CHAPTER 1
Introduction

Michael D. Geschwind and Caroline Racine Belkoura

University of California, San Francisco, San Francisco, CA, USA

This book was developed in order to provide a clinically relevant review of non-Alzheimer's and atypical dementia syndromes. Specifically, we felt there was a need for a broad but comprehensive overview of the differential diagnoses for atypical dementia that could be utilized by health-care providers who encounter these patients in their clinical practice, including neurologists, primary care providers, psychiatrists, neuropsychologists, nurses, social workers, etc. Where relevant, we have included clinical case studies in each chapter to help illustrate key or unique diagnostic features of each disorder and to provide a "real-world" view of how each disorder might present in the clinic.

Multidisciplinary evaluation of the atypical dementia patient

In this chapter, the editors review a framework for the clinical evaluation of the patient with a suspected atypical dementia syndrome. In particular, we focus on the benefits of a multidisciplinary evaluation with a team that includes a combination of a neurologist, neuropsychologist, psychiatrist, nurse, and social worker. Each team member brings a unique set of skills to the evaluation, which enables an in-depth and comprehensive assessment of a variety of domains, including relevant history, neurological function, cognitive abilities, mood and behavior, and daily function. Obtaining information from both the patient and a close family member or friend is essential as many atypical syndromes lead to loss of insight, and thus, more accurate reporting might come from someone other than the patient themselves. We have found that a case conference approach, where all team members meet after seeing the patient to review all relevant findings and discuss the case in detail, leads to a more accurate differential diagnosis, which can then be relayed to the patient and their family members in a timely fashion.

Atypical Alzheimer's disease

In this chapter, Sharon Sha and Gil Rabinovici review the atypical presentations of Alzheimer's disease (AD), which by definition present with symptoms other than memory loss and therefore might not meet most standard diagnostic criteria for AD. These patients tend to be younger than "typical" AD cases and might present with visuospatial complaints, executive dysfunction, behavioral changes, or language impairment. Additionally, often, patients meet diagnostic criteria for posterior cortical atrophy (PCA, a visual dysfunction syndrome), corticobasal syndrome (CBS, executive dysfunction or behavioral syndrome), and/or primary progressive aphasia (PPA, language syndrome) disorders that have not historically associated with AD pathology; however, recent research has demonstrated that a significant portion of these clinical syndromes are ultimately found to have AD pathology at autopsy. Neuropsychological testing and atrophy patterns on MRI often are very helpful in the differential diagnosis of the clinical syndrome. PET imaging with amyloid binding agents such as Pittsburgh compound B (PiB) or florbetapir F18 might provide additional, if not even more convincing, evidence of underlying AD pathology. The recognition of AD pathology as a causative factor in these atypical syndromes is important because of available symptomatic treatments and ongoing clinical trials for AD. Future diagnostic criteria for AD will need to incorporate the possibility of atypical presentations in order to increase sensitivity.

Vascular cognitive impairment: Diagnosis and treatment

In this comprehensive chapter, Helena Chui and Liliana Ramirez Gomez first review the complex history and terminology of vascular contributions to cognitive impairment. They postulate that the physiological effects of vascular brain impairment (VBI) lead to variable vascular cognitive impairment (VCI), depending on the location, extent, and severity of injury. White matter imaging methods including structural (i.e., white matter hyperintensities) and functional (diffusion tensor imaging) techniques provide the most useful information regarding the extent of VBI. VCI usually involves slowed processing speed and executive dysfunction but can vary widely depending on the location of pathology. The effect of VBI is additive and might be worsened by the presence of other underlying neuropathological conditions (i.e., AD). Risk factors for VBI/VCI include hypertension, hyperlipidemia, and diabetes, which suggest that the risk profile for cognitive impairment in many individuals could be lowered via lifestyle modifications. Current pharmacological treatments (i.e., cholinesterase inhibitors, NMDA receptor blockers) are symptomatic in nature, and firm evidence regarding their utility is lacking.

