Dementias

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Chapter 66 Dementias

Dementia Syndrome

The term dementia is of Latin origin and means “devoid of the mind.” It is used to describe a persistent state of serious cognitive, functional, and emotional deterioration from a previously higher level of functioning and should not be confused with mental retardation, which denotes deficient cognitive development. Dementia can result from sudden significant brain insults such as strokes or trauma, infectious or metabolic disorders resulting in irreversible brain parenchymal changes, or most commonly from insidious progressive neurodegenerative processes. Regardless of the cause, all dementias have a significant impact on health and an individual’s ability to take care of him- or herself. The burden of dementia on patients’ quality of life, their relatives, and friends should not be underestimated.

Epidemiology

The exact incidence and prevalence of dementia from any cause remains unknown. The most common etiologies for the dementia syndrome are neurodegenerative disorders. Neurodegenerative dementias typically occur in late life with age; heretability; preexisting conditions, such as Parkinson disease; and vascular risk factors being the most important contributors. As the proportion of elderly individuals is rapidly increasing worldwide, dementia is becoming a highly significant global healthcare problem. Between 1997 and 2025, the elderly population—defined as persons 65 years of age and older—is projected to increase from 62.7 to 136.9 million in the Americas, from 17.7 to 37.9 million in Africa, from 112.5 to 169.8 million in Europe, from 60.5 to 166.7 million in Southeast Asia, and from 110.7 to 267.7 million in the Western Pacific Region of Asia (World Health Organization, 1998).

Recently the National Institutes of Health–funded Aging, Demographics, and Memory Study (ADAMS) published representative data of dementia prevalence in the United States (Langa et al., 2005; Plassman et al., 2007). One of ADAMS enrollment criteria was age of 70 years or older, and approximately a third of participants were older than 85 years. The study included a detailed cognitive battery (Langa et al., 2005). Diagnosis of dementia was based on Diagnostic and Statistical Manual of Mental Disorders (DSM)-III-R and DSM-IV criteria. Dementia prevalence increased from 5% among 71- to 79-year-olds to 37.4% in those 90 years and older (Plassman et al., 2007). In addition to older age, the authors reported that African American race and lower educational achievement independently contributed to increased odds of dementia syndrome of any etiology.

Diagnostic Criteria

In 2001, the Practice Parameters Subcommittee of the American Academy of Neurology (AAN) published a summary of evidence-based guidelines for early detection, diagnosis, and management of dementia (Knopman et al., 2001). These guidelines offered basic recommendations for diagnosis and both pharmacological and nonpharmacological management of dementia. The experts recommend the use of the American Psychiatric Association’s DSM criteria (the most recent being the DSM-IV) for establishing a diagnosis of dementia syndrome (Box 66.1). It should be noted, however, that despite the requirement for memory impairment in some forms of dementia, memory impairment is not an early symptom.

Increased focus on the earliest stages of dementia has led to the recognition of a state called mild cognitive impairment (MCI). MCI was initially considered a transition state between normal aging and dementia of the Alzheimer type, but the concept quickly evolved to denote an intermediate state between normal cognitive aging and any type of dementia. Practice parameters on MCI from the Quality Standards Subcommittee of the AAN have been published (Petersen et al., 2001b). MCI is an increasingly important focus of research and clinical attention. Identifying early disease—especially Alzheimer disease (AD) and vascular cognitive impairment—and initiating therapeutic interventions to prevent or slow decline are the goals. However, the concept of MCI as a clinical entity has undergone refinement and multiple modifications (Dubois and Albert, 2004; Petersen et al., 2001a, 2006; Petersen and Morris, 2005; Winblad et al., 2004) and has most recently been challenged as an artificial construct (Dubois et al., 2007). MCI is now recognized as a nonspecific state that may progress to AD or a non-AD dementia, may remain stable, or may revert to normal cognition. Many studies now attempt to define MCI of the AD type as the harbinger of AD. Because the onset of functional decline is typically late in the course of the disease, the combination of characteristic cognitive features in the presence of positive disease biomarkers has been proposed as sufficient for the diagnosis of the disease in the early predementia stages. These new criteria were proposed for use in AD (Dubois et al., 2007), but it is very likely this idea will be adopted for other dementias in the near future.

