Blood-based biomarkers for Alzheimer's disease and related dementias: Keys to success and things to consider

During the last two decades, considerable progress has been made in the field of fluid and imaging biomarkers for neurodegenerative dementias. As a result, the most recent research and clinical guidelines (the National Institute on Aging and Alzheimer's Association, International Working Group 2, National Institute for Health and Care Excellence) incorporate cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers in the diagnostic criteria of dementia and mild cognitive impairment due to Alzheimer's disease (AD) [[1], [2], [3]]. However, as both CSF and amyloid PET examinations require expert knowledge and are of limited availability outside specialized memory clinics, there is no doubt that blood tests would be much easier to implement in clinical medicine and as screening tools when recruiting patients for clinical trials

Tau Imaging in Alzheimer's Disease Diagnosis and Clinical Trials

In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer's disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols

Association of Hypercholesterolemia with Alzheimer’s Disease Pathology and Cerebral Amyloid Angiopathy

Background: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer’s disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. Objective: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. Methods: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer’s Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. Results: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. Conclusion: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions

The Functional Ability of MCI and Alzheimer’s Patients Predicts Caregiver Burden

Research shows that caregivers of dementia patients experience burden and psychological distress, but it is unclear whether or not caregivers of individuals with cognitive impairments that do not meet a diagnosis for dementia also experience similar burdens and psychological problems. Sixty patients and their caregivers participated in this study designed to examine caregiver burden. The patients completed activities-of-daily-living tasks and several neuropsychological tests assessing memory, abstract reasoning, and language. Caregivers completed self-report measures assessing caregiver burden and psychological distress. Results revealed that the caregivers of patients with mild Alzheimer’s disease (mAD) reported greater physical burden and feelings of missing out on life compared to individuals with mild cognitive impairment (MCI) caregivers. The mAD caregivers indicated greater depression and anxiety relative to MCI caregivers. Stepwise regression found that patient neuropsychological scores were worse predictors of caregiver burden than patients’ daily functioning. The conclusions of this study suggest that (1) caregivers of mAD are likely to experience more severe types of burden and psychological distress relative to caregivers of MCI patients, and that (2) patients’ daily functional abilities better predict caregivers’ burden and psychological distress than patients’ neuropsychological functioning. Study findings suggest that caregivers of those in the early stages of dementia, even in persons not yet meeting a diagnosis, experience psychological symptoms and burden, and that these caregivers’ experiences can be best predicted by the patients daily functional ability than by patients’ neuropsychological test scores

Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study

Objective To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline. Methods 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer’s disease dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative received (18F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher’s exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status. Results No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects. Conclusions Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia

Genome-wide association study of language performance in Alzheimer's disease

Language impairment is common in prodromal stages of Alzheimer's disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome-wide association study (GWAS) using a composite measure of language performance from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p<5×10-8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD

Visual contrast sensitivity is associated with the presence of cerebral amyloid and tau deposition

Visual deficits are common in neurodegenerative diseases including Alzheimer’s disease. We sought to determine the association between visual contrast sensitivity and neuroimaging measures of Alzheimer’s disease-related pathophysiology, including cerebral amyloid and tau deposition and neurodegeneration. A total of 74 participants (7 Alzheimer’s disease, 16 mild cognitive impairment, 20 subjective cognitive decline, 31 cognitively normal older adults) underwent the frequency doubling technology 24-2 examination, a structural MRI scan and amyloid PET imaging for the assessment of visual contrast sensitivity. Of these participants, 46 participants (2 Alzheimer’s disease, 9 mild cognitive impairment, 12 subjective cognitive decline, 23 cognitively normal older adults) also underwent tau PET imaging with [18F]flortaucipir. The relationships between visual contrast sensitivity and cerebral amyloid and tau, as well as neurodegeneration, were assessed using partial Pearson correlations, covaried for age, sex and race and ethnicity. Voxel-wise associations were also evaluated for amyloid and tau. The ability of visual contrast sensitivity to predict amyloid and tau positivity were assessed using forward conditional logistic regression and receiver operating curve analysis. All analyses first were done in the full sample and then in the non-demented at-risk individuals (subjective cognitive decline and mild cognitive impairment) only. Significant associations between visual contrast sensitivity and regional amyloid and tau deposition were observed across the full sample and within subjective cognitive decline and mild cognitive impairment only. Voxel-wise analysis demonstrated strong associations of visual contrast sensitivity with amyloid and tau, primarily in temporal, parietal and occipital brain regions. Finally, visual contrast sensitivity accurately predicted amyloid and tau positivity. Alterations in visual contrast sensitivity were related to cerebral deposition of amyloid and tau, suggesting that this measure may be a good biomarker for detecting Alzheimer’s disease-related pathophysiology. Future studies in larger patient samples are needed, but these findings support the power of these measures of visual contrast sensitivity as a potential novel, inexpensive and easy-to-administer biomarker for Alzheimer’s disease-related pathology in older adults at risk for cognitive decline

Cognitive Correlates of Hippocampal Atrophy and Ventricular Enlargement in Adults with or without Mild Cognitive Impairment

We analyzed structural magnetic resonance imaging data from 58 cognitively normal and 101 mild cognitive impairment subjects. We used a general linear regression model to study the association between cognitive performance with hippocampal atrophy and ventricular enlargement using the radial distance method. Bilateral hippocampal atrophy was associated with baseline and longitudinal memory performance. Left hippocampal atrophy predicted longitudinal decline in visuospatial function. The multidomain ventricular analysis did not reveal any significant predictors

Volumetric comparison of hippocampal subfields extracted from 4-minute accelerated vs. 8-minute high-resolution T2-weighted 3T MRI scans

The hippocampus has been widely studied using neuroimaging, as it plays an important role in memory and learning. However, hippocampal subfield information is difficult to capture by standard magnetic resonance imaging (MRI) techniques. To facilitate morphometric study of hippocampal subfields, ADNI introduced a high resolution (0.4 mm in plane) T2-weighted turbo spin-echo sequence that requires 8 min. With acceleration, the protocol can be acquired in 4 min. We performed a comparative study of hippocampal subfield volumes using standard and accelerated protocols on a Siemens Prisma 3T MRI in an independent sample of older adults that included 10 cognitively normal controls, 9 individuals with subjective cognitive decline, 10 with mild cognitive impairment, and 6 with a clinical diagnosis of Alzheimer’s disease (AD). The Automatic Segmentation of Hippocampal Subfields (ASHS) software was used to segment 9 primary labeled regions including hippocampal subfields and neighboring cortical regions. Intraclass correlation coefficients were computed for reliability tests between 4 and 8 min scans within and across the four groups. Pairwise group analyses were performed, covaried for age, sex and total intracranial volume, to determine whether the patterns of group differences were similar using 4 vs. 8 min scans. The 4 and 8 min protocols, analyzed by ASHS segmentation, yielded similar volumetric estimates for hippocampal subfields as well as comparable patterns of differences between study groups. The accelerated protocol can provide reliable imaging data for investigation of hippocampal subfields in AD-related MRI studies and the decreased scan time may result in less vulnerability to motion