Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App knock-in mouse model of Alzheimer's disease.

Background: Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.

Methods: CSF, serum, and brain tissue were collected from 3- to 18-month-old App knock-in mice (n = 48) and 2-18-month-old App knock-in mice (n = 35).

Associations between dietary patterns and dementia-related neuroimaging markers.

Background: The exploration of associations between dietary patterns and dementia-related neuroimaging markers can provide insights on food combinations that may impact brain integrity.

Methods: Data were derived from the Swedish Gothenburg H70 Birth Cohort Study (n = 610). Three dietary patterns were obtained using principal component analysis.

Plasma amyloid-β42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer's disease.

The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer's disease is mostly unexplored. We collected plasma amyloid-β42/40, apolipoprotein E ε4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.

Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads.

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare independent associations between multiple plasma biomarkers (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p-tau217 and p-tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p-tau231 were only associated with plaques (ρ [95%CI] = -0.

Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background.

Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia.

Background And Objectives: Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia.

Apathy in Alzheimer's disease: A neurocircuitry based perspective.

In addition to memory deficits and other cognitive disturbances, patients with Alzheimer's disease (AD) experience neuropsychiatric symptoms, notably apathy, which is a state of impaired motivation observed by deficits in goal directed behavior. Apathy is a multifaceted neuropsychiatric condition and appears to be a prognostic indicator, correlating with the progression of AD. Strikingly, recent studies point out that the neurodegenerative pathology of AD may drive apathy independent of cognitive decline.

APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals.

Purpose: To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants.

Methods: The 352 CU participants (mean aged 61.1 [4.

Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by Status.

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aβ) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Depositions might be related to the circulating IAPP levels, but it warrants further investigation. Autoantibodies recognizing toxic IAPP oligomers (IAPP) but not monomers (IAPP) or fibrils have been found in T2D, but studies on AD are lacking.

Diagnosis and Management of Posterior Cortical Atrophy.

Purpose Of Review: The study aims to provide a summary of recent developments for diagnosing and managing posterior cortical atrophy (PCA). We present current efforts to improve PCA characterisation and recommendations regarding use of clinical, neuropsychological and biomarker methods in PCA diagnosis and management and highlight current knowledge gaps.

Recent Findings: Recent multi-centre consensus recommendations provide PCA criteria with implications for different management strategies (e.

Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n=126), amyotrophic lateral sclerosis (ALS, n=141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer’s disease (n=304).

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers.

Importance: Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.

Discriminative accuracy of the A/T/N scheme to identify cognitive impairment due to Alzheimer's disease.

Introduction: The optimal combination of amyloid-β/tau/neurodegeneration (A/T/N) biomarker profiles for the diagnosis of Alzheimer's disease (AD) dementia is unclear.

Methods: We examined the discriminative accuracy of A/T/N combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non-AD neurodegenerative diseases in the TRIAD, BioFINDER-1 and BioFINDER-2 cohorts (total  = 832) using area under the receiver operating characteristic curves (AUC).

Results: For the diagnosis of AD dementia (vs.

Robustness of CSF Aβ42/40 and Aβ42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes.

Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology).

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study.

Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.

Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit).

Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R ≥ 0.

The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer's disease: a literature review.

The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics.

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.

Introduction: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD.

Methods: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.

Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest.

Background/aim: Signs of hypoxic ischaemic encephalopathy (HIE) on head computed tomography (CT) predicts poor neurological outcome after cardiac arrest. We explore whether levels of brain injury markers in blood could predict the likelihood of HIE on CT.

Methods: Retrospective analysis of CT performed at 24-168 h post cardiac arrest on clinical indication within the Target Temperature Management after out-of-hospital cardiac arrest-trial.

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients.

Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials.

Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ) ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline.

[F]RO948 tau positron emission tomography in genetic and sporadic frontotemporal dementia syndromes.

Purpose: To examine [F]RO948 retention in FTD, sampling the underlying protein pathology heterogeneity.

Methods: A total of 61 individuals with FTD (n = 35), matched cases of AD (n = 13) and Aβ-negative cognitively unimpaired individuals (n = 13) underwent [F]RO948PET and MRI. FTD included 21 behavioral variant FTD (bvFTD) cases, 11 symptomatic C9orf72 mutation carriers, one patient with non-genetic bvFTD-ALS, one individual with bvFTD due to a GRN mutation, and one due to a MAPT mutation (R406W).

Antibody-free measurement of cerebrospinal fluid tau phosphorylation across the Alzheimer's disease continuum.

Background: Alzheimer's disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology.

The genetic regulation of protein expression in cerebrospinal fluid.

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.