Frontotemporal dementia

In this chapter by David Perry and Howard Rosen, the clinical syndrome of frontotemporal dementia (FTD) and its underlying pathological etiologies (frontotemporal lobar degeneration (FTLD)) are reviewed. Newly developed diagnostic criteria for FTD have been developed, which identify three core clinical syndromes: (i) behavioral variant FTD (bvFTD), (ii) semantic variant primary progressive aphasia (svPPA, also called semantic dementia), and (iii) nonfluent variant primary progressive aphasia (nfvPPA). The most common presentation is bvFTD, with initial symptoms that might include apathy, disinhibition, loss of empathy, and other personality changes and MRI revealing relative atrophy of the fronto-insular cortex and underlying white matter. Cognitive testing often reveals relative deficits in executive function, although cognition might be relatively preserved early in the disorder. The hallmark features of svPPA include word-finding deficits and loss of semantic knowledge for words and objects, with MRI usually revealing relative atrophy in the left anterior temporal lobe. Bilateral temporal lobe atrophy becomes more prevalent over the course of the disease with additional frontal lobe involvement and behavioral symptoms including loss of empathy, and compulsions might appear (although they are not usually a presenting feature as in bvFTD). Slow and effortful speech is a classic feature of nfvPPA, with frank mutism being common over the course of the disease. MRI typically reveals asymmetric atrophy of the left inferior frontal cortex. Other clinical syndromes, including motor neuron disease (i.e., amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)), can overlap significantly with FTD syndromes and are referred to as FTD spectrum disorders. The underlying neuropathology of FTD is complex, and research in this field is evolving rapidly. As a general guideline, svPPA tends to be associated with TDP-43 pathology, nfvPPA tends to be associated with tau pathology, and bvFTD is associated with a variety of pathologies (TDP-43, tau, FUS, PSP, and CBD). Treatments for these disorders are currently symptomatic, although clinical trials are in development.

Lewy body dementias

In this chapter, dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) are reviewed by Carol Lippa and Katherine Possin. Both disorders feature a parkinsonian motor syndrome (i.e., rigidity, bradykinesia, tremor), cognitive impairment (visuospatial dysfunction, fluctuations in attention/arousal, and executive dysfunction), and neuropsychiatric symptoms (depression, anxiety, visual hallucinations). DLB is usually associated with relatively simultaneous onset of cognitive and motor symptoms, while PDD is associated with cognitive impairment in the setting of an established PD diagnosis (usually occurring?>1 year after motor symptoms). Both syndromes are disorders of alpha-synuclein and are associated with underlying Lewy body pathology. Concomitant AD pathology is often present. Structural MRI findings are often grossly normal for age, while clinical symptoms associated with alpha-synuclein disorders (i.e., REM sleep behavior disorder, anosmia, autonomic dysfunction) might provide additional confirmation of a suspected DLB or PDD diagnosis. The treatment of the motor symptoms is usually with standard dopaminergic therapies utilized in PD, while acetylcholinesterase inhibitors often improve attention deficits and visual hallucinations. Neuropsychiatric symptoms might require SSRIs or low doses of newer antipsychotic agents such as quetiapine. These patients are susceptible to delirium, and exposure to anesthetics, anticholinergics, and antipsychotics should be closely monitored.

Corticobasal degeneration and progressive supranuclear palsy

Suzee Lee and Bruce Miller define the terms in the title of their chapter as reflecting the neuropathological entities of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), which are both disorders of tau. They move on to discuss the typical clinical presentations of CBD as (i) nonfluent variant PPA (nfvPPA), (ii) an executive motor (EM) syndrome, and (iii) behavioral variant FTD (bvFTD). The clinical syndromes of nfvPPA and bvFTD have been reviewed in Chapter 5. EM syndrome typically presents with early executive dysfunction and motor impairment, often including axial rigidity and dystonia. MRI findings might include relative atrophy in the left frontal cortex. The clinical syndrome associated with pathological PSP is labeled PSP syndrome (PSP-S), which typically presents with oculomotor abnormalities (reduced saccade velocity and...