General Approach to Dementia Diagnosis

The essential feature of dementia is the acquired and persistent compromise in multiple cognitive domains that is severe enough to interfere with everyday functioning (see Box 66.1). This definition stands in contrast to delirium or acute confusional states (ACSs), which are distinguished primarily by prominent deficits or fluctuations in attentional processing. Although dementia syndromes tend to be chronic, progressive, and irreversible, and ACSs tend to be acute to subacute, fluctuating, and reversible, these distinctions are more relative than absolute. Toxic, metabolic, or other systemic physiological disturbances are more likely to be reversible which is not the case for neurodegenerative or cerebrovascular dementia syndromes. On the other hand, dementia renders the patient more vulnerable to delirium, highlighting the need for a comprehensive evaluation of potentially reversible etiological disorders in the context of even well-established dementia syndrome. Careful evaluation of persons referred for dementia evaluation can identify treatable or reversible disorders in up to 20% of cases (Hejl et al., 2002).

Distinguishing cognitive impairment associated with an underlying disorder from potentially reversible cognitive symptoms (e.g., depression, metabolic encephalopathy) often demands ongoing evaluation, including appropriate diagnostic tests and sometimes a therapeutic challenge with an antidepressant drug. Abrupt onset of thinking changes in temporal relation to a psychological stressor, poor effort on cognitive testing (particularly with demanding tasks), and prominent neurovegetative signs such as insomnia and anorexia are characteristic of depression-associated cognitive impairment. Drug-induced cognitive impairment occurring as a result of anticholinergic agents, sedative-hypnotic drugs (e.g., benzodiazepines), or opiate analgesics commonly occurs in the elderly and may cause or contribute to cognitive symptomatology. Any temporal association of cognitive decline with initiation or titration of certain drugs should prompt taper and withdrawal of the offending agent. Multifactorial etiology is common in the elderly, and the search for potentially reversible or modifiable conditions should be done with vigor and vigilance.

History

A detailed comprehensive history of the presenting illness is the single most important part of the evaluation of cognitively impaired subjects. In general, the history should be obtained from both the patient and a reliable and knowledgeable informant, because cognitive deficits, lack of insight, and lapses in judgment actively interfere with accurate self-reporting. A comprehensive history should determine the initial manifestations, mode of onset, and course over time (Box 66.2).

Box 66.2 Historical Components of the Dementia Evaluation

Insidious onset and gradual progression over time are characteristic for degenerative disorders as the cause of dementia, whereas abrupt or discrete temporal onset raises suspicion for an associated neurological condition such as a stroke or a tumor, extenuating life circumstances, or medication change. Age, cultural background, educational level, and prevailing social and occupational demands modulate the clinical expression of dementia and its clinical significance. Recognizing changes from a previous level of functioning or altered behavioral patterns may help discern subtle diagnostically relevant clinical deficits. AD typically manifests with recent memory impairment combined with variable degrees of language, visuospatial, and executive dysfunction. Initial isolated disturbances in any of the latter cognitive domains, especially in the settings of preserved episodic memory or prominent initial changes in behavior and composure, warrant considering alternative diagnoses, such as cerebrovascular disease, mass lesion, or a focal neurodegenerative condition. Early parkinsonian features prompt an evaluation for dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD) or another parkinsonian dementing disorder, vascular dementia, and normal-pressure hydrocephalus. Concurrent medical conditions, history of neurological insults, and primary disturbances of sleep are other factors that have to be accounted for as possible causes of dementia or concomitant factors that exacerbate its expression.

