On January 4, 2011, the President of the United States signed the National Alzheimer’s Project Act (NAPA) to benefit Alzheimer’s and related disorders. The act charges the Secretary of Health and Human Services to coordinate research, to accelerate treatments to prevent, reverse, or halt Alzheimer’s, to coordinate care and treatment of Alzheimer’s patients, including ethnic and racial populations experiencing higher risk, and, finally to coordinate with international bodies to fight the disease. 1 The act is welcome news to all who care for those affected by Alzheimer’s and related dementias, as well as to scientists who strive to find causes and treatments for these disorders. The purposes of this chapter are to review the diagnostic criteria of the major types of neurodegenerative dementia, to contrast their phenotypes, and to identify diagnostic and intervention approaches useful to speech-language pathologists (SLPs). To this end, new diagnostic criteria articulated by National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines (NIA-AA workgroup) are highlighted. 2, 3, 4, 5 Because this chapter consolidates material from two chapters in the second edition of Johnson and Jacobson’s Medical Speech-Language Pathology (2007), readers are referred to Horner et al 6 and Norman et al 7 in the earlier volume for comprehensive descriptive and bibliographic detail. The Diagnostic and Statistical Manual of Mental Disorders, fifth edition text8, uses the term neurocognitive disorders (NCDs) as the umbrella for disorders such as dementia, delirium, amnestic and other cognitive disorders defined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition 9. A major NCD is one in which there is “evidence of a significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition); . . . the cognitive deficits interfere with independence in everyday activities; . . . the cognitive deficits do not occur exclusively in the context of delirium; . . . [and], the cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia)” (DSM-5, pp. 602-603). A mild NCD is similar but cognitive decline is modest; and cognitive deficits do not interfere with independence “but greater effort, compensatory strategies, or accommodation may be required” (DSM-5, p. 605). Although the term dementia is retained in DSM-5 because of its customary usage by clinicians, DSM-5 notes that neurocognitive disorder encompasses not only the neurodegenerative dementias affecting older adults but also those NCDs manifesting in younger individuals (e.g., after traumatic brain injury) as well as those NCDs affecting single cognitive domains (e.g., amnestic disorder) (DSM-5, p. 591). The Einstein Aging Study examined 1,944 community-dwelling adults, age 70 or older, for presence of Alzheimer dementia (AD), amnestic mild cognitive impairment (aMCI), and nonamnestic mild cognitive impairment (naMCI). Overall dementia incidence was 2.9/100 person-years (2.3/100 for AD; 3.8 for aMCI; 3.9 for naMCI). Overall dementia prevalence was 6.5% (4.9% for AD; 11.6% for aMCI; 9.9% for naMCI). With the exception of naMCI, rates increased significantly with age. 12 According to the Alzheimer’s Association, 13 an estimated 5.4 million Americans had Alzheimer’s disease in 2012; this represents 13% of individuals over age 65 and 45% of those over age 85. According to the National Institute on Aging, 10 “the number of people with Alzheimer’s doubles for every 5-year interval past age 65. And the ranks of the very elderly, those 85 and older and at the highest risk for Alzheimer’s, are expected to triple by 2050.” The various NCDs are clinical syndromes defined by prominent clinical signs, age of onset, and pattern of progression. In DSM-5, NCDs are also subtyped base don “known or presumed etiological/pathological entity or entities” (p. 606), e.g., an Alzheimer’s disease genetic mutation or family history (p. 611). History and clinical testing are centerpieces of the examination, supplemented by biomarker techniques (fluid analyses, neuroimaging, and genetic testing) and longitudinal follow-up. A definitive diagnosis of the underlying disease is often not possible until autopsy, when neuropathologists examine brain cells using histopathologic techniques. Thus, clinicians differentiate the dementias on the basis of clinical signs and biomarkers; neuroradiologists, on the basis of static images of brain