Classification of the Dementias

Overview

Dementia is a critical public health problem worldwide, especially as populations age. As a consequence, physicians dealing with a range of other age-associated problems can expect to see such problems in patients with dementia. Dementia diagnosis is evolving. Here, we review recent developments in the syndromic approach to dementia, and then highlight aspects of its differential diagnosis. Dementia generally has been defined in terms of multifocal cognitive impairment sufficient to impair function and typically is distinguished from cognitive decline of lesser severity and impact. Since the seventh edition of this book was published in 2010, several changes in dementia conceptualization have been proposed. These include a new lexicon and several new sets of diagnostic criteria, as well as growing support for the claim that “subjective cognitive impairment,” even “subjective memory complaints,” are important risks for developing dementia. Especially important have been the proposals to diagnose what previously were understood as dementing illnesses, notably Alzheimer disease, without dementia being present. Even so, the new criteria must be considered in light of potential challenges raised by prospective, community-based autopsy studies. As detailed next, pathologic changes consistent with pathologically defined entities, including Alzheimer disease (plaques and tangles), Parkinson disease (α-synuclein/Lewy bodies), and cerebrovascular disease (large and small vessel strokes, white matter changes), can be seen in patients with cognitive decline short of dementia. Moreover, such pathologic changes often overlap in individuals. Furthermore, these studies show that some individuals can have clinical dementia without clear pathologic markers.

Limitations of Current Classification

The syndrome of dementia remains largely as it always has been. The fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders has renamed dementia as a “Major Neurocognitive Disorder.” Although there are many important details for research, including an attempt to provide a common language for the description of overlapping aspects of dementia, delirium, and depression, the new criteria require validation and appear to have little practical impact on how to proceed. Awaiting more widespread adoption of this inclusive term, we will stick with dementia in this chapter. It remains the case that, as they age, most people find that their memory is not as good as it used to be. Many fewer actually have dementia. Where to draw the line between memory complaints and dementia—and how many lines to draw—is controversial, highlighting the artificiality of the definition as a purely discrete entity. In addition, other aspects of behavior, such as neuropsychiatric problems (including depression) and mobility difficulties, precede dementia and are associated with cognitive decline, highlighting the restrictive nature of current classifications based mainly on cognitive criteria. Nevertheless, making a diagnosis of the dementia syndrome in relation to the severity of cognitive impairment and a clinically important impact on activities of daily living remains practical. It recognizes that care needs are present or anticipated, and it assists in linking cognitive and behavioral syndromes to pathology.

Against this traditional approach is the view that waiting until the disease is clinically evident is to wait too long. This desire to get at the dementing illnesses before their clinical onset motivates the new criteria (especially the proposal for preclinical diagnosis), which hold that to do so is to wait past a time when intervention might alter the clinical course of dementia, perhaps even preventing it entirely. We will consider this, and the prospect of disease-modifying drugs, later.

Turning to other limitations of the how dementia is approached as a syndrome, the issue of the onset of clinically important change is another area of potential controversy. Delirium is considered a syndrome of acute onset with fluctuating attention and an identifiable cause. Delirium does not always reverse. Indeed, persisting delirium is now recognized as a state that not uncommonly merges with dementia, likely reflecting shared elements of pathophysiology in relation to neurodegenerative and inflammatory processes. Whether this is because the delirium causes the chronic, persistent, cognitive impairment or simply because the delirium occurred in the setting of dementia (or predementia), or whether many delirium symptoms that fall short of meeting delirium criteria are signaling an at-risk state for which our current descriptions are inadequate, is not clear. Acute onset of dementia can occur and does not always indicate delirium.

