Introduction: Recent success has been achieved in Alzheimer's disease (AD) clinical trials targeting amyloid beta (ß), demonstrating a reduction in the rate of cognitive decline. However, testing methods for amyloid-ß positivity are currently costly or invasive, motivating the development of accessible screening approaches to steer patients toward appropriate diagnostic tests. Here, we employ a pre-trained language model (Distil-RoBERTa) to identify amyloid-ß positivity from a short, connected speech sample. We further use explainable AI (XAI) methods to extract interpretable linguistic features that can be employed in clinical practice. Methods: We obtained language samples from 74 patients with primary progressive aphasia (PPA) across its three variants. Amyloid-ß positivity was established through the analysis of cerebrospinal fluid, amyloid PET, or autopsy. 51% of the sample was amyloid-positive. We trained Distil-RoBERTa for 16 epochs with a batch size of 6 and a learning rate of 5e-5, and used the LIME algorithm to train interpretation models to interpret the trained classifier's inference conditions. Results: Over ten runs of 10-fold cross-validation, the classifier achieved a mean accuracy of 92%, SD = 0.01. Interpretation models were able to capture the classifier's behavior well, achieving an accuracy of 97% against classifier predictions, and uncovering several novel speech patterns that may characterize amyloid-ß positivity. Discussion: Our work improves previous research which indicates connected speech is a useful diagnostic input for prediction of the presence of amyloid-ß in patients with PPA. Further, we leverage XAI techniques to reveal novel linguistic features that can be tested in clinical practice in the appropriate subspecialty setting. Computational linguistic analysis of connected speech shows great promise as a novel assessment method in patients with AD and related disorders.
Identifying individuals with early stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would allow professionals and loved ones to make better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau PET in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. In this study, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes (Posterior Cortical Atrophy, logopenic variant Primary Progressive Aphasia, and amnestic syndrome with multi-domain impairment and age of onset < 65 years). All patients underwent structural magnetic resonance imaging (MRI), tau (18F-Flortaucipir) PET, and amyloid (either 18F-Florbetaben or 11C-Pittsburgh Compound B) PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Our sample of early atypical AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, d = 0.95. These AD patients showed prominent baseline tau burden in posterior cortical regions including the major nodes of the default mode network, including the angular gyrus, posterior cingulate cortex/precuneus, and lateral temporal cortex. Greater baseline tau in the broader default mode network predicted faster clinical decline. Tau in the default mode network was the strongest predictor of clinical decline, outperforming baseline clinical impairment, tau in other functional networks, and the magnitude of cortical atrophy and amyloid burden in the default mode network. Overall, these findings point to the contribution of baseline tau burden within the default mode network of the cerebral cortex to predicting the magnitude of clinical decline in a sample of atypical early AD patients one year later. This simple measure based on a tau PET scan could aid the development of a personalized prognostic, monitoring, and treatment plan tailored to each individual patient, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.
Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
This study challenges the conventional psycholinguistic view that the distinction between nouns and verbs is pivotal in understanding language impairments in neurological disorders. Traditional views link frontal brain region damage with verb processing deficits and posterior temporoparietal damage with noun difficulties. However, this perspective is contested by findings from patients with Alzheimer's disease (pwAD), who show impairments in both word classes despite their typical temporoparietal atrophy. Notably, pwAD tend to use semantically lighter verbs in their speech than healthy individuals. By examining English-speaking pwAD and comparing them with Persian-speaking pwAD, this research aims to demonstrate that language impairments in Alzheimer's disease (AD) stem from the distributional properties of words within a language rather than distinct neural processing networks for nouns and verbs. We propose that the primary deficit in AD language production is an overreliance on high-frequency words. English has a set of particularly high-frequency verbs that surpass most nouns in usage frequency. Since pwAD tend to use high-frequency words, the byproduct of this word distribution in the English language would be an over-usage of high-frequency verbs. In contrast, Persian features complex verbs with an overall distribution lacking extremely high-frequency verbs like those found in English. As a result, we hypothesize that Persian-speaking pwAD would not have a bias toward the overuse of high-frequency verbs. We analyzed language samples from 95 English-speaking pwAD and 91 healthy controls, along with 27 Persian-speaking pwAD and 27 healthy controls. Employing uniform automated natural language processing methods, we measured the usage rates of nouns, verbs, and word frequencies across both cohorts. Our findings showed that English-speaking pwAD use higher-frequency verbs than healthy individuals, a pattern not mirrored by Persian-speaking pwAD. Crucially, we found a significant interaction between the frequencies of verbs used by English and Persian speakers with and without AD. Moreover, regression models that treated noun and verb frequencies as separate predictors did not outperform models that considered overall word frequency alone in classifying AD. In conclusion, this study suggests that language abnormalities among English-speaking pwAD reflect the unique distributional properties of words in English rather than a universal noun-verb class distinction. Beyond offering a new understanding of language abnormalities in AD, the study highlights the critical need for further investigation across diverse languages to deepen our insight into the mechanisms of language impairments in neurological disorders.
INTRODUCTION: This research investigates the psycholinguistic origins of language impairments in Alzheimer's Disease (AD), questioning if these impairments result from language-specific structural disruptions or from a universal deficit in generating meaningful content. METHODS: Cross-linguistic analysis was conducted on language samples from 184 English and 52 Persian speakers, comprising both AD patients and healthy controls, to extract various language features. Furthermore, we introduced a machine learning-based metric, Language Informativeness Index (LII), to quantify informativeness. RESULTS: Indicators of AD in English were found to be highly predictive of AD in Persian, with a 92.3% classification accuracy. Additionally, we found robust correlations between the typical linguistic abnormalities of AD and language emptiness (low LII) across both languages. DISCUSSION: Findings suggest AD linguistics impairments are attributed to a core universal difficulty in generating informative messages. Our approach underscores the importance of incorporating biocultural diversity into research, fostering the development of inclusive diagnostic tools.
Introduction: Visual naming ability reflects semantic memory retrieval and is a hallmark deficit of Alzheimer's disease (AD). Naming impairment is most prominently observed in the late-onset amnestic and logopenic variant Primary Progressive Aphasia (lvPPA) syndromes. However, little is known about how other patients across the atypical AD syndromic spectrum perform on tests of auditory naming, particularly those with primary visuospatial deficits (Posterior Cortical Atrophy; PCA) and early onset (EOAD) syndromes. Auditory naming tests may be of particular relevance to more accurately measuring anomia in PCA syndrome and in others with visual perceptual deficits. Methods: Forty-six patients with biomarker-confirmed AD (16 PCA, 12 lvPPA, 18 multi-domain EOAD), at the stage of mild cognitive impairment or mild dementia, were administered the Auditory Naming Test (ANT). Performance differences between groups were evaluated using one-way ANOVA and post-hoc t-tests. Correlation analyses were used to examine ANT performance in relation to measures of working memory and word retrieval to elucidate cognitive mechanisms underlying word retrieval deficits. Whole-cortex general linear models were generated to determine the relationship between ANT performance and cortical atrophy. Results: Based on published cutoffs, out of a total possible score of 50 on the ANT, 56% of PCA patients (mean score = 45.3), 83% of EOAD patients (mean = 39.2), and 83% of lvPPA patients (mean = 29.8) were impaired. Total uncued ANT performance differed across groups, with lvPPA performing most poorly, followed by EOAD, and then PCA. ANT performance was still impaired in lvPPA and EOAD after cuing, while performance in PCA patients improved to the normal range with phonemic cues. ANT performance was also directly correlated with measures of verbal fluency and working memory, and was associated with cortical atrophy in a circumscribed semantic language network. Discussion: Auditory confrontation naming is impaired across the syndromic spectrum of AD including in PCA and EOAD, and is likely related to auditory-verbal working memory and verbal fluency which represent the nexus of language and executive functions. The left-lateralized semantic language network was implicated in ANT performance. Auditory naming, in the absence of a visual perceptual demand, may be particularly sensitive to measuring naming deficits in PCA.
