Day, Gregory S.

AbstractBackgroundRapidly progressive dementia (RPD) is variably defined across published cohorts. A standardized definition is needed to support multicenter studies required to inform the causes of RPD and optimize recognition and management of treatment‐responsive causes. An optimal definition will capture the broad spectrum of causes of RPD, adequately differentiate patients with rapid and typically progressive presentations of neurodegenerative disease, and be reliably implemented across healthcare settings and centers.MethodThe Clinical Dementia Rating® (CDR) is a validated dementia staging tool that is widely used in clinical trials and observational studies. We applied the CDR to diagnose RPD in patients who developed dementia (CDR ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. This definition was prospectively applied to patients with suspected RPD at Mayo Clinic in Florida (MCF: Jacksonville, FL; Jan 2020 – Oct 2023) and Washington University in St. Louis (WU: Saint Louis, MO; Jun 2016 – Dec 2019), and retrospectively applied to individuals within the National Alzheimer’s Coordinating Center (NACC) dataset. Criteria performance was compared across cohorts.ResultTwo‐hundred twenty‐six patients were referred with suspected RPD at MCF‐WU. Of these, 155/226 (68.6%) met our proposed RPD criteria, including patients with Alzheimer disease and related dementias (ADRD; 34/155, 21.9%), Creutzfeldt Jacob disease (CJD; 25/155, 16.1%), autoimmune encephalitis (52/155, 33.5%), vascular pathologies (14/155, 9.0%), toxic/metabolic disruptions (7/155, 4.5%) and primary psychiatric disorders (4/155, 2.6%). A small subset of NACC participants met our proposed RPD criteria (836/20,418; 0.04%), emphasizing the unique nature of RPD. Causes of RPD in NACC included ADRD (676/836, 80.1%), CJD (72/836, 8.6%), and vascular pathologies (24/836, 2.9%). Rates of progression (∆CDR sum‐of‐boxes/year) clearly distinguished patients with RPD from non‐RPD in both cohorts (MCF‐WU, 13.6±5.8 vs 4.7±5.9, p<0.001; NACC, 6.7±3.1 vs. 1.7±1.4, p<0.001).ConclusionOur CDR‐based definition of RPD distinguished patients with a broad spectrum of causes of RPD from those with typically progressive dementia across multiple cohorts. Broad application of this criteria would standardize diagnosis of RPD and support the design and implementation of multicenter studies RPD.

AbstractBackgroundThe term rapidly progressive dementia (RPD) may be applied to patients with precipitous declines in cognitive function resulting in dementia within one year or complete incapacitation within two‐years of symptom onset. Although most patients present with subacute, progressive declines, selected patients develop complete incapacitation within seven days of symptom onset. The differential diagnosis and clinical characteristics of patients with abrupt‐onset dementia are not known.Method187 patients with RPD were prospectively enrolled from February 2016 to September 2023 in a study of RPD at Mayo Clinic (Jacksonville, Florida) and Washington University (Saint Louis, Missouri). Patients with ≤7 days from first symptom to onset of RPD were labelled as abrupt onset. Patient characteristics, results of investigations, and causes of abrupt‐onset dementia were further characterized. We further explored the causes of abrupt‐onset dementia in the extant literature to refine the differential diagnosis and approach to evaluation and management of these patients.ResultTwo patients in our study of RPD had abrupt‐onset RPD (2/187, 1.1%), attributed to autoimmune and vascular. An additional 63 cases were identified through comprehensive meta‐narrative review of the literature (40 publications). Causes of abrupt‐onset dementia include vascular, infectious, inflammatory, and toxic. Compromise of structures within the Papez circuit was a common unifying feature common across patients with varying etiologies, informing the localization of abrupt‐onset dementia. 20% cases had potentially treatment‐responsive causes of abrupt‐onset dementia.ConclusionCases of abrupt‐onset dementia are rare overall and associated with a limited differential diagnosis. Evaluation of patients with abrupt‐onset dementia should prioritize testing for vascular, autoimmune, infectious, and toxic causes. Early‐recognition of patients with potentially treatment‐responsive causes of dementia may promote earlier intervention leading to better outcomes in selected patients.

AbstractBackgroundAlzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region. Understanding the biological underpinnings of these variants is crucial for deciphering AD’s heterogeneity.MethodParticipants diagnosed with AD dementia (n = 54, female = 25, Age: 75.23±6.52), PCA (n = 9, female = 8, Age: 62.78±7.21), and lvPPA (n = 6, female = 2, Age: 66.33±6.38) from the Knight Alzheimer Disease Research Center (Knight ADRC) underwent 18F‐AV‐1451 tau‐PET imaging. Tau deposition, along with nine biological properties, was mapped to the cortical surface (Figure 1A): gene expression, myelin, cortical thickness, sensorimotor association axis, evolutionary expansion, cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of glucose (CMRglu) (Figure 1B). Correlation matrices and generalized linear models (GLMs) assessed relationships between tau accumulation and biological properties.ResultA correlation matrix (Figure 2A) shows significant positive associations (p<0.05) between evolutionary expansion patterns and tau accumulation in AD (r = 0.53), PCA (r = 0.29), and lvPPA (r = 0.56); and gene expression in PCA (r = 0.51). Conversely, strongest negative associations were observed in AD (r = ‐0.38, r = ‐0.15) and lvPPA (r = ‐0.18, r = ‐0.28) for CBF and myelin mapping, respectively, and in PCA (r = ‐0.25, ‐0.23) for cortical thickness and sensorimotor association axis. GLMs demonstrated significant relationships between cerebrovascular health and evolutionary expansion with tau measures across all groups. AD (r = ‐0.52) and PCA (r = ‐0.19) exhibited negative associations with gene expression and myelin mapping, respectively. Additionally, lvPPA (r = 0.39) displayed positive association with the sensorimotor association cortex.ConclusionResults elucidate distinct tau deposition patterns in AD, PCA, and lvPPA, providing insights into subtype‐specific pathophysiology. The correlation matrix and GLMs highlight the significance of evolutionary expansion and cerebrovascular health in tau accumulation. Associations underscore the complex interplay of gene expression, myelin mapping, and cortical thickness with tau pathology. Findings contribute to understanding heterogeneity within AD spectrum disorders, emphasizing the multifaceted nature of neurodegenerative processes. Further research promises refined diagnostic and therapeutic strategies tailored to distinct neurobiological profiles in AD, PCA, and lvPPA.

AbstractBackgroundPatients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.MethodPatients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.ResultOf 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.ConclusionHallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐ score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐ score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

AbstractObjectivePrion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG‐PET) imaging for this purpose.MethodsFDG‐PET were performed in 40 clinic patients with prion disease. FDG‐PET images were projected onto latent factors generated in an external dataset to yield patient‐specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data‐driven clusters, which were compared by survival time.ResultsMedian age at FDG‐PET was 65.3 years (range 23–85). Median time from FDG‐PET to death was 3.7 months (range 0.3–19.0). Four data‐driven clusters were generated, termed “Neocortical” (n = 7), “Transitional” (n = 12), “Temporo‐parietal” (n = 13), and “Deep nuclei” (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG‐PET‐patterns were not associated with demographic (age and sex) or clinical (CSF total‐tau, 14‐3‐3) variables.InterpretationGreater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG‐PET informs large‐scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG‐PET may enrich multimodal prion disease prognostication models.

Abstract The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer’s disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer’s disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

AbstractINTRODUCTIONWe investigated longitudinal associations between self‐reported exercise and Alzheimer's disease (AD)‐related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.METHODSParticipants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aβ) measured by positron emission tomography were investigated.RESULTSGreater volume of weekly exercise at baseline was associated with slower accumulation of brain Aβ at preclinical disease stages β = –0.16 [–0.23 to –0.08], and a slower decline in multiple brain regions including hippocampal volume β = 0.06 [0.03 to 0.08].DISCUSSIONExercise is associated with more favorable profiles of AD‐related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented.Highlights Greater self‐reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self‐reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.