Biomarkers are objectively measured characteristics of a biologic or pathogenic process, which can have a variety of applications, including diagnosing disease and measuring response to therapeutic interventions. Historically, the diagnosis of dementing neurodegenerative diseases has relied on clinical characterization of patients during life, using established clinical diagnostic criteria to assign the diagnosis that best matches the patient’s phenotype, and later performing postmortem brain autopsy to make a definitive diagnosis. Biomarkers have been developed to measure pathophysiological changes that are hallmarks of different neurodegenerative diseases. For example, in Alzheimer’s disease (AD), biomarkers can detect and measure the two pathological hallmarks, amyloid plaques and tau tangles, in living people, using PET, CSF, or plasma testing. Biomarkers have the potential to redefine the diagnosis of AD and neurodegenerative diseases as biological processes rather than as clinical entities. Biomarkers will transform our ability to evaluate and treat neurodegenerative diseases by improving diagnostic accuracy.

Alzheimer’s disease typically manifests age 65 or older with a predominant memory dysfunction followed by a progressive impairment of other cognitive domains. Aging is the main risk factor for AD development. However, up to 10% of patients present an early onset (under 65), manifesting more frequently with atypical phenotypes. Amyloid plaques and neurofibrillary tangles due to tau deposition are the main hallmarks of the disease. Despite sharing the same neuropathological features, AD phenotypes present differential tau distribution patterns in cortical areas, being tau-pathology topographically related to the clinical syndrome. In addition to aging, several other factors may contribute to AD pathology and its clinical expression. AD is currently understood as a disease continuum starting with a preclinical phase, progressively leading to mild cognitive impairment and dementia. The development of biological and neuroimaging biomarkers detecting in vivo the defining features of AD has remarkably improved the accuracy and early diagnosis of AD in the last decades.

This chapter discusses the neuropathology of dementia, focusing on the degenerative dementia syndromes commonly encountered by dementia specialists. It highlights the concept of selective vulnerability, where specific neuron types in specific brain regions decline and die, leading to progressive dysfunction. Alzheimer’s disease (AD) is the most prevalent cause of dementia, characterized by neurofibrillary pathology and the presence of neuritic plaques and neurofibrillary tangles. Dementia with Lewy Bodies (DLB), multiple system atrophy (MSA), and frontotemporal dementia (FTD) are also discussed, along with their respective clinical features and underlying pathology. The chapter emphasizes the complexity of neurodegenerative diseases and the need for more integrative models to understand their pathogenesis and develop effective therapies.

This chapter considers the changes that occur with age-related disorders. For Alzheimer’s disease and amnestic mild cognitive impairment, the chapter reviews structural changes that occur in the brain and then turns to functional changes. These include coverage of changes related to memory and cognition, attention, and self and emotion. Next, neuroimaging research on amyloid and tau are reviewed, and some literature on relevant genes is discussed. The chapter then reviews literature on other age-related neurodegenerative diseases, considering effects on cognitive and social functions. These include Parkinson’s disease, Huntington’s disease, frontotemporal dementias (including progressive nonfluent aphasia, semantic dementia, behavioral variant frontotemporal dementia, and amyotrophic lateral sclerosis).

This chapter looks at Alzheimer’s disease, the most common cause of dementia. Incidence and prevalence figures are reviewed, along with an explanation of the two abnormal proteins involved in the development of the disorder, and the ‘amyloid cascade’ hypothesis. Cognitive assessment of Alzheimer’s disease is considered in terms of where this fits within the diagnostic process and diagnostic criteria. The bulk of the chapter focuses on the typical form of Alzheimer’s disease, and the chapter concludes with discussion of some atypical variants, such as posterior cortical atrophy (PCA), logopenic primary progressive aphasia (lvPPA), and frontal variant.

The neurodegenerative diseases Alzheimer’s, Parkinson’s, frontotemporal lobar degeneration, Lewy body disease, and amyotrophic lateral sclerosis are all age-related and caused by genes in only 1-10 percent of cases. Dementia describes a syndrome in which there are cognitive difficulties including impaired memory, judgment, planning, language, and other deficits. Alzheimer’s is the commonest cause of dementia. In the brain in neurodegenerative diseases there is abnormal folding of proteins creating thread-like filaments called amyloid. There is also abnormal activation of inflammation with free radicals and harmful cells. There are things we can do regarding diet and other actions that can lower the risk of developing neurodegenerative diseases with aging. High levels of physical and mental activity throughout life along with attention to a healthy plant-based diet can enhance our four reserves and diminish amyloid deposition and overactivity of the immune system. Lifestyle measures can also protect us from the effect of brain pathologies that may develop. There are many causes of memory loss other than Alzheimer’s disease which are completely reversible when properly recognized.