Cognitive Assessment

Standardized assessments such as the Mini-Mental State Examination (MMSE) (Folstein et al., 1975) provide a brief focused survey of cognitive domains most often affected in AD. The MMSE is a crude assessment that offers very limited assessment of memory and executive functions, however. The Montreal Cognitive Assessment (MoCA) is another short focused test that can be easily adopted in the busy private neurologist’s practice (Nasreddine et al., 2005). In addition to the cognitive domains tapped into by the MMSE, the MoCA also includes drawing a cube, the clock-drawing test, and a shortened version of Trails B, a test of working memory, set shifting, and complex attention, as well as a more detailed verbal memory test. MoCA may be better suited for detection of cognitive changes in the predementia stage of AD and other types of dementia (Gagnon et al., 2010; Hoops et al., 2009; Nazem et al., 2009; Smith et al., 2007; Videnovic et al., 2010). Additional tests for attention, language, praxis, executive and visuomotor functioning, and abstract thinking should be used selectively at the bedside or during an office visit to augment the initial crude cognitive screen (Table 66.1). Finally, for more refined cognitive assessment, patients should be referred for an evaluation by a trained neuropsychologist. Assessment by the latter is especially informative in borderline cases when the physician is uncertain of the presence of cognitive decline beyond what is expected by aging alone or under special circumstances such as limited education.

Table 66.1 Clinical Cognitive Assessment* (Normal Ranges)

Cognitive Feature Means of Assessment
Working memory Digit span forward (7 ± 2)
Complex attention (require manipulation of items in working memory) Digit span backward (6 ± 2)Months in reverse order (15-20 seconds)
Orientation Time, location, autobiographical data
Language Confrontational naming (high- and low-frequency items)
  Verbal fluency (e.g., animals, grocery items) (18 ± 6/1 minute)
  Repetition (sentences of varying length)
  Comprehension (yes-or-no questions; performing multistep tasks)
  Reading aloud/comprehension
  Sentence writing (spontaneous, to dictation)
Visuospatial Figure copying (two- and three-dimensional figures)
  Visual scene analysis (describe whole and individual parts)
  Line bisection (place “X” in center of horizontal line)
  Clock drawing (draw clock face with hands set to “10 after 11”)
Verbal recent memory Word list (3-5 words): immediate/delayed/recognition recall
  Paragraph recall
Nonverbal recent memory Figure copy recall
Remote memory Historical events (family milestones, recent presidents)
Abstract conceptualization Similarities (rose/tulip, poem/statue); proverb interpretation
Praxis Have patient demonstrate saluting a flag, hammering a nail
Sequencing Graphomotor sequencing (have patient draw a simple alternating pattern)
  Luria gestures (sequentially alternating fist, side, palm)

* Further details regarding administration and interpretation can be found in Hodges, J.R., 1994. Cognitive Assessment for Clinicians. Oxford University Press, Oxford.

Neuropsychiatric Assessment

Neuropsychiatric symptoms are exceedingly common among the cognitively impaired. Mood state (depressed, euphoric), vegetative status (eating, sleeping), changes in personality (apathetic, disinhibited), and alterations in perception (hallucinations) or thought (delusions) are major areas to be probed in the course of diagnostic assessment. The presence or absence of certain neuropsychiatric symptoms may guide the physician in the differential diagnosis. For instance, while apathy is exceedingly common among all neurodegenerative dementias, euphoria is only rarely seen in AD or DLB but common in frontal-variant frontotemporal dementia (fvFTD). Early hallucinations, delusions, and fluctuations, which can also predate the onset of cognitive decline, point to DLB. Attention to these and other neuropsychiatric concomitants of dementia is important because they represent treatable components of excess morbidity and often have a profound impact on caregiver burden and the need for institutionalization (Kaufer et al., 1998).

Differentiating between primary neurodegenerative disorder with concomitant depressive symptoms and primary depressive disorder that can result in pseudodementia can be challenging. Good history taking is essential and sometimes a trial of antidepressants is warranted. It is also very important to distinguish apathy (loss of interest or motivation) from primary depression on the basis of neutral affect and the absence of vegetative signs.

Although structured interviews for neuropsychiatric assessment in dementia have been developed, their use is restricted primarily to research settings. Recently a brief questionnaire version of the Neuropsychiatric Inventory (NPI) (Cummings, 1997) was designed for the practice setting. The Neuropsychiatric Inventory Questionnaire (NPIQ) (Kaufer et al., 2000) is relatively easy to administer and can provide a clinical screening examination for common neuropsychiatric manifestations of dementia and their associated impact on caregivers.

