Biomarkers in the primary progressive aphasias

Background: Primary progressive aphasia (PPA) is a progressive disorder of language that is increasingly recognised as an important presentation of a specific spectrum of neurodegenerative conditions.

Aims: In an era of etiologically specific treatments for neurodegenerative conditions, it is crucial to establish the histopathologic basis for PPA. In this review, I discuss biomarkers for identifying the pathology underlying PPA.

Main Contribution: Clinical syndromes suggest a probabilistic association between a specific PPA variant and an underlying pathology, but there are also many exceptions. A considerable body of work with biomarkers is now emerging as an important addition to clinical diagnosis. I review genetic, neuroimaging and biofluid studies that can help determine the pathologic basis for PPA.

Conclusions: Together with careful clinical examination, there is great promise that supplemental biomarker assessments will lead to accurate diagnosis of the pathology associated with PPA during life and serve as the basis for clinical trials in this spectrum of disease.     

Progressive, isolated language disturbance: its significance in a 65-year-old-man. A case report with implications for treatment and review of literature

Language disturbances are common features occurring in different neurodegenerative diseases, including Alzheimer's disease (AD) and the Frontotemporal Lobar Degeneration (FTLD) variants Primary Progressive Aphasia (PPA) and Semantic Dementia (SD). Despite AD and FTLD are supposed to have a different pathophysiology, PPA has been demonstrated to have in some cases an AD pathological component. The syndromic and etiological heterogeneity is crucial for the differential diagnosis and consequently for a therapeutical approach. Here, the case of a patient with progressive isolated language disturbances is presented, and further discussed on the basis of current diagnostic criteria and available guidelines for treatment.     

Cerebrospinal fluid markers detect Alzheimer's disease in nonamnestic dementia

Introduction

The accuracy of cerebrospinal fluid (CSF) biomarkers for detecting Alzheimer's disease (AD) pathology has not been fully validated in autopsied nonamnestic dementias.

Accelerated clinical decline in well-educated patients with frontotemporal lobar degenerations

Education seems to protect against symptoms of neurodegeneration, but highly educated individuals experience faster cognitive decline after the onset of dementia. No studies on the effects of education on the clinical course in frontotemporal lobar degenerations (FTLD) exist. The aim of the study was to explore the effect of education on the rate of clinical deterioration in patients with FTLD. Thirty-five patients with FTLD were recruited and followed up for 20 months in average. A correlation was calculated between years of education and monthly rate of change on the clinical dementia rating scale sum of the boxes (CDR-SOB). A linear regression analysis with the CDR-SOB monthly rate of change as dependent, and the educational years and other variables possibly associated with the rate of clinical decline as independent variables was performed. There was a significant positive association between education and CDR-SOB monthly rate of change, indicating a faster decline in the well-educated. Education was the only significant predictor of clinical deterioration.     

Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations

Introduction

Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown.

Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

Introduction

The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI is a multisite, longitudinal, observational study that has collected many biomarkers since 2004. Recent publications highlight the multifactorial nature of late-onset AD. We discuss selected topics that provide insights into AD progression and outline how this knowledge may improve clinical trials.

Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes

Frontotemporal lobar degeneration (FTLD) can be classified as tau-positive (FTLD-tau) and tau-negative FTLD. The most common form of tau-negative FTLD is associated with neuronal inclusions that are composed of TAR DNA-binding protein 43 (TDP-43) (FTLD-TDP). Recent evidence suggests that FTLD-TDP can be further subdivided into at least three major histologic variants based on patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN) in neocortex and hippocampus. The aim of this study was to extend the histologic analysis to other brain regions and to determine if there were distinct clinical and pathologic characteristics of the FTLD-TDP subtypes. Thirty-nine FTLD-TDP cases were analyzed (Mackenzie type 1 n = 24, Mackenzie type 2 n = 9, Mackenzie type 3 n = 6). There was a highly significant association between clinical syndrome and FTLD-TDP subtype, with progressive non-fluent aphasia associated with type 1, semantic dementia with type 2, and behavioral variant frontotemporal dementia with types 1, 2 and 3. Semi-quantitative analysis of NCI and DN demonstrated different patterns of involvement in cortical, subcortical and brainstem areas that were characteristic for each of the three types of FTLD-TDP. Type 1 had a mixture of NCI and DN, as well as intranuclear inclusions in most cases and TDP-43 pathology at all levels of the neuraxis, but less in brainstem than supratentorial structures. Type 2 cases were characterized by predominance of long, thick DN in the cortex, as well as numerous NCI in hippocampus, amygdala and basal ganglia, but virtually no NCI and only sparse DN in diencephalon and brainstem. Type 3 had a paucity of DN at all levels of the neuraxis and significantly more NCI in the hypoglossal nucleus than the other types. These findings extend previously described clinicopathological associations of FTLD-TDP subtypes and support the notion that FTLD-TDP subtypes may be distinct clinicopathologic disorders.     

