Clinical Diagnosis Of Dementia Research Articles

Disentangling the causal effects of education and participation bias on Alzheimer's disease using Mendelian Randomization.

People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects. Educational attainment reduced the risk of AD (OR IVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (OR IVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (OR IVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (OR IVW 95% CI= 0.76 [0.62, 0.92], p = 0.006). Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63–0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69–0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67–0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ42 and arterial Aβ40 forms (r = 0.76–0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

Accuracy of clinical diagnosis of behavioural variant frontotemporal dementia: a protocol for a systematic review and meta-analysis

IntroductionBehavioural variant frontotemporal dementia (bvFTD) characterisation has evolved, but diagnosis remains challenging, relying on clinical diagnostic criteria that have undergone revisions over time. In this systematic review, our aims are...

Clinical Predictors of Postmortem Amyloid and Nonamyloid Cerebral Small Vessel Disease in Middle-Aged to Older Adults.

Sporadic cerebral small vessel disease (CSVD) is a class of important pathologic processes known to affect the aging brain and to contribute to cognitive impairment. We aimed to identify clinical risk factors associated with postmortem CSVD in middle-aged to older adults. We developed and tested risk models for their predictive accuracy of a pathologic diagnosis of nonamyloid CSVD and cerebral amyloid angiopathy (CAA) in a retrospective sample of 160 autopsied cases from the Edinburgh Brain Bank. Individuals aged 40 years and older covering the spectrum of healthy aging and common forms of dementia (i.e., highly-prevalent etiologies such as Alzheimer disease (AD), vascular cognitive impairment (VCI), and mixed dementia) were included. We performed binomial logistic regression models using sample splitting and cross-validation methods. Demographics, lifestyle habits, traditional vascular risk factors, chronic medical conditions, APOE4, and cognitive status were assessed as potential predictors. Forty percent of our sample had a clinical diagnosis of dementia (AD = 33, VCI = 26 and mixed = 5) while others were cognitively healthy (n = 96). The mean age at death was 73.8 (SD 14.1) years, and 40% were female. The presence of none-to-mild vs moderate-to-severe nonamyloid CSVD was predicted by our model with good accuracy (area under the curve [AUC] = 0.84, sensitivity [SEN] = 72%, specificity [SPE] = 95%), with the most significant clinical predictors being age, history of cerebrovascular events, and cognitive impairment. The presence of CAA pathology was also predicted with high accuracy (AUC = 0.86, SEN = 93%, SPE = 79%). Significant predictors included alcohol intake, history of cerebrovascular events, and cognitive impairment. In a subset of atypical dementias (n = 24), our models provided poor predictive performance for both nonamyloid CSVD (AUC = 0.50) and CAA (AUC = 0.43). CSVD pathology can be predicted with high accuracy based on clinical factors in patients within the spectrum of AD, VCI, and normal aging. Whether this prediction can be enhanced by the addition of fluid and neuroimaging biomarkers warrants additional study. Improving our understanding of clinical determinants of vascular brain health may lead to novel strategies in the prevention and treatment of vascular etiologies contributing to cognitive decline. This study provides Class II evidence that selected clinical factors accurately distinguish between middle-aged to older adults with and without cerebrovascular small vessel disease (amyloid and nonamyloid) pathology.

Strength together: examining risk and protective factors associated with dementia and cognitive impairment in Aboriginal and Torres Strait Islander peoples through harmonisation of landmark studies

