUSIONS: Treatment initiation with levodopa was most frequent among persons aged ≥ 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.

Biometal Dyshomeostasis in Olfactory Mucosa of Alzheimer's Disease Patients.

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.

Single-Cell RNA-Seq Analysis of Olfactory Mucosal Cells of Alzheimer's Disease Patients.

Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer's disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer's disease patients. We report increased amyloid-beta secretion in Alzheimer's disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer's disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer's disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease.

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.

Upper limb dysfunction and activities in daily living in idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease with a characteristic symptom triad of gait disturbance, cognitive decline, and incontinence. Recently, also dysfunctions in upper limbs have been described in iNPH and reported to improve after shunt surgery. We aim to describe the role of upper limb motor function in the clinical assessment of iNPH patients and its influence on activities of daily living (ADL). METHODS: Seventy-five consecutive patients with probable iNPH were studied pre-operatively and at 3 and 12 months after shunt surgery. The pre-operative evaluation included lumbar drainage of cerebrospinal fluid (tap test). Motor functions were assessed in upper and lower limbs with Grooved Pegboard Test (GPT), Box & Block Test (BBT), Total Score of Gait (TSG), and balance test. ADL was assessed with Barthel's index and cognition in accordance with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). RESULTS: Patients showed improvement in all motor tests and ADL at 3 months after shunt surgery. The improvement remained stable during the 12-month post-operative follow-up. The motor function tests correlated with each other and with ADL. CONCLUSIONS: A 3-month follow-up period after shunt surgery is adequate to show improvement in motor tasks, and a positive outcome will last for at least 12 months. A shunt-responsive dysfunction of upper limb motor performance plays a major role in ADL of iNPH patients. Therefore, we suggest an evaluation of upper limb motor performance to be included in routine evaluation of iNPH patients.