Neuroimaging

Based on evidence-based methodology, the AAN guidelines for diagnostic evaluation of dementia (Knopman et al., 2001) recommended the use of neuroimaging to screen patients with cognitive impairment. These recommendations resulted from the findings of one class II study showing that 5% of all patients with cognitive complaints harbored a causative nondegenerative lesion such as a slow-growing brain neoplasm (most commonly of the frontal lobes), subdural hematoma (SDH), or normal-pressure hydrocephalus (NPH) (Chui and Zhang, 1997). Inasmuch as the vast majority of MCI patients harbor neurodegenerative pathology, it is sensible to extend the guidelines for diagnostic imaging to that patient cohort as well. Justification for a structural imaging evaluation of the cognitively impaired individual is twofold: it can help detect a potentially treatable disorder in need of urgent targeted intervention, and it can identify vascular ischemic comorbidity that could either be the source of or a contributing factor to cognitive decline. Magnetic resonance imaging (MRI) is preferred, but in those instances where MRI technology is not available or when an MRI is contraindicated (for instance in patients in pacemakers), computed tomography (CT) should be used.

Although several other neuroimaging techniques and analytic approaches are vigorously being developed as candidate diagnostic and prognostic biomarkers, none of them are yet ready for routine clinical use. The scientific advances based on these technologies will be discussed in detail in the specific disorders sections that follow.

Neurodegenerative Dementias

Alzheimer Disease

AD was originally described in 1907 by the German psychiatrist and neuropathologist, Alois Alzheimer. The index case was a 51-year-old woman with paranoid delusions, progressive memory impairment, and subsequent progressive aphasia. At autopsy, Alzheimer noted brain atrophy, and as he applied the newly available silver stains, he uncovered the senile plaques (now termed neuritic or amyloid plaques) consisting of dystrophic neurites clustered around what subsequently was revealed to be a central amyloid core. He also described a second deposition, the neurofibrillary tangle, consisting of intraneuronal staining in a fibrillar pattern. In honor of Alois Alzheimer, Kraepelin subsequently named the condition Alzheimer’s disease. What initially was considered a presenile condition was later appreciated to be far more common in the elderly after 65 years of age, and with the age distinction removed, AD became the most common neurodegenerative disorder and one of the most common diseases of the aging population. It is now listed as the fifth most common cause of death (Alzheimer’s Association, 2010).

Advancing knowledge of the clinical onset and progression, neuroimaging, genetics, neurochemistry and neuropathological cascades, and molecular biology of neuritic plaques and neurofibrillary tangles has set the stage for current and future therapeutic interventions. Autosomal dominant AD has been traced to three genetic mutations in the amyloid precursor protein (APP) gene and the presenilin-1 and presenilin-2 (PS1, PS2) genes. These cases typically affect the middle-aged population. The roles of genetic risk factors for the more common sporadic late-onset disease are the subject of intense research. Inheritance of the E4 allele of the apolipoprotein E (ApoE) gene remains the most established genetic risk factor for AD. Many other candidates are under study, consonant with advances in collecting and analyzing population samples and in human genome screening and gene identification. Improved understanding of the pathological mechanisms will be the basis for future therapies.

Diagnostic Criteria

The most commonly used and widely accepted criteria for dementia of the Alzheimer type are the National Institute of Aging and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al., 1984). While these criteria are very useful and well operationalized for the dementia state of AD, the accumulating evidence of a long prodromal (or latent) AD state has challenged our former understanding of AD and resulted in incredibly insightful research into the MCI state and more recently into prodromal AD. The AD field is now rapidly moving toward early and presymptomatic AD diagnosis that will rely heavily on disease biomarkers as outlined in the Dubois criteria for prodromal AD (Dubois et al., 2007) (Box 66.3). As such, AD has moved from being a “diagnosis of exclusion,” post documenting normal findings on a battery of laboratory studies, to a specific diagnosis based on clinical course and a characteristic pattern (or evolving pattern) of neuropsychological deficits in the presence of disease-associated biomarkers.