structure as well as dynamic images of brain metabolism; and neuropathologists, on the basis of postmortem analysis of brain tissue. In contrast, geneticists, microbiologists, and epidemiologists seek to understand the origins of dementia. Epidemiologic studies suggest that one’s susceptibility to disease is multifactorial, reflecting interactions among genetic, environmental, experiential, nutritional, and other factors. In short, clinical studies are concerned with patterns of behavior and cognition associated with dementing illnesses; neuroradiologic studies, with structural and functional abnormalities of brain tissue, both at cortical and subcortical sites; postmortem studies, with actual pathologic changes in the brain; and, biologic, genetic, and epidemiologic studies, with the pathogenesis (the origins) of the underlying disease. 11 Refined diagnostic guidelines were promulgated in 2011 by the NIA-AA workgroups on diagnostic guidelines for AD. 2, 3, 4, 5 The NIA-AA workgroup distinguished a preclinical phase (asymptomatic patients with abnormal metabolic or structural biomarkers) from a clinical phase of AD (signs of dementia with or without biomarker confirmation). “Biomarkers are parameters (physiological, biochemical, anatomic) that can be measured in vivo and that reflect specific features of disease-related pathophysiological processes,” 3 such as abnormal levels of beta-amyloid protein in cerebrospinal fluid (CSF), or hypometabolism during positron emission tomography (PET), or atrophy on magnetic resonance imaging (MRI). 5 The contributing scientists examined the relationship of clinical and biomarker signs. They reported (1) patients might be asymptomatic and be free of extensive AD biomarker pathology, or patients might present either typical or atypical clinical signs of AD in the presence of AD pathology; (2) amyloid biomarkers are often abnormal as long as 10 to 20 years before clinical signs appear; and (3) signs of neurodegeneration (particularly synapse loss) appear later and are more closely tied to cognitive impairment than amyloid protein disturbance. 3 Two comprehensive and useful documents are the National Institute on Aging’s “2010 Alzheimer’s Disease Progress Report” 10 and the Alzheimer’s Association’s “2012 Alzheimer’s Disease Facts and Figures” report. 13 ▶ Table 6.1 summarizes differences among mild cognitive impairment (MCI), all-cause dementia, and probable Alzheimer dementia (AD). ▶ Table 6.2 summarizes the differential clinical features of the major neurodegenerative dementias: Alzheimer dementia, vascular dementia, Lewy body dementia, and frontotemporal lobar dementia, drawing from the literature to summarize the major features of each category relative to onset and course, subtypes, cognitive profile, communication, associated behavior, physical signs, genetics, imaging, and definitive diagnosis. Mild Cognitive Impairment All-Cause Dementia Probable AD Probable AD with evidence of AD pathophysiological process (research application) Daily activity No significant interference Interference Interference Interference Change in prior level of functioning Preserved indepen-dence in functional abilities Decline Decline, particularly when verified by longitudinal examinations Decline, particularly when verified by longitudinal examination Delirium or psychiatric disorder None None None None Cognitive or behavioral impairment At least 1 domain: memory, reasoning, visuospatial abilities, language, executive functioning* At least 2 domains: memory, reasoning, visuospatial abilities, language, personality, behavior or comportment Either amnestic presentation (most common) or nonamnestic presentation: language, visuospatial, or executive dysfunction Either amnestic presentation (most common) or nonamnestic presentation: language, visuospatial, or executive dysfunction Substantial concomitant cerebrovascular disease No Only in vascular dementia No No Positive biomarkers If present in symptomatic patients, there is increased risk for conversion to clinical AD Depends on type of dementia Positive biomarkers increase certainty of diagnosis. Amyloid biomarkers are evident first; neuronal injury biomarkers, later. Neuronal injury biomarkers parallel worsening of clinical symptoms Present** Sources: Albert et al 2; Jack et al 3; McKhann et al 4; Sperling et al. 5 * “An impairment in episodic memory (i.e., the ability to learn and retain new information) is seen most commonly in MCI patients who subsequently progress to a diagnosis of AD dementia.” 