Exacerbated mitochondrial dynamic abnormalities without evident tau pathology in rapidly progressive Alzheimer's disease.

Background: Rapidly progressive Alzheimer's disease (rpAD) is a clinical subtype distinguished by its rapid cognitive decline and shorter disease duration. rpAD, like typical AD (tAD), is characterized by underlying neuropathology of amyloid plaques and neurofibrillary tangles. There is early evidence that the composition of amyloid plaques could vary between the rpAD and tAD.

Multidisciplinary lifestyle interventions for neurological disorders during the Silent phase (MINDS) study: a multi-omics randomized controlled trial protocol.

Introduction: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers.

Hemispheric asymmetries in hippocampal volume related to memory in left and right temporal variants of frontotemporal degeneration.

In addition to Alzheimer's disease (AD), the hippocampus is now known to be affected in variants of frontotemporal degeneration (FTD). In semantic variant primary progressive aphasia (svPPA), characterized by language impairments, hippocampal atrophy is greater in the left hemisphere. Nonverbal impairments (e.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

Background And Purpose: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Introduction: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage.

Methods: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk.

The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration.

In 2022, Bruce Willis' family released a statement saying that he had been diagnosed with aphasia (an acquired language impairment) and would no longer be acting. Ten months later, the Willis family released another statement indicating that he received a more specific diagnosis of frontotemporal degeneration (FTD). This resulted in an explosion of media coverage, as prominent news outlets scrambled to produce stories describing FTD to a public largely unfamiliar with the disease.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

Introduction: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis.

Methods: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category.

Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer's disease.

Background: The relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer's disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD.

Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias.

Introduction: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials.

Methods: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically.

Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice.

Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in of HFD] C57BL/6J mice using heavy water (HO)-based metabolic labeling approach.

Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer's Disease.

Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner.

Association of Variation in Behavioral Symptoms With Initial Cognitive Phenotype in Adults With Dementia Confirmed by Neuropathology.

Importance: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP).

Objectives: To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP.

Design, Setting, And Participants: This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019.

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD.

Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOEɛ4 Status.

Background: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups.

Objective: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOEɛ4 carriers and non-carriers.

Methods: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOEɛ4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia.

Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.

Sleep dysfunction has been identified in the pathophysiology of Alzheimer's disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease.

Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia.

Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

Background: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP).

Spatial patterns of correlation between cortical amyloid and cortical thickness in a tertiary clinical population with memory deficit.

To estimate regional Alzheimer disease (AD) pathology burden clinically, analysis methods that enable tracking brain amyloid or tau positron emission tomography (PET) with magnetic resonance imaging (MRI) measures are needed. We therefore developed a robust MRI analysis method to identify brain regions that correlate linearly with regional amyloid burden in congruent PET images. This method was designed to reduce data variance and improve the sensitivity of the detection of cortical thickness-amyloid correlation by using whole brain modeling, nonlinear image coregistration, and partial volume correction.

Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases.

Purpose: To investigate the association between outer retinal layer metrics, including photoreceptor outer segment volume, on spectral-domain optical coherence tomography (OCT) and brain volume on MRI in normal aging, Alzheimer's disease and Parkinson's disease.

Methods: This was an exploratory analysis of a cross-sectional cohort study that was approved by the Cleveland Clinic Institutional Review Board to evaluate neurodegenerative disorders. Subjects aged ≥ 50 were recruited.

Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

Objective: To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration.

Methods: A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform.

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease.

Objective: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD).

Methods: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations.

Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer's Disease.

Background: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels.

Amygdala sign, a FDG-PET signature of dementia with Lewy Bodies.

Background: Biomarkers are being used increasingly to support the diagnosis of dementia with Lewy bodies (DLB). Novel biomarkers that increase diagnostic specificity of DLB are needed. We assessed previously known FDG-PET occipital cortex hypometabolism, and cingulate island sign biomarkers of DLB against a novel amygdala signature.

Lack of Accurate Self-appraisal is Equally Likely in MCI from Parkinson's Disease and Alzheimer's Disease.

Background: How accurate are mild cognitive impairment (MCI) patients in assessing their cognitive and functional deficit is often unclear to the clinician. The accuracy of patient self-appraisal in Parkinson's disease-MCI (PD-MCI) has received less attention than amnestic MCI (a-MCI) often associated with Alzheimer's disease. We evaluated if PD-MCI patients demonstrate accurate self-appraisal of their cognitive deficits compared to patients with amnestic a-MCI or non-amnestic MCI (na-MCI).