Box 66.3 Dubois Diagnostic Criteria for Alzheimer Disease

Epidemiology

AD is the most common cause of dementia worldwide. ADAMS recently published nationally representative data of dementia prevalence in the United States (Langa et al., 2005; Plassman et al., 2007). Diagnosis of dementia of the Alzheimer type was based on the NINCDS-ADRDA criteria. Overall dementia of the Alzheimer type accounted for 70% of dementia cases, ranging from 47% among those aged 71 to 75 years to 80% in the age 90+ group. The ADAMS data revealed that as of 2002, there were 3.4 million dementia cases in the United States (95% confidence interval [CI], 2.8-4.0), of whom 2.4 million (95% CI, 1.9-2.9) were due to AD. In addition to older age, the authors reported that African American race, lower educational achievement, and ApoE E4 genotype independently contributed to increased odds of dementia syndrome of any etiology (Plassman et al., 2007). In a following publication (Plassman et al., 2008) the ADAMS investigators reported that an estimated 22.2% (or 5.4 million Americans) 71 years or older have cognitive impairment in the absence of overt dementia. Of these, 2 million subjects were reported to have prodromal AD, defined as cognitive impairment without dementia but with a pattern of clinical symptoms or performance on neuropsychological testing suggestive of prodromal AD and no other medical or neuropsychiatric condition present to preclude an eventual diagnosis of AD. The annualized rate of progression to dementia of the Alzheimer type in prodromal AD subjects was substantially higher than the rate of progression to dementia among all cognitively impaired (17%-20% per year in prodromal AD versus 12% in cognitive impairment but no dementia from any cause). Among those who progressed to dementia, 83% were diagnosed with dementia of the Alzheimer type, 16.7% were diagnosed with vascular dementia, and 0.4% with dementia of undetermined cause (Plassman et al., 2008).

Based on our discussion thus far, it should not be surprising that advancing age is the most powerful risk factor for the development of AD. Other risk factors include the presence of one or more of the following: ApoE E4 allele in a given individual, lower education level, family history of AD, and cardiovascular risk factors (Bendlin et al., 2010; Rocchi et al., 2009; Steptoe et al., 2011). Prevalence but not incidence appears to be higher in women than in men, suggesting that susceptibility is similar, but duration of survival is greater in women. Midlife hypertension, elevated homocysteine, and elevated fat in the diet (the latter perhaps in combination with presence of an ApoE E4 allele) also are reported risk factors (Bendlin et al., 2010).

Clinical Presentation

AD is a progressive disorder of recent episodic memory, language, visuospatial function, and executive function associated with high frequency of neurobehavioral abnormalities at some point in the course. Onset of AD usually is in late life. If onset age is younger than 45 years, an autosomal dominant pedigree usually is involved. Most commonly, a PS1 mutation is the cause. In elderly individuals presenting with mild memory loss, the diagnosis of prodromal AD could be somewhat challenging owing to the presence of comorbid conditions that may alter cognition (e.g., congestive heart failure, cerebrovascular disease) or if medications for such conditions have anticholinergic side effects. Serial follow-up evaluations may be necessary to establish decline and a characteristic pattern of dementia. Nonetheless, if memory is not a prominent early complaint, other potential causes of dementia should be considered. In unselected series, diagnostic accuracy has been relatively low when tested against autopsy diagnosis. Using established diagnostic criteria for AD such as those of the NINCDS/ADRDA in conjunction with a standardized evaluation, clinical diagnostic accuracy of about 90% can be achieved (Knopman et al., 2001), accuracy approaching 90% can be anticipated, and few if any “treatable causes” are missed.

Memory Loss

Memory impairment is a sine qua non in the diagnosis of AD. Although AD can manifest with neuropsychological deficits other than memory (e.g., aphasia, abnormal executive function, apathy or other personality change), memory tasks in general are the earliest deficits noted. Memory is a complex cognitive function involving several anatomical systems underlying different types of memory. Terminology for memory is varied, and definitions are not always interchangeable.