BackgroundRates of dementia for Aboriginal and Torres Strait Islander peoples are three to five times greater compared to non-Indigenous Australians, with earlier age of onset. However, the risk and protective factors that drive these higher rates vary across existing cohort studies, with minimal findings on the role of vascular risk factors beyond stroke. Harmonisation of data across studies may offer greater insights through enhanced diversity and strengthened statistical capabilities. This study aims to combine three landmark cohort studies of Aboriginal and Torres Strait Islander participants to better understand the determinants of cognitive health and dementia.Methods/designThree cohort studies - the Kimberley Healthy Adults Project (KHAP, N = 363), Koori Growing Old Well Study (KGOWS, N = 336) and Torres Strait Dementia Prevalence Study (TSDPS, N = 274) - share a similar research methodology with demographic, medical history, psychosocial factors, cognitive tests and consensus clinical diagnoses of cognitive impairment and dementia. Associations between risk and protective factors of interest and the presence of dementia and/or cognitive impairment diagnoses will be evaluated by univariable and multivariable logistic regression in a harmonised cross-sectional cohort of 898 participants. Factors associated with incident dementia and/or cognitive impairment will be assessed in a subset of KHAP (n = 189) and KGOWS participants (n = 165) who were available in longitudinal follow-up, after exclusion of those with baseline dementia or cognitive impairment. Analyses in relation to outcome measure of death or dementia will be conducted to account for the competing risk of death. Logistic regression will be used to evaluate the association between the individual components of the 16-component Kimberley Indigenous Cognitive Assessment (KICA) tool and the presence of dementia and cognitive impairment determined by independent consensus diagnoses. Multivariable binary logistic regression will be used to adjust for the effect of confounding variables. Results will be reported as odds ratios (OR) with 95% confidence intervals (95% CI).DiscussionGreater understanding of risk and protective factors of dementia and cognitive impairment relevant to Aboriginal and Torres Strait Islander peoples may improve approaches across the life course to delay cognitive decline and reduce dementia risk.

Alzheimer's Disease and Related Dementias Diagnosis in the United States Among US-Born and Foreign-Born White, Black, Hispanic, and Asian Older Adults.

Timely clinical diagnosis of Alzheimer's disease and related dementias (ADRD) is important for resource allocation, mitigating safety concerns, and improving quality of life. While studies have examined ADRD diagnosis disparities by race/ethnicity, few include its intersection with nativity. Our aims were to (1) estimate the odds of diagnosed ADRD among US- and foreign-born racial/ethnic groups compared to US-born White older adults and (2) make comparisons by nativity within each racial/ethnic group. We linked 2000-2017 National Health Interview Survey (NHIS) and 2001-2018 Medical Expenditure Panel Survey (MEPS) data (65 + years; n = 38,033). Race/ethnicity and nativity were measured using NHIS data. Diagnosed ADRD was determined using ICD-9 (290/294/331/797) or ICD-10 (F01/F03/G30/G31) billing codes created from self-reports during MEPS household interviews. Bivariate and multivariable analyses were adjusted for covariates based on Anderson's behavioral model of health services use. US-born Black (OR = 1.74; 95% CI = 1.48-2.05), Hispanic (OR = 1.62; 95% CI = 1.14-2.29), and foreign-born Hispanic (OR = 1.63; 95% CI = 1.24-2.15) older adults, but not foreign-born Black or Asian older adults, had higher odds of diagnosed ADRD compared to US-born White older adults after adjusting for age and sex. After additional adjustment for education, health insurance, usual source of care, and chronic conditions, only US-born Black older adults continued to show higher odds (OR = 1.54; 95% CI = 1.27-1.87) of diagnosed ADRD compared to US-born White older adults. There were no differences in ADRD diagnosis by nativity within each racial/ethnic group. Findings highlight the need for including nativity in studies comparing racial/ethnic groups to Whites to fully capture the ADRD burden among US-born Black older adults.

A clinical case report of HIV-associated encephalopathy

Due to the fact that neurological and psychiatric symptoms are frequent manifestations of NeuroAIDS, a neurologist and a psychiatrist may be the first to meet with an HIV-infected patient in clinical practice. The article presents a clinical case of HIV-associated encephalopathy identified in a patient in a psychiatric hospital; the clinical picture and diagnosis of dementia caused by the human immunodeficiency virus are described. The case study method and MRI analysis were used. It has been concluded that there is a need for more careful monitoring of patients registered with AIDS centers, achieving 100 % HAART coverage of HIV patients at the early stages of the disease, which will significantly reduce residual neurological and psychiatric consequences, as well as mortality from HIV-associated lesions of the central nervous system.

Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation.

MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

Awareness and cognitive rehabilitation in Alzheimer's disease and frontotemporal dementia.

Awareness influences the evolution of neurodegenerative dementias. We gathered participants' and caregivers assessments of dependence in daily activities and we studied how each score would be related to next year participant autonomy, independently of other explicative variables. We retrospectively analyzed data from mildly demented participants with a clinical diagnosis of Alzheimer's disease (AD, n = 186) and frontotemporal dementia (FTD, n = 29) and their relatives. A research tool was used to assess participant dependence in 98 daily activities and associated caregiver burden. A discrepancy score between the patient's and relative's judgment was calculated to evaluate awareness of dependence in activities at baseline. This dependence scores, as well as sex, age, education, and 1 year difference in Mini-Mental State Examination were taken as possible explicative variables for dependence in activities adapted by therapists during a 1-year cognitive rehabilitation program. Patients with FTD showed less awareness for daily dependence (discrepancy 20.9% vs. 11.8% in AD). Both groups benefited from cognitive rehabilitation (25% decrease in dependence) and subjective burden of relatives was decreased in both groups. In the AD group, there was a significant positive relationship between both caregiver (P < 0.001) and participant's (P < 0.02) evaluation of dependence in daily activities at inclusion and dependence of participants in adapted activities after 1 year. Awareness of impairment in daily activities is a clinical symptom that is more important at inclusion in FTD than in AD. However, in participants with AD who, as a group, significantly benefit from a cognitive rehabilitation program, not only caregiver's but also participant's assessment of dependence at baseline is correlated to subsequent, next year greater dependence in daily activities adapted by the therapists. Although discrepant, both caregiver and participant evaluations appear to be important variables to understand the evolution and the benefit of care in participants at early stages of dementia.

Classification Prediction of Alzheimer's Disease and Vascular Dementia Using Physiological Data and ECD SPECT Images.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia. However, their neuropsychological and pathological features often overlap, making it difficult to distinguish between AD and VaD. In addition to clinical consultation and laboratory examinations, clinical dementia diagnosis in Taiwan will also include Tc-99m-ECD SPECT imaging examination. Through machine learning and deep learning technology, we explored the feasibility of using the above clinical practice data to distinguish AD and VaD. We used the physiological data (33 features) and Tc-99m-ECD SPECT images of 112 AD patients and 85 VaD patients in the Taiwanese Nuclear Medicine Brain Image Database to train the classification model. The results, after filtering by the number of SVM RFE 5-fold features, show that the average accuracy of physiological data in distinguishing AD/VaD is 81.22% and the AUC is 0.836; the average accuracy of training images using the Inception V3 model is 85% and the AUC is 0.95. Finally, Grad-CAM heatmap was used to visualize the areas of concern of the model and compared with the SPM analysis method to further understand the differences. This research method can quickly use machine learning and deep learning models to automatically extract image features based on a small amount of general clinical data to objectively distinguish AD and VaD.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. There were lower levels of tau pathology (β = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

The "Continu-A-mente" project: an interdisciplinary program to promote the continuity of care between hospital and community for people with dementia and their caregivers. Study Protocol.