2 ** Positive amyloid biomarkers (may be evident 10–20 years before clinical presentation): Brain amyloid-beta protein deposition (low CSF amyloid-beta) and positive amyloid imaging on positron emission tomography (PET). Positive neuronal degeneration or injury biomarkers: (1) Elevated CSF tau, both total tau and phosphorylated tau; (2) decreased fluorodeoxyglucose (FDG) uptake on PET in temporal-parietal cortex; and (3) disproportionate atrophy on structural magnetic resonance imaging in medial, basal, and lateral temporal lobe, and medial parietal cortex. 4 Alzheimer’s Disease (AD) Vascular Dementia (VaD) Lewy Body Dementia (LBD) Frontotemporal Lobar Dementia (FTLD) Onset and course Insidious onset; more likely after age 65; progressive course; slow course with plateaus not unusual Abrupt deterioration within 3 months after stroke; course may be stable, improving or worsening (stepwise or fluctuating) Periods of normal cognition alternate with abnormal cognition in early stages; course is progressive, often rapid (1–5 years) Insidious onset; more likely before age 65; progressive course, often slow Subtypes Nonfamilial or familial onset before or after age 65; or coexistence of other conditions, such as Parkinson’s disease Depends on location, type, and extent of cerebrovascular disease (CVD) Not described Focal atrophy syndromes include FTLD frontal variant, FTLD temporal variant, and FTLD nonfluent aphasia variant Cognitive profile Deficits in memory and cognition; no disturbance of consciousness; impaired function in daily life Deficits in memory and cognition; no disturbance of consciousness; impaired function in daily life Core features include fluctuating attention, visual hallucinations, and parkinsonism Executive dysfunction common in the frontal lobe variant; semantic deficits in the temporal lobe variant; and, nonfluent progressive aphasia in the nonfluent apahasia variant Communication Aphasia is common, starting as either fluent or nonfluent; semantic system most affected; syntax and phonology later; gradual progression to mutism Motor speech disorder; simplification of grammar and impaired writing; slowness and reduced initiation; abulic at later stages Parkinsonian dysarthric features, e.g., hypophonia Primary progressive aphasia (PPA) not uncommon; dysarthria unlikely; progression may be very slow Associated behavior Depression, insomnia, incontinence, delusions, agitation Depression and mood changes Periods of delirium (confusion) not uncommon as well as episodes of “going blank,” daytime drowsiness, and transient confusion upon waking Wide range of associated behaviors, most notable in the frontal lobe variant Physical signs In advanced disease, increased tone, myoclonus or gait disorder Gait disorder or frequent falls; hemiparesis; motor and sensory changes in cranial nerve distributions; visual deficits; pseudobulbar signs; dysarthria Parkinsonian features common Not a major feature of FTLD Genetics Familial AD (FAD) linked to chromosomes 1, 14, and 21 (5–10% of cases); sporadic AD linked to ApoE E4 allele on chromosome 19 in 30% of probable AD; tau and amyloid proteins affected; routine genotyping not recommended at this time Genetic abnormalities linked to all risk factors for stroke, e.g., hypertension, arteriovenous malformation; routine genotyping not recommended at this time Synuclein protein abnormalities linked to LBD, Parkinson’s disease, and multisystem atrophy; routine genotyping not recommended at this time Mutations on chromosome 17 and 3; abnormal tau protein; routine genotyping not recommended at this time Imaging Bilateral atrophy, medial temporal lobe, hippocampus and thalamus affected; temporoparietal hypoperfusion Single or multiple lesions in distribution of either large or small vessels, including periventricular white matter Bilateral frontal and temporal atrophy and insular cortex; relatively preserved medial temporal lobe, hippocampus, and amygdala Focal atrophy; frontal hypoperfusion Definitive diagnosis Clinical diagnosis by exclusion; dementia not attributable to other systemic disorder or brain disease; definitive examination only by postmortem examination (proliferation of amyloid plaques and neurofibrillary tangles) Clinical diagnosis