Primary progressive aphasia (PPA) is a neurodegenerative disorder that primarily affects language abilities. There are three main variants of PPA: semantic variant PPA (svPPA), nonfluent variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). Each variant has distinct clinical features, neuroimaging findings, and genetic and pathological associations. However, some cases do not fit neatly into these categories, known as PPA not otherwise specified. Diagnosis of PPA requires a comprehensive evaluation of language and cognitive abilities, along with neuroimaging and biomarker data. Future directions in PPA research include the development of computerized algorithms for speech analysis, the exploration of non-verbal aspects of the disorder, and the investigation of potential therapeutic interventions.

Diagnosing, treating, and caring for individuals with dementia-related syndroms raises unique legal and ethical questions. Individuals with dementia may be more likely to lack decision-making capacity. Additionally, along with their families, individuals with dementia will face complicated health care related decisions – complicated by limited therapy options. This chapter identifies key legal and ethical questions that come up in the clinical and non-clinical setting relevant to dementia-related syndromes.

There are currently no disease-modifying therapies for the frontotemporal dementias (FTD), but there are ways to enhance the lives of patients and their families by targeting the symptoms and stressors that arise. Accurate diagnosis and education are important for patients and families, and safety measures are necessary to prevent harm. Advanced care planning and caregiver support are critical for a chronic disease. Non-pharmacological treatments, such as behavioral management and a multidisciplinary approach, are recommended. The pharmacotherapy options include antidepressants, antipsychotics, and other medications, but there is limited evidence to support their use. This chapter provides information on clinical trials in FTD, including patient selection and enrollment, trial design, and potential disease-modifying treatments being explored. Further research is needed to develop effective treatments for FTD.

Prion diseases (PrDs) are a group of uniformly fatal neurodegenerative diseases that affect humans and other mammals. At a molecular level, all PrDs are caused by the misfolding of the normal prion protein (PrPC, in which C stands for the normal cellular form) into an abnormal, misfolded form called the prion or PrPSc (in which Sc stands for the scrapie, the prion disease of sheep and goats). Progressive misfolding of prion proteins and spread of prions in the brain lead to unique pattern of neurodegeneration (1). Clinically, the molecular and neuropathological changes lead to protean neurobehavioral manifestations in humans (2, 3). Most cases of human prion disease (hPrD) develop sporadically and are called sporadic Creutzfeldt-Jakob disease (sCJD), but there are also genetic (often familial) forms, and very rarely acquired forms (aCJD) from iatrogenic (i.e., iCJD) or environmental exposure to tissues infected with prions (1). The main objective of this chapter is to provide a clinical description of these three forms of hPrD.

Alzheimer’s disease (AD) is the most common type of dementia, accounting for approximately 60% of dementia cases (either alone or in combination); vascular dementia (VaD) accounts for another 10–20%. Most epidemiologic research on dementia has examined prevalence, incidence, and risk factors for either all-cause dementia or AD. This chapter discusses the epidemiology of all-cause dementia and AD, as well as advancement in VaD-related risk factors. Numerous prospective, observational studies have identified a variety of factors that may prevent or delay dementia onset. To better understand the epidemiology of dementia and the potential benefits of implementing interventions, future studies need to address the life course and long preclinical aspects of this disorder. More work is needed to understand the epidemiology and risk factors for non-AD or VaD dementias.

Neurologic practice has classically focused on the diagnosis and management of problematic daytime symptoms associated with dementia. This chapter discusses the assessment tools and diagnostic schemes for sleep-related issues in patients with dementia. It emphasizes the importance of recognizing and treating sleep disturbances in these patients to improve their quality of life. The chapter also highlights the association between sleep disorders and neurodegenerative diseases, such as Alzheimer’s disease and Lewy body disease.

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are neurodegenerative diseases associated with tau protein abnormalities. CBD is characterized by asymmetric parkinsonism, apraxia, and cognitive and behavioral symptoms. PSP is characterized by supranuclear gaze palsy, postural instability, and cognitive and behavioral changes. Both diseases have heterogeneous clinical presentations and can be difficult to diagnose. There are currently no disease-modifying treatments available for CBD or PSP, but symptomatic relief can be provided through medications and therapy. Research is ongoing to develop biomarkers and therapies for these diseases.

Normal pressure hydrocephalus (NPH) is divided into idiopathic (iNPH) and secondary causes such as tumors, infections, trauma, or intracranial hemorrhage. More people are now overweight, and BMI correlates with CSF pressure so many patients have higher CSF pressure making the “normal” in NPH a partial misnomer. The dominant symptom is gait impairment often accompanied by cognitive and urinary difficulty. NPH requiring treatment is relatively rare but potentially underdiagnosed. A clinical approach to NPH should start with a differential diagnosis of the gait difficulty, as in early stages, patients may not have the full symptom triad. Those with anomia may have Alzheimer’s dementia or primary progressive aphasia, and there can be additional patients with concomitant NPH and other disorders such as Alzheimer’s, Parkinson’s, and cervical myelopathy that may require treatment of both pathologies. The most useful diagnostic tests in the workup of NPH include magnetic resonance imaging (MRI) of the brain and a CSF drainage trial, with either high volume lumbar puncture or lumbar drain trial, with the videotaping of the gait before and after the CSF removal. The primary treatment remains a CSF diversion procedure with placement of a shunt, and several shunt surgical advances have resulted in less mortality and morbidity.

Vascular cognitive impairment (VCI) is a cognitive syndrome caused by cerebrovascular disease, and it includes vascular dementia (VaD) and vascular mild cognitive impairment (VaMCI). VaD is characterized by cognitive impairment and imaging evidence of cerebrovascular disease. VaMCI is considered the "vascular" equivalent of mild cognitive impairment. The clinical patterns of VaD differ depending on the vessels involved and the location of vascular lesions. Large vessel disease can cause single or multiple territorial infarctions in cortical or subcortical locations, while small vessel disease usually involves subcortical structures such as the basal ganglia and thalamus. The diagnostic criteria for VaD include the presence of cognitive impairment, imaging evidence of cerebrovascular disease, and a temporal relationship between a vascular event and onset of cognitive deficits. The diagnostic criteria for VaMCI are similar but without the requirement of a temporal relationship. Patients with VaD often have focal neurological deficits, while those with VaMCI may have executive dysfunction and memory deficits. The neuropsychological profile of VaD includes deficits in executive function, attention, and speed, while memory and visuospatial function may be relatively preserved. Patients with VaD may also experience behavioral and affective changes .

Magnetic resonance imaging (MRI) has become essential for the study of dementia. It is a supporting tool for the diagnosis of most neurodegenerative diseases and has shed light on many important aspects of disease etiology and progression. In Alzheimer’s disease and frontotemporal lobar degeneration in particular, it has helped to describe brain networks exhibiting selective vulnerability to neurodegeneration and facilitated the characterization of heterogeneity between clinical and genetic subtypes. MRI is also important for assessing vascular pathology and prion disease. Finally, most MRI modalities capture changes occurring up to decades prior to symptom onset, enabling early disease diagnosis and even prevention. Here,the main MRI techniques used to assess gray matter atrophy, among others, are described. We review recent studies in the different neurodegenerative diseases and describe the most common methodologies used, from visual rating scales to automated morphometry algorithms. Finally, we highlight progress in the theoretical modeling of neurodegenerative diseases and discuss more applied uses of MRI.