Background: Nonpharmacological approaches are recommended as first-line treatment for the neuropsychiatric symptoms of persons living with dementia. Tailored Activity Program is a non-pharmacological approach which has shown to reduce neuropsychiatric symptoms and functional dependence of persons living with dementia at the community, as well as caregiver’s distress. The aim of the study is to assess the feasibility of a project in which the Tailored Activity Program is delivered partially at an acute hospital ward and partially at the patient's home. Material and Methods: The study is aimed at enrolling 50 dyads (patients/caregivers) from the memory clinic, acute geriatric ward, or short-stay emergency department at the IRCCS San Gerardo dei Tintori, Monza (Italy). Inclusion criteria are: the patient’s clinical diagnosis of dementia, clinically detectable neuropsychiatric symptoms (Neuro Psychiatric Inventory, NPI score &gt;6 in at least one item), the ability to participate in activities of daily living (Katz’s index ≥ 2), the presence of a caregiver (aged ≥ 21 years; minimum 4 hours of daily care), and the willingness of the dyad patient/caregiver to participate in the project. Treatment is delivered both i) in hospital (2 sessions) and ii) at home (6 sessions), including occupational therapy, telemedicine and nursing care provided once a week. The following variables are measured: Neuro Psychiatric Inventory, Time Up and Go Test, Katz’s Index and the level of caregiver’s sense of competence with the Sense of Competence Questionnaire. Data are collected both at baseline, at the end of the treatment, with a follow-up scheduled at 4 months after enrollment. Primary outcome measure is the dyad's retention rate at 4-month follow-up. Secondary outcomes are the reduction in the patient’s frequency and severity of NPS; the improvement in the patient’s Time Up and Go Test score; the improvement in the patient's levels of autonomy and participation in activities of daily living and improvement in the caregiver’s Sense of Competence Questionnaire score. Results and Conclusion: We seek to evaluate whether the Tailored Activity Program is well-received by the patient/caregiver dyad and, consequently, whether our project is feasible. If this objective is achieved, and if we also report some improvement in the secondary outcomes, we can then plan a larger multicenter study aimed at evaluating the effectiveness of this approach, partly delivered at the hospital and partly at patient’s home.

A Multi-modal Classification Method for Early Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease Using Three Paradigms with Various Task Difficulties.

Alzheimer's Disease (AD) accounts for the majority of dementia, and Mild Cognitive Impairment (MCI) is the early stage of AD. Early and accurate diagnosis of dementia plays a vital role in more targeted treatments and effectively halting disease progression. However, the clinical diagnosis of dementia requires various examinations, which are expensive and require a high level of expertise from the doctor. In this paper, we proposed a classification method based on multi-modal data including Electroencephalogram (EEG), eye tracking and behavioral data for early diagnosis of AD and MCI. Paradigms with various task difficulties were used to identify different severity of dementia: eye movement task and resting-state EEG tasks were used to detect AD, while eye movement task and delayed match-to-sample task were used to detect MCI. Besides, the effects of different features were compared and suitable EEG channels were selected for the detection. Furthermore, we proposed a data augmentation method to enlarge the dataset, designed an extra ERPNet feature extract layer to extract multi-modal features and used domain-adversarial neural network to improve the performance of MCI diagnosis. We achieved an average accuracy of 88.81% for MCI diagnosis and 100% for AD diagnosis. The results of this paper suggest that our classification method can provide a feasible and affordable way to diagnose dementia.

Imaging Approaches in Dementia: A Retrospective Cohort Study of Cross-sectional Imaging in the Indian Population

Introduction: Dementia is a broad medical term that describes the progressive cognitive decline of brain function due to disease or impairment, resulting in interference with daily activities. Magnetic Resonance Imaging (MRI) is commonly used for the clinical diagnosis of dementia by identifying cerebral atrophy and structural alterations. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect biochemical abnormalities in dementia patients, which may be beneficial for early diagnosis and treatment. Aim: To provide a comprehensive protocol and a guidance tool for radiologists to effectively diagnose dementia and its subtypes {Alzheimer’s Disease (AD), frontotemporal lobe dementia, etc.} based on radiological findings coupled with volumetry, spectroscopy, and Arterial Spin Labelling (ASL) findings. Materials and Methods: A retrospective observational study was conducted in the Department of Radiology, Nanavati Max Superspeciality Hospital, Mumbai, Maharashtra, India, between June 2022 and June 2023. A total of 125 patients were analysed to observe the correlation between whole brain volume, Intracranial Volume (ICV) of different cortical regions, hippocampal atrophy, and MRS findings. Descriptive statistics were used, and results were expressed as means and standard deviations for continuous variables, and as frequencies and percentages for categorical variables. Results: Out of 125 patients, 71 (56.8%) were males, and 54 (43.2%) were females, with ages ranging from 41 to 96 years. The majority presented with Mild Cognitive Impairment (MCI) 36 patients (28.8%) and Vascular Dementia (VaD) (18 patients - 14.4%). Some clinical features and imaging findings overlapped, resulting in some cases being a combination of different types of dementia. MRI, MRS, and Medial Temporal Atrophy (MTA) played a crucial role in allowing clinicians to perform a differential diagnosis. Conclusion: The use of MR volumetry and spectroscopy aids in classifying the type of dementia, which, in turn, gives treating clinicians a better perspective for further treatment and its outcomes.