Recent efforts demonstrated the efficacy of identifying early-stage neuropathology of Alzheimer's disease (AD) through lumbar puncture cerebrospinal fluid assessment and positron emission tomography (PET) radiotracer imaging. These methods are effective yet are invasive, expensive, and not widely accessible. We extend and improve the multiscale structural mapping (MSSM) procedure to develop structural indicators of ß-amyloid neuropathology in preclinical AD, by capturing both macrostructural and microstructural properties throughout the cerebral cortex using a structural MRI. We find that the MSSM signal is regionally altered in clear positive and negative cases of preclinical amyloid pathology (N = 220) when cortical thickness alone or hippocampal volume is not. It exhibits widespread effects of amyloid positivity across the posterior temporal, parietal, and medial prefrontal cortex, surprisingly consistent with the typical pattern of amyloid deposition. The MSSM signal is significantly correlated with amyloid PET in almost half of the cortex, much of which overlaps with regions where beta-amyloid accumulates, suggesting it could provide a regional brain 'map' that is not available from systemic markers such as plasma markers.
Alzheimer Disease , Amyloid beta-Peptides , Humans , Amyloid beta-Peptides/metabolism , Brain/metabolism , Alzheimer Disease/pathology , Positron-Emission Tomography/methods , Magnetic Resonance Imaging/methods , Amyloid/metabolism
Introduction: Posterior Cortical Atrophy (PCA) is a syndrome characterized by a progressive decline in higher-order visuospatial processing, leading to symptoms such as space perception deficit, simultanagnosia, and object perception impairment. While PCA is primarily known for its impact on visuospatial abilities, recent studies have documented language abnormalities in PCA patients. This study aims to delineate the nature and origin of language impairments in PCA, hypothesizing that language deficits reflect the visuospatial processing impairments of the disease. Methods: We compared the language samples of 25 patients with PCA with age-matched cognitively normal (CN) individuals across two distinct tasks: a visually-dependent picture description and a visually-independent job description task. We extracted word frequency, word utterance latency, and spatial relational words for this comparison. We then conducted an in-depth analysis of the language used in the picture description task to identify specific linguistic indicators that reflect the visuospatial processing deficits of PCA. Results: Patients with PCA showed significant language deficits in the visually-dependent task, characterized by higher word frequency, prolonged utterance latency, and fewer spatial relational words, but not in the visually-independent task. An in-depth analysis of the picture description task further showed that PCA patients struggled to identify certain visual elements as well as the overall theme of the picture. A predictive model based on these language features distinguished PCA patients from CN individuals with high classification accuracy. Discussion: The findings indicate that language is a sensitive behavioral construct to detect visuospatial processing abnormalities of PCA. These insights offer theoretical and clinical avenues for understanding and managing PCA, underscoring language as a crucial marker for the visuospatial deficits of this atypical variant of Alzheimer's disease.
Normal aging is commonly accompanied by a decline in cognitive abilities, including memory, yet some individuals maintain these abilities as they get older. We hypothesize that semantic clustering, as an effective strategy for improving performance on episodic recall tasks, may contribute to the maintenance of youthful memory in older adults. We investigated the dynamics of spontaneous production and utilization of the semantic clustering strategy in two independent samples of older adults who completed a list learning paradigm (N1 = 40 and N2 = 29, respectively). Specifically, we predicted and observed that older adults who spontaneously used a semantic clustering strategy throughout the encoding process learned more words by the culmination of the encoding trials (Sample 1, R2= 0.53, p < 0.001; Sample 2, R2= 0.51, p < 0.001), and that those who utilized this strategy during retrieval recalled more words, when compared to older adults who did not produce or utilize a semantic clustering strategy during both a short (Sample 1, R2 = 0.81, p < 0.001; Sample 2, R2 = 0.70, p < 0.001) and long delay retrieval (Sample 1, R2 = 0.83, p < 0.001; Sample 2, R2 = 0.77, p < 0.001). We further predicted and observed that older adults who maintained a youthful level of delayed free recall (i.e., "Superagers") produced (Sample 1, F(1, 38) = 17.81, p < 0.0001; Sample 2, F(1, 27) = 14.45, p < 0.0001) and utilized (Sample 1, F(1, 39) = 25.84, p < 0.0001; Sample 2, F(1, 27) = 12.97, p < 0.01) more semantic clustering than did older individuals with normal memory for their age. These results suggest one cognitive mechanism through which Superagers maintain youthful memory function and raise the possibility that older adults may be able to train themselves to use strategies to promote better memory.
INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.
Alzheimer Disease , Resilience, Psychological , Humans , Alzheimer Disease/pathology , tau Proteins , Neurofibrillary Tangles/pathology , Magnetic Resonance Imaging , Amyloid beta-Peptides
BACKGROUND: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID-19 pandemic, and lay the foundation for future work using this cohort. METHODS: SAGES II is a prospective observational cohort study of community-dwelling adults age 65 and older undergoing major non-cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID-19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. RESULTS: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty-eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID-19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1-month follow-up; nearly 90% of enrolled participants completed interviews through 6-month follow-up. CONCLUSION: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers-including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource.
COVID-19 , Delirium , Humans , Aged , Delirium/epidemiology , Prospective Studies , Pandemics , Aging , Biomarkers
Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.
COVID-19 , Neurology , Neuropsychiatry , Telemedicine , Humans , Hospitals, General , Pandemics , Activities of Daily Living , Massachusetts , Cognition
The temporal pole (TP) is considered one of the major paralimbic cortical regions, and is involved in a variety of functions such as sensory perception, emotion, semantic processing, and social cognition. Based on differences in cytoarchitecture, the TP can be further subdivided into smaller regions (dorsal, ventrolateral and ventromedial), each forming key nodes of distinct functional networks. However, the brain structural connectivity profile of TP subregions is not fully clarified. Using diffusion MRI data in a set of 31 healthy subjects, we aimed to elucidate the comprehensive structural connectivity of three cytoarchitectonically distinct TP subregions. Diffusion tensor imaging (DTI) analysis suggested that major association fiber pathways such as the inferior longitudinal, middle longitudinal, arcuate, and uncinate fasciculi provide structural connectivity to the TP. Further analysis suggested partially overlapping yet still distinct structural connectivity patterns across the TP subregions. Specifically, the dorsal subregion is strongly connected with wide areas in the parietal lobe, the ventrolateral subregion with areas including constituents of the default-semantic network, and the ventromedial subregion with limbic and paralimbic areas. Our results suggest the involvement of the TP in a set of extensive but distinct networks of cortical regions, consistent with its functional roles.
Introduction: Posterior Cortical Atrophy (PCA) is a syndrome characterized by a progressive decline in higher-order visuospatial processing, leading to symptoms such as space perception deficit, simultanagnosia, and object perception impairment. While PCA is primarily known for its impact on visuospatial abilities, recent studies have documented language abnormalities in PCA patients. This study aims to delineate the nature and origin of language impairments in PCA, hypothesizing that language deficits reflect the visuospatial processing impairments of the disease. Methods: We compared the language samples of 25 patients with PCA with age-matched cognitively normal (CN) individuals across two distinct tasks: a visually-dependent picture description and a visually-independent job description task. We extracted word frequency, word utterance latency, and spatial relational words for this comparison. We then conducted an in-depth analysis of the language used in the picture description task to identify specific linguistic indicators that reflect the visuospatial processing deficits of PCA. Results: Patients with PCA showed significant language deficits in the visually-dependent task, characterized by higher word frequency, prolonged utterance latency, and fewer spatial relational words, but not in the visually-independent task. An in-depth analysis of the picture description task further showed that PCA patients struggled to identify certain visual elements as well as the overall theme of the picture. A predictive model based on these language features distinguished PCA patients from CN individuals with high classification accuracy. Discussion: The findings indicate that language is a sensitive behavioral construct to detect visuospatial processing abnormalities of PCA. These insights offer theoretical and clinical avenues for understanding and managing PCA, underscoring language as a crucial marker for the visuospatial deficits of this atypical variant of Alzheimer's disease.
INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.
Alzheimer Disease , Humans , Alzheimer Disease/pathology , Reproducibility of Results , Temporal Lobe/pathology , Magnetic Resonance Imaging/methods , Atrophy/pathology , Biomarkers
INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
Alzheimer Disease , Humans , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , C9orf72 Protein/genetics , Genetic Testing , Longitudinal Studies , Mutation , Presenilin-1/genetics , Presenilin-2/genetics
BACKGROUND: By 2030, approximately 75 million adults will be living with Alzheimer disease and related dementias (ADRDs). ADRDs produce cognitive, emotional, and behavioral changes for persons living with dementia that undermine independence and produce considerable stressors for persons living with dementia and their spousal care-partners-together called a "dyad." Clinically elevated emotional distress (ie, depression and anxiety symptoms) is common for both dyad members after ADRD diagnosis, which can become chronic and negatively impact relationship functioning, health, quality of life, and collaborative management of progressive symptoms. OBJECTIVE: This study is part of a larger study that aims to develop, adapt, and establish the feasibility of Resilient Together for Alzheimer Disease and Related Dementias (RT-ADRD), a novel dyadic skills-based intervention aimed at preventing chronic emotional distress. This study aims to gather comprehensive information to develop the first iteration of RT-ADRD and inform a subsequent open pilot. Here, we describe the proposed study design and procedures. METHODS: All procedures will be conducted virtually (via phone and Zoom) to minimize participant burden and gather information regarding feasibility and best practices surrounding virtual procedures for older adults. We will recruit dyads (up to n=20) from Mount Sinai Hospital (MSH) clinics within 1 month of ADRD diagnosis. Dyads will be self-referred or referred by their treating neurologists and complete screening to assess emotional distress and capacity to consent to participate in the study. Consenting dyads will then participate in a 60-minute qualitative interview using an interview guide designed to assess common challenges, unmet needs, and support preferences and to gather feedback on the proposed RT-ADRD intervention content and design. Each dyad member will then have the opportunity to participate in an optional individual interview to gather additional feedback. Finally, each dyad member will complete a brief quantitative survey remotely (by phone, tablet, or computer) via a secure platform to assess feasibility of assessment and gather preliminary data to explore associations between proposed mechanisms of change and secondary outcomes. We will conduct preliminary explorations of feasibility markers, including recruitment, screening, live video interviews, quantitative data collection, and mixed methods analyses. RESULTS: This study has been approved by the MSH Institutional Review Board. We anticipate that the study will be completed by late 2023. CONCLUSIONS: We will use results from this study to develop the first live video telehealth dyadic resiliency intervention focused on the prevention of chronic emotional distress in couples shortly after ADRD diagnoses. Our study will allow us to gather comprehensive information from dyads on important factors to address in an early prevention-focused intervention and to explore feasibility of study procedures to inform future open pilot and pilot feasibility randomized control trial investigations of RT-ADRD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45532.
INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.
Alzheimer Disease , Cognitive Dysfunction , Humans , Female , Alzheimer Disease/metabolism , Electrons , Prospective Studies , tau Proteins/metabolism , Positron-Emission Tomography/methods , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/metabolism , Amyloid/metabolism , Biomarkers
INTRODUCTION: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. METHODS: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. RESULTS: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. DISCUSSION: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. HIGHLIGHTS: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.
Alzheimer Disease , Memory, Episodic , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/psychology , Neuropsychological Tests , Memory Disorders/diagnosis , Memory Disorders/etiology , Longitudinal Studies , Amyloidogenic Proteins