AD is classically associated with episodic memory impairment. Episodic memory is the memory store for personal experiences that occur in a particular spatial and temporal context. Unlike working memory (see later discussion), episodic memory does not have to be actively maintained (or “rehearsed”) for successful retrieval. Episodic memory is dependent on a number of neocortical structures, but the medial temporal lobes, particularly the hippocampus, play a central role. AD even in its earliest stages prominently impairs episodic memory, particularly for recent events. Recent episodic memory is assessed by delayed recall (i.e., remembering material over intervals longer than 30 seconds to a few minutes, during which an intervening distracting task is given to prevent active rehearsal). Other tests of episodic memory include information about orientation (e.g., date and location) and current events. Deficits in episodic memory can only be definitively established in the context of sufficiently preserved attention and concentration. For instance, distractibility and inattention can prevent the delirious patient from successfully encoding any incoming information, and he or she will fail a later recall test. Such deficits should not be attributed to AD-type pathology until the patient is retested in a more lucid state.

Early in the disease course of AD, distant episodic memories (i.e., memories before disease onset) tend to be spared. This somewhat paradoxical phenomenon may be accounted for by neocortical consolidation of episodic memories over time, which renders old memories less dependent on hippocampal function. Although detailed examination of remote memory may reveal some impairment, especially later in the disease course, the brunt of the early symptomatology lies in recent episodic memory.

Working memory is a limited-capacity storage system in which internal representations are actively held “on line.” Working memory can be divided into two systems: one responsible for maintenance or storage of information, and a second central executive system responsible for coordinating information processing and manipulation. Tasks that involve simple rehearsal of items, such as keeping a phone number “on line” (or forward digit span) and word and block span, appear to require both inferior prefrontal cortex for maintenance and more posterior cortical regions for storage. Working memory tasks that require manipulation of items, also known as complex attention tasks (e.g., digit span backwards, letter/number sequencing), require a more diffuse network including the dorsolateral prefrontal cortex. Mild impairment in these complex attention tasks may be noted relatively early in the course of AD, whereas the more simple working memory tasks tend not to be impaired until later in the disease course.

A third type of memory, semantic memory (Tulving, 1987, 1992), is defined as our knowledge of facts about the world and is not associated with a spatiotemporal context of the learning event. For example, while we know that a tiger has stripes and that Washington DC is the capital of the United States, we do not recall the context in which we learned these pieces of information. Although episodic memory impairment is more prominent in AD, semantic memory is also impaired relatively early in the disease course. Some of the language impairment seen in AD relates to disintegration of semantic memory. A common test of semantic memory is the category fluency test, when the patient is asked to name as many items as possible from a given category such as animals or vegetables. Semantic memory can be reduced in the early stages of AD.

Finally, procedural memory, which depends on the implicit learning of tasks and actions, is usually preserved in AD. AD patients are capable of procedural or implicit learning in the absence of any apparent parallel declarative learning.

Aphasia, Apraxia, and Visuospatial Impairment

Language disturbance, especially verbal fluency and word finding, generally is an early feature of AD. In some patients, aphasia may be a prominent early feature, with more widespread cognitive disturbance occurring later. A helpful diagnostic aid in AD is that naming in semantic categories (e.g., animals) is more impaired than orthographically constrained tasks (e.g., words starting with a particular letter). This finding has been attributed to a breakdown in semantic memory. In practice, this means that patients with AD will produce more words beginning with a given letter (phonemic fluency task) than animals (semantic fluency task). This may be particularly useful in differentiating early AD from the effects of depression, in which the opposite pattern is seen. Of note, a reduction in category fluency also occurs with aging, so that in the “oldest old” (>80 years), it may be less informative in relation to the presence or absence of AD (Ravdin et al., 2003).

Difficulties with praxis usually occur later in the course after memory and language disturbances are evident, although in some cases, apraxia may be a prominent early feature.

Decline in visuospatial skills is a common symptom. Perceptual deficits can be prominent early in the course—even prior to diagnostic ascertainment.

Subtle executive deficits usually are found even in the predementia stages if carefully sought, but more overt frontal lobe deficits such as intrusiveness, difficulty shifting attention or maintaining set, as well as lack of self-care usually occur later. This is in contrast with fvFTD, where these phenomena occur early and often are the presenting features.

As noted earlier, anosognosia, or unawareness of the cognitive deficit, can be an early feature of AD. This denial of any problems may present a difficult management problem and place stress on caregivers.

Atypical Alzheimer Disease Variants

In addition to the classic AD presentation, several relatively rare variants of AD should be recognized.