Depressive symptoms in the entire spectrum of cognitive ageing in Greece: evidence from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD)

Objectives To study (i) the prevalence of mild and moderate-to-severe depressive symptoms in the entire spectrum of cognitive ageing in Greece and (ii) the relationship between these symptoms and demographic and clinical data. Methods The study was based on the randomly selected cohort of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Depressive symptoms were assessed with the 15‐item version of the Geriatric Depression Scale. Participants also received a comprehensive neuropsychological assessment, while the clinical diagnoses of dementia and mild cognitive impairment were established according to international diagnostic criteria. Statistical analyses relied on comparison tests and a logistic (proportional odds) ordinal regression model. Results Depressive symptoms were detected in 19.5% of the 1936 study participants, while 11.3% of both people with MCI and dementia had moderate-to-severe depressive symptoms. The regression model revealed that older adults with more severe depressive symptoms were more likely female, cognitively impaired, less educated, were treated with psychotropic medication and lived in Attica versus Thessaly. Conclusions Since depressive symptoms were detected in almost one in five older adults, healthcare professionals in Greece should safeguard the timely detection and effective treatment of such symptoms and the post-diagnostic care of older adults with depression. Key points Depressive symptoms are present in approximately 20% of older adults. More than 10% of older individuals with dementia or mild cognitive impairment report moderate-to-severe depressive symptoms. Female sex, lower education, lower cognitive performance, living in urban areas and treatment with psychotropic medication pertain to more severe depressive symptoms in ageing. Timely detection and effective treatment of depressive symptoms are crucial in the clinical practice of the care of older adults. Further research is needed in order to elucidate the complex relationship between depressive symptoms and cognitive impairment in ageing.

A retinal tauopathy with a characteristic molecular pattern points to the existence of a “Primary retinal tauopathy”

AbstractBackgroundPathogenic processes characteristic of neurodegenerative brain diseases, such as accumulation of phosphorylated Tau protein (pTau), can also be detected in the retina. Given the advanced state of retinal imaging technology and its potential to aid in the clinical diagnosis of Alzheimer’s disease (AD), it is imperative to investigate the part the retina plays in neurodegenerative diseases of the brain, as well as the associated eye‐specific degenerative processes.MethodsRetinas from 129 individuals who underwent eyeball resection/evisceration for severe ophthalmological conditions and from 35 post‐mortem donors with or without AD were analyzed. Paraffin‐embedded sections from cross‐sectioned retinas were stained with antibodies against different pTau species and Gallyas staining to detect neurofibrillary tangles. Retinal pTau accumulation, its distribution over the retinal layers, and molecular composition were determined neuropathologically and correlated with visual performance, age, and the presence of dementia.ResultsRetinal pTau pathology showed a consistent topographical expansion pattern that allowed distinguishing four stages: Stage 0: no pTau pathology; Stage 1: thread‐like pTau in the outer plexiform layer; Stage 2: additional cytoplasmic pTau in the inner nuclear layer; Stage 3: thread‐like pTau also in the inner plexiform layers. Antibodies against pTauS202/pT205 (AT8), pTauT231 (AT180), and anti‐MC‐1 Tau showed comparable results. Neurofibrillary tangles were not found. The stage of retinal tauopathy was correlated with age (r = 0.176, p = 0.024, n = 164), the underlying ophthalmologic diseases (p = 0.001; β = 0.292), and independently associated with vision impairment (p = 0.030; β = 0.192) in a linear regression model. Cases with a clinical diagnosis of dementia were associated with slightly higher stages of retinal tauopathy (binary logistic regression: p = 0.026; odds ratio (OR) = 1.685 [95% C.I.1.066‐2.664), although some demented cases were free of pTau pathology.ConclusionsThese results point towards the existence of a primary retinal tauopathy (PReT). It differs in its molecular composition from cerebral tauopathies by the lack of argyrophilic inclusions and the predominance of 3‐repeat Tau. However, PReT may be a prerequisite for developing AD pathology in the retina. Altogether, these findings support the presence of retinal neurodegenerative changes that may reflect changes in the brain.FundingSAO/FRA 2020/017