Especially in the emerging era of presymptomatic diagnosis of dementing illnesses, the issue of how best to consider multiple causes requires consideration anew. An important challenge is the realization that the specificity of cause, symptoms, and neuropathology is much fuzzier than had been appreciated, especially in very old people. Dementia chiefly happens not just in older adults but, as is becoming clear from an emerging body of evidence, it arises largely in people who have many health deficits. Despite many patients having distinct symptomatic profiles in relation to the type of dementia that they have, as age increases, overlap of symptoms is common. This overlap also extends to the underlying neuropathology, something that especially has been revealed by prospective, community-based studies. The fact that autopsy series in community-dwelling older adults show that many have mixed pathologies (up to three quarters in some series) has implications, especially for our understanding of mechanisms. Interpretations vary as to how often dementia arises as a result of complex constellations of underlying neuropathology versus the simple fact of cumulative damage. Whether neuropathology under these circumstances will retain its iconic “gold standard” status or whether it will be viewed best as an aspect of construct validation (another factor to be considered) is debatable. Other consequences arise. From a clinical standpoint, DSM-V modifications have been argued to be most in line with this new reality and are held to provide clinicians with a common language that can thereby be used to describe overlapping symptoms and set these in the context of distinct profiles. Against this background, it remains to be seen how much sense it makes to view patients with single-gene mutations in early-onset dementia as offering “proof of concept” for disease-modifying therapy that might avoid late life dementia in people with a panoply of causes. Very early attempts at combining biomarkers (e.g., within cerebrospinal fluid [CSF] or across modalities) showed that dementia tests are not exempt from trade-offs in sensitivity and specificity.

An additional challenge to the interpretation of the many causes that give rise to dementia in older people is overlapping pathology, which may be more the rule in older adults where Alzheimer pathology can overlap with vascular or Lewy bodies and other age-related changes. Furthermore, each of these pathologic markers can be present in patients who are apparently cognitively intact. Further challenging the present understanding is that older people can decline cognitively without obvious brain changes other than atrophy, at least as detectable by current techniques.

Dementia Definitions

General criteria for dementia (and its congeners) include the DSM-V criteria and International Classification of Diseases, 10th revision (ICD-10) criteria; each features the requirements of both cognitive impairment (in more than one domain of cognition) and functional impairment. Memory impairment is specified as a domain for ICD-10. Competing sets of criteria for vascular dementia have been supplanted by a proposal from the Society for Vascular Cognitive Impairment (VASCOG). Current dementia with Lewy bodies criteria include the presence of distinctive clinical features, such as REM sleep behavior disorder, and laboratory findings such as decreased dopamine transporter binding. Even so, although the criteria have increased in specificity, this has come at a cost of less sensitivity; interestingly, one proposed remedy has been the use of composite scores, reflecting a general theme of paying attention to both quantitative and qualitative aspects of dementia diagnosis, especially in late life. The definition of Parkinson dementia has been addressed, although its main distinction in relation to Lewy body dementia (how long motor symptoms preceded cognitive ones) is artificial. Criteria for frontotemporal lobar degeneration that predict pathologic findings have also been put forward. Recent criteria for the behavioral variant of frontotemporal dementia have been validated in autopsy series, with individual items showing moderate-substantial interrater reliability. Similarly, subtypes of primary progressive aphasias, which have varied pathologies, have been related to autopsy findings, albeit with imperfect clinical-pathologic correlation.

Risk Factors

Dementia Associated with Other Disorders

Numerous disorders can cause dementia because of effects on brain function. Approximately 7% to 10% of dementias can come on suddenly, often indicating a cerebrovascular event or other medical problem. When onset is abrupt, it is possible that the onset marks a delirium, and investigations and interventions should proceed accordingly. Although the differential diagnosis of delirium can overlap with that of dementia, and people with dementia are at risk for delirium, the two should be considered distinct. The disorders discussed in this section can give rise to prolonged illness that can lead to confusion with degenerative disorders. In some cases they are treatable and can potentially be cured, although this is unusual. Strictly speaking, such disorders are among issues that should be excluded for a patient to meet criteria for a degenerative dementia; however, sometimes they can cause irreversible change in the absence of a neurodegenerative disorder.