Defining imaging biomarker cut points for brain aging and Alzheimer's disease

Introduction

Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.

Longitudinal brain structural changes in preclinical Alzheimer's disease

Introduction

Brain structural changes in preclinical Alzheimer's disease (AD) are poorly understood.

Cortical microstructural changes along the Alzheimer's disease continuum

Introduction

Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD).

Clinical and genetic analyses of familial and sporadic frontotemporal dementia patients in Southern Italy

Introduction

We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease.     

Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer's disease

Introduction

The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear.

2017 Alzheimer's disease facts and figures

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, costs of care, and the overall impact on caregivers and society. The Special Report examines how the use of biomarkers may influence the AD diagnostic process and estimates of prevalence and incidence of the disease. An estimated 5.5 million Americans have Alzheimer's dementia. By mid-century, the number of people living with Alzheimer's dementia in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's dementia every 66 seconds. By 2050, one new case of Alzheimer's dementia is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2014, official death certificates recorded 93,541 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥65 years. Between 2000 and 2014, deaths resulting from stroke, heart disease, and prostate cancer decreased 21%, 14%, and 9%, respectively, whereas deaths from AD increased 89%. The actual number of deaths to which AD contributes is likely much larger than the number of deaths from AD recorded on death certificates. In 2017, an estimated 700,000 Americans age ≥65 years will have AD when they die, and many of them will die because of the complications caused by AD. In 2016, more than 15 million family members and other unpaid caregivers provided an estimated 18.2 billion hours of care to people with Alzheimer's or other dementias. This care is valued at more than $230 billion. Average per-person Medicare payments for services to beneficiaries age ≥65 years with Alzheimer's or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2017 for health care, long-term care, and hospice services for people age ≥65 years with dementia are estimated to be $259 billion. In recent years, efforts to develop and validate AD biomarkers, including those detectable with brain imaging and in the blood and cerebrospinal fluid, have intensified. Such efforts could transform the practice of diagnosing AD from one that focuses on cognitive and functional symptoms to one that incorporates biomarkers. This new approach could promote diagnosis at an earlier stage of disease and lead to a more accurate understanding of AD prevalence and incidence.     

额叶变异型阿尔茨海默病的临床和影像学特征一例

目的额叶变异型阿尔茨海默病(AD)是一种以精神行为等症状为主要表型的少见特殊类型AD,本文报道1例额叶变异型AD的临床特点、影像学特征,以增加临床医生对该病的认识。方法报道1例额叶变异型AD患者的临床资料,分析其临床表现、辅助检查及影像学资料。结果本例患者以妄想和行为异常等为主要和最早临床表现,发病2年后才出现记忆力减退、言语表达困难、计算不能等症状,头颅MRI提示双侧额颞叶萎缩,以左侧为著。头颅SPECT显示:双侧额叶、颞叶和顶叶葡萄糖摄取普遍减低。PIB-PET(淀粉样蛋白PET):大脑皮质PIB显著滞留,考虑为PIB阳性显像。结论额叶变异型AD与行为变异型额颞叶痴呆临床表现类似,淀粉样蛋白PET检查可有效区分两者。     

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.     

2018 Alzheimer's disease facts and figures

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, costs of care, and the overall impact on caregivers and society. The Special Report examines the benefits of diagnosing Alzheimer's earlier in the disease process, in the stage of mild cognitive impairment due to Alzheimer's disease. An estimated 5.7 million Americans have Alzheimer's dementia. By mid-century, the number of people living with Alzheimer's dementia in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. In 2015, official death certificates recorded 110,561 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥65 years. Between 2000 and 2015, deaths resulting from stroke, heart disease, and prostate cancer decreased, whereas deaths from AD increased 123%. In 2017, more than 16 million family members and other unpaid caregivers provided an estimated 18.4 billion hours of care to people with Alzheimer's or other dementias. This care is valued at more than $232 billion, but its costs extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes. Average per-person Medicare payments for services to beneficiaries age ≥65 years with Alzheimer's or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2018 for health care, long-term care and hospice services for people age ≥65 years with dementia are estimated to be $277 billion. With the identification of AD biomarkers in recent years, our understanding of the disease has moved from one based on symptoms to one based on brain changes. Because these changes begin well before clinical symptoms arise, Alzheimer's has the potential to be diagnosed before the dementia stage. Early diagnosis of AD could have important personal and financial benefits. A mathematical model estimates that early and accurate diagnosis could save up to $7.9 trillion in medical and care costs.     

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

Introduction

Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01101-x.     

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.