The frontal variant of AD presents with prominent behavioral and/or personality changes in addition to short-term memory loss. These patients often are impatient, irritable, impulsive, and disinhibited. They show impairments on tests of frontal executive performance such as categorical verbal fluency and Trail-Making A (Chen et al., 1998; Johnson et al., 1999), as well as on response inhibition and set shifting (Chen et al., 1998) and show greater pathological involvement of the frontal neocortex (Johnson et al., 1999).

Posterior cortical atrophy (PCA) is a relatively rare AD variant. PCA patients present with prominent visuospatial dysfunction such as partial or full Balint syndrome (simultanagnosia, ocular apraxia and ocular ataxia), partial or full Gerstmann syndrome (acalculia, agraphia, right/left disorientation, finger agnosia), apperceptive visual agnosia, and environmental disorientation. In addition they frequently show visual-field deficits or constructional, dressing, and ideomotor apraxia. Relatively preserved memory and insight until later in the disease course is the norm (Mendez et al., 2002; Renner et al., 2004; Tang-Wai et al., 2004). The visual processing deficits can be related to both dorsal (“where”) and ventral (“what”) visual-stream impairment but tend to involve the former more prominently, consistent with the topography of the pathology. This form of AD is associated with profound parieto-occipital atrophy and higher AD pathology burden in the primary visual and secondary visual-association cortices (Renner et al., 2004; Tang-Wai et al., 2004). Other pathological conditions with this syndrome have been described, including the Heidenhain variant of Creutzfeldt-Jakob disease (CJD), DLB, corticobasal degeneration, and dementia lacking distinctive histological features (Renner et al., 2004; Tang-Wai et al., 2004).

Finally, the occasional AD patient may also present with early progressive language involvement (Kramer and Miller, 2000) or significant parkinsonian signs and symptoms (Cummings, 2000; Kurlan et al., 2000).

Neuropsychiatric Features

While dementia is classically defined by cognitive impairment, almost all AD patients exhibit a wide range of neuropsychiatric symptoms. Mood state (depressed, euphoric), vegetative status (eating, sleeping), changes in personality (apathetic, disinhibited), and alterations in perception (hallucinations) or thought (delusions) are the major areas to be probed in the course of diagnostic assessment. Although structured interviews for neuropsychiatric assessment in dementia have been developed, their use is restricted primarily to research settings. As noted earlier, a brief questionnaire version of the Neuropsychiatric Inventory (NPI) designed for practice settings—the Neuropsychiatric Inventory Questionnaire (NPIQ)—has been developed to provide a clinical screening examination for common neuropsychiatric manifestations of dementia and their associated impact on caregivers (Kaufer et al., 2000).

Neuropsychiatric assessment plays an important role in differential diagnosis and sometimes reveals the most pressing therapeutic needs. For instance, in the moderate to advanced stages of AD, patients may present with irritability and agitation to the point of violent verbal and physical outbursts, sundowning, hallucinations, and paranoid delusions may create a strain on the spouse, family, and caregivers. When prominent, these symptoms may have to be addressed first, even prior to initiation of anticholinergic medications or memantine. Behavioral symptoms once manifest tend to worsen over the course of the disease; however, for the individual patient, symptoms may fluctuate and may not be present at each clinical evaluation (Cummings, 2000).

Apathy can be found in 42% of those with mild, 80% of those with moderate, and 92% of those with advanced AD (Mega et al., 1996). It presents with loss of interest in previously enjoyed activities (e.g., hobbies, social outings, spending time with beloved relatives), aloofness, diminished spontaneity and emotional behavior, and reduced motivation. It is thought to reflect disruption of the connections within the frontosubcortical–anterior cingulate circuitry and their connections with other cortical regions. Apathy and depression commonly co-occur, but they are not synonymous with each other (Cummings, 2003). Apathy can be distinguished from primary depression on the basis of its neutral affect and the absence of vegetative signs.

Depression is very common in AD, occurring in 10% of mild, 40% to 60% of moderate, and 60% or more of severe AD patients (Mega et al., 1996). The symptoms are rarely severe enough to merit diagnosis of major depressive disorder; more often they represent minor depression/dysphoria