by inclusion of positive history for CVD; definitive diagnosis must rule out all other causes by clinical presentation, neurologic examination, and neuroimaging Definitive diagnosis depends on presence of Lewy bodies, typically in cortex, subcortex, and brainstem; Alzheimer changes may co-occur, but presence of plaques and neuron loss not essential Clinical diagnosis depends on isolated cognitive impairment (not global dementia); definitive diagnosis depends on postmortem analysis of brain tissue (e.g., Pick’s bodies, neuronal loss) AD is defined clinically by its insidious, progressive course of cognitive disability; biologically, by in vivo biomarkers (of amyloid metabolism or imaging abnormalities, such as atrophy); neuropathologically (at autopsy), by an abundance of plaques and tangles; and genetically by abnormalities is some patients. The dementia is heterogeneous, 14 its underlying cause is illusive, and its cure is as yet undiscovered. 15, 16, 17 The second most prevalent type of dementia, VaD is typically caused by white matter ischemic necrosis with neuronal loss (leukencephalopathy) and multiple brain infarcts, including lacunar infarcts. 18, 19, 20, 21 “The clinical patterns of VaD differ, depending on the vessels involved (large versus small vessel), location of vascular lesions and the stages of disease.” 22 To the extent that cerebrovascular disease can be identified and treated, VaD is unique among the dementias, because it is preventable. 23 Although cerebrovascular disease co-occurs with, or predisposes individuals to, AD, 24 VaD often occurs in the absence of AD pathology. 20 According to the NIA-AA workgroup, the diagnosis of probable AD dementia should not be applied when there is evidence of (a) substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) core features of dementia with Lewy bodies other than dementia itself; or (c) prominent features of behavioral variant frontotemporal dementia; or (d) prominent features of semantic variant primary progressive aphasia; or (e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition. 4 Lewy body disease with dementia (LBD) is one of the most challenging of the neurodegenerative dementias. Three Lewy body syndromes have been described: movement disorder, autonomic failure, and dementia. 25, 26, 27 The diagnostic challenge arises not only because of the variant syndromes, but also because the presence of Lewy bodies is not exclusive to LBD (Lewy bodies can coexist with the plaques and tangles of Alzheimer’s disease), and because both cortical and subcortical sites are affected. 28 In LBD, fluctuating attention is typical and is characterized by marked shifts in alertness (within or between sessions), daytime drowsiness in some, and transient confusion on waking. In addition, probable LBD patients have recurrent, detailed, and persistent hallucinations, including animate and inanimate figures and scenes. Visual hallucinations appear “to be the only psychotic symptom that reliably discriminates LBD from AD or VaD.” 29 In summary, LBD is characterized by cortical and subcortical disease, has less medial temporal lobe involvement than AD, shares common neuropathological and neurogenetic features with Parkinson’s disease, and is distinguished from the other neurodegenerative diseases by fluctuating attention, visual hallucinations, and parkinsonism. Contemporary researchers now prefer the term frontotemporal lobe dementia (FTLD) for what was formerly thought of as a singular entity known as Pick’s dementia. The common thread among the different FTLD syndromes is focal atrophy, implying neuronal loss in particular cortical regions. Several subtypes are recognized: “behavioral or frontal-variant frontotemporal dementia (fv-FTD; sometimes simply called FTD); the temporal variant (tv-FTD), or semantic dementia (SD); and a left frontal and insular predominant degeneration called progressive non-fluent aphasia (PNFA).” 30 Hodges 31 emphasized that semantic dementia implies not only anomia but also a breakdown in semantic memory, that is, problems with not only word-finding, but also word comprehension and object recognition. AD and the FTLD variants resulting from lobar atrophy demonstrate distinctive profiles of cognitive impairment, and the FTLD syndromes are distinguishable from AD, both behaviorally 32 and neuroradiologically. 