The loss of oocytes and reduced oocyte quality contribute to age-associated ovarian decline and decreased fertility, which is at odds with the social trend toward delayed family building. Females are born with a finite cohort of germ cells, arrested from mid-gestation, and they progressively lose them throughout their reproductive lifespan, reaching a state of near depletion at menopause. Declining oocyte number, however, is not the sole culprit for age-related infertility. Oocyte competence, the ability to fertilize, develop, implant, and produce a live offspring, deteriorates more or less in concert with declining ovarian reserve. The uterus likely also plays a role, further hindering reproduction later in life, though additional studies are needed.

Cerebral amyloid angiopathy (CAA) is characterised by the deposition of Aß proteins in the media and adventitia of small and mid-sized cortical and leptomeningeal arteries (and, less frequently, veins). It is a component of any disorder in which amyloid is deposited in the brain, and it is not associated with systemic amyloidosis. The prevalence of CAA increases with advancing age. Some autopsy series have found CAA in 5% of individuals in the seventh decade but in 50% of those older than 90 years. While often asymptomatic, CAA is being increasingly recognised as an important cause of ICH in the elderly, accounting for up to one-fifth of all spontaneous ICH in this group. We present an 82 year-old gentleman who was diagnosed with cSAH and fulfilled the criteria for probable CAA

There has been a rapid development of cerebrospinal fluid (CSF) and also blood biomarkers in the field of Alzheimer’s disease (AD) clinical research and drug development. Clinical research studies support that the core AD CSF biomarkers amyloid beta (Aβ42 and Aβ42/40 ratio), total-tau (t-tau), and hyperphosphorylated tau (p-tau) reflect key elements of AD pathophysiology. The “Alzheimer CSF profile”, decreased Aβ42/40 ratio together with increased t-tau and p-tau, has high diagnostic value, and high concordance with amyloid PET. These biomarkers have undergone thorough standardization and are today available on fully automated laboratory analyzers. Recent technical developments in the field of ultrasensitive immunoassays and mass spectrometry methods also allow for measurement of these AD biomarkers in blood samples. Blood neurofilament light may also be a biomarker to grade axonal degeneration in AD and other neurodegenerative disorders. These biomarkers are important in AD drug development, for screening tools and diagnostic markers, and the verification of target engagement of candidate molecules in early trials and identification of downstream drug effects in late-stage trials.

Imaging biomarkers are important in the diagnosis and evaluation of treatment effect in AD. The “A/T/N” (amyloid/tau/neurodegeneration) classification notably focused on disease characteristics measurable using imaging or CSF biomarkers. Information obtained with imaging biomarkers can address several challenges in AD trials, by confirming pathology for patient inclusion and target engagement, enabling stratification for analysis based on likely rate of clinical decline, and detecting treatment effect with fewer subjects; it also help to characterize treatment responders and to better understand the neurological basis for clinical response. This chapter discusses how imaging data are generated, the applicability of various imaging endpoints within the overall AD progression pathway, technical issues influencing the reliability and interpretability of the data, and practical steps to incorporate imaging into clinical trials. Applications of volumetric MRI, MRI used in safety assessment, amyloid PET, tau PET, and FDG PET measurement of glucose metabolism are described. Relevant regulatory guidance and the fit of imaging data with blood based or other biomarkers are discussed.

The bone marrow (BM) extracellular matrix (ECM) is often inconspicuous, and hence neglected in a normal BM trephine biopsy (BMB), but it has essential functions in the homeostasis of bone and the maturation of haematopoiesis (see Chapter 2). The ECM surrounds the bony trabeculae, which are covered by osteoblasts and osteoclasts, the latter an essential component of the stem cell niche, and embeds the maturing haematopoietic cells. It is rich in hyaluronic acid, type III collagen (reticulin), fibronectin and laminin.

Plasma cell neoplasms are derived from mature, IG heavy chain class-switched terminally differentiated B-cells, which usually secrete a monoclonal immunoglobulin or M-protein and consist of a homogeneous population of neoplastic plasma cells [1]. Plasma cell myeloma (PCM) is a common malignancy, manifesting itself by bone marrow (BM) infiltration and bone destruction, and therefore representing an entity frequently encountered in BM biopsies(BMB). Its precursor lesion, non-IgM monoclonal gammopathy of unknown significance (MGUS) is a frequent finding in elderly individuals and shows a low, but definite risk for progression to PCM. In this chapter, we will discuss the diagnosis and differential diagnosis of PCM, MGUS and clonal plasma cell disorders with associated paraneoplastic syndromes, including POEMS syndrome and TEMPI syndrome. Amyloidosis is discussed in Chapter 3, and other mature B-cell neoplasms with a clonal plasma cell component in Chapter 15.

We discuss cases where overrliance on ancillary studies and overlooking the clinical picture were asssociated with misdiagnosis.