Frailty and behavioral and psychological symptoms of dementia: a single center study

AbstractBackgrounddementia is a clinical syndrome characterized by progressive cognitive decline and loss of independence in activities of daily living. Alongside the cognitive symptoms, Behavioral and Psychological Symptoms of Dementia (BPSD) may arise, causing considerable distress to both patients and caregiversMethodaim of this retrospective study was to evaluate the correlation between frailty and BPSD in a population of older patients with dementia. BPSD were classified in three clusters: “mood/apathy”, “psychosis” and “hyperactivity”. Using the Clinical Frailty Scale (CFS), patients were categorized as “severely frail”, “mild/moderately frail” and “robust” (CFS ≥ 7, 4‐6 and ≤ 3, respectively). In order to better understand the complex pattern of relationships between the different factors, we performed a network analysis.Result209 patients (71.3% women, mean age 83.24±4.98 years) with a clinical diagnosis of dementia were enrolled. The most represented group was the mild/moderately frail one (n = 155, 74%); lower numbers were seen in the robust (n = 18, 9%) and severely frail (n = 36, 17%) ones. Among the “severely frail” the percentage of BPSD was higher compared to the “mild/moderate” and “robust” groups. A significant correlation between frailty and “hyperactivity” cluster emerged, both at baseline and follow up visits (p&lt;0.001, p = 0.022, p = 0.028 respectively). At the network analysis, the degree of frailty related to behavioral and psychological symptoms of the hyperactivity cluster, such as agitation and motor aberrant activity; the relationship was still positive although not so strong with other symptoms like apathy and hallucinations.Conclusionin this study an association between frailty and the number of neuropsychiatric symptoms of the “hyperactivity” cluster was found; however, whether the loss of independence is a possible cause of frailty or viceversa is still to be determined. The assessment of frailty may help identifying patients at risk of developing behavioral and psychological symptoms of dementia, and could provide the clinicians with a time‐window to target intervention in the earliest phases of both frail condition and BPSD.

Longitudinal tau binding in tau‐PET negative patients with clinical Alzheimer’s disease

AbstractBackgroundDifferent tau‐PET patterns have been observed in Alzheimer’s disease (AD) which may be associated with demographic factors, copathology and resilience. We and others previously found that not all Aβ‐positive AD patients are tau‐PET positive. It is currently not known whether tau pathology develops in these groups over time. Therefore, we aimed to examine longitudinal tau binding in tau‐PET negative individuals with symptomatic AD.MethodWe included 97 Aβ‐positive participants with clinical diagnosis of mild cognitive impairment or dementia due to AD (MCI/AD) of which 12 (13%) were tau‐PET negative. To compare, we included 131 tau‐PET negative cognitively unimpaired individuals (CU) of which 93 (71%) were Aβ‐negative and 38 (29%) Aβ‐positive. Tau‐status was defined by [18F]flortaucipir PET consensus visual read of two nuclear physicians according to US Food and Drug Administration‐approved guidelines. [18F]flortaucipir SUVr at baseline (N = 225) and after ±2 years (N = 81) was quantified in an early tau region reflecting Braak I (entorhinal cortex), the medial temporal lobe (MTL), and a combined visual read region of interest (ROI) (parietal, occipital, and posterior lateral temporal lobe). We used age‐and sex‐adjusted linear mixed models to compare tau accumulation.ResultDemographics are shown in table 1. Compared to MCI/AD A+T+, MCI/AD A+T‐ were older (p&lt;0.001) and more often male (p = 0.015). MCI/AD A+T‐ did not differ from CU A‐T‐ in baseline tau‐PET SUVr, but had a slightly lower SUVr in Braak I compared to CU A+T‐ (p = 0.040) (figure 1). After ±2 years, all MCI/AD A+T‐ participants who underwent follow up remained visual read tau negative. However, MCI/AD A+T‐ showed a steeper increase in Braak I and MTL tau‐PET SUVr compared to CU A‐T‐ (figure 2A,B) and in Braak I compared to CU A+T‐ (β = 0.31, p = 0.036). Interestingly, MCI/AD A+T‐ showed a significantly steeper tau‐PET SUVr increase compared to MCI/AD A+T+ in Braak I (β = 0.29, p = 0.029) (figure 2A).ConclusionAlthough visual read tau‐PET status remains stable over time, our results indicate that tau‐negative MCI/AD patients do accumulate tau over time, most pronounced in early tau regions. This highlights the relevance of quantifying tau regionally over time in tau‐PET negative individuals with clinical AD diagnosis.

Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.MethodMeasures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐e4 genotype, ß‐amyloid (Aß) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aß was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aß+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aß levels and cognition covarying for the participant’s age, sex, and years of education where relevant.ResultAs previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aß (p&lt;0.001). The association between Aß and history in both parents remained significant when covarying for APOE‐e4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐e4 and Aß. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p&lt;0.001) and in those with only maternal family history (n = 1776, p&lt;0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: ß = 0.03, p&lt;0.001 in individuals with maternal history, ß = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (ßmaternal = 0.02, pmaternal = 0.01; ßpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.ConclusionWe confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐e4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aß burden among asymptomatic older individuals.

Initial experiences with amyloid‐related imaging abnormalities in patients receiving aducanumab following accelerated approval

AbstractBackgroundAducanumab is the first approved amyloid‐lowering immunotherapy for Alzheimer’s disease (AD). There is little real‐world data to guide the management of amyloid‐related imaging abnormality (ARIA), a potentially serious side‐effect requiring surveillance with serial magnetic resonance imaging (MRI). The current study seeks to characterize the symptoms, clinical course and management of ARIA in memory clinic patients treated with aducanumab.MethodWe conducted a non‐blinded, observational case series of patients who received aducanumab from June 16, 2021 to August 1, 2022 at the Butler Hospital Memory and Aging Program. Inclusion: (1) Clinical diagnosis of mild cognitive impairment (MCI) or mild dementia due to AD, (2) confirmed amyloid positivity (PET/CSF), and (3) Mini Mental State Exam (MMSE) = 20‐30. Exclusions: (1) MRI with &gt; 4 microhemorrhages, &gt; 1 area of superficial siderosis or significant cerebrovascular disease, (2) MRI contraindication, (3) anticoagulation and (4) unstable medical/psychiatric conditions. Participants received monthly aducanumab infusions, titrated to a dose of 10 mg/kg, with ApoE genotyping and enhanced MRI monitoring adapted from the phase 3 trials. The primary outcome of the study was the identification of ARIA‐E by MRI. Secondary outcomes included severity of ARIA, clinical course, and time to resolution.ResultOut of 24 patients treated with aducanumab, we identified ARIA‐E in 6 patients (25%), all ApoE‐ε4 carriers, and 4 of whom had moderate‐severe radiographic severity. Comorbid ARIA‐H occurred in 3 patients, 1 of whom also had new onset of cerebellar metastatic cancer. Symptomatic ARIA occurred in 3 patients and included headache, confusion, gait instability, and word‐finding difficulties. Treatment was discontinued in 4 cases of moderate‐severe ARIA‐E, temporarily held in 1 moderate/asymptomatic case, and dosed through in 1 mild/asymptomatic case. All cases of ARIA‐E resolved without hospitalization or corticosteroids (mean duration = 3 months, range, 1 ‐ 6 months).ConclusionAdditional amyloid‐lowering antibodies, associated with ARIA, may soon become clinically available. These data support the careful patient selection, ApoE genotyping, MRI surveillance and individualized dosing recommended in the updated FDA prescribing information and Appropriate Use Recommendations.