33 As Perry and Hodges 34 pointed out, the emergence of pharmacologic treatments for both memory and behavioral problems of FTLD mandates careful differential diagnosis. In summary, FTLD is an umbrella term referring to a host of clinical syndromes that share the common feature of focal cortical atrophy. There are three variants—frontal, temporal, and nonfluent aphasia—that reflect the location of the atrophy, not the underlying neuropathological disease. The variants are particularly important to speech-language pathologists because they present with executive disability, semantic impairments, and Broca’s-like aphasia, respectively. To introduce the topic of mild cognitive impairment (MCI), Petersen et al 35 explained that “the use of research criteria for the classification of dementia identifies three groups of subjects: those who are demented, those who are not demented, and individuals who cannot be classified because they have a cognitive…impairment but do not meet criteria for dementia.” The last group—those who have a measurable cognitive deficit but do not have dementia—are referred to as having MCI. Initially MCI was conceived of as being an isolated memory impairment (amnestic MCI), but a working group on MCI more recently identified other affected cognitive areas, so-called nonamnestic MCI. 2, 36, 37 Individuals have MCI if they (1) do not meet the criteria for dementia; (2) demonstrate abnormal cognition (as compared to age- and education-matched peers) by subjective report and corroborated by a family member, or measured objectively; and (3) preserve independence in daily functional activities. 2, 37 A major focus of research is whether MCI will ultimately evolve to AD. According to Albert et al, 2 MCI is at risk for conversion to AD if there is an abnormality of the gene for apolipoprotein E (APOE). Risk for conversion is also present if CSF analysis shows low levels of the beta-amyloid protein, and/or if the tau protein is elevated in CSF; beta-amyloid and tau are biomarkers for amyloid plaques, neurofibrillary tangles, and loss of neuronal connections and cell death. 2, 10 For a vivid display of these changes, see “Inside the Brain: Unraveling the Mystery of Alzheimer’s Disease,” a four-minute video available on the National Institute on Aging Website. 38 In contrast, Sattler et al 39 reported several protective factors that independently influenced late-onset AD in patients with MCI, namely, participation in cognitive leisure activities (CLA), higher education, and higher socioeconomic status (SES). As compared to matched subjects followed over a 12-year period, these individuals reduced their risk for AD by 62% (CLA), 85% (education), and 69% (SES), suggesting the importance of a lifelong pattern of establishing and maintaining “cognitive reserve.” 39 A clinical entity of particular interest to SLPs is primary progressive aphasia (PPA). The syndrome is characterized, initially, by isolated language disturbance that slowly progresses and may or may not lead to global deterioration of cognitive abilities. Following Mesulam’s 40 fascinating case study of “slowly progressive aphasia without generalized dementia,” many cases have been published (see Horner et al 6 for a review of this literature). Agreement about the definition and subtypes of PPA, however, did not occur until 2011. 41 Despite its heterogeneous causes (overlapping with FTLD and AD), most cases of PPA commonly present as frontotemporal lobe degeneration. Language disorder is the prominent sign of PPA and is the reason for impaired daily functioning; impaired functioning is not attributable to memory disorders or visuospatial impairments; and PPA is not attributable to other medical disorders or psychiatric illness. 41 The working group identified three variants of PPA: the nonfluent/agrammatic variant (apraxia of speech may also be present); the semantic variant; and the logopenic variant (in which word-retrieval and sentence-repetition deficits are prominent) (see Gorno-Tempini et al 41 for detail).
6.2 Diagnostic Features of Neurodegenerative and Other Dementias
6.2.1 Differentiating All-Cause Dementia from Alzheimer Dementia (AD) and Mild Cognitive Impairment
Alzheimer Dementia (AD)
Vascular Dementia (VaD)
Lewy Body Dementia (LBD)
Frontotemporal Lobar Dementia (FTLD)
Mild Cognitive Impairment
Primary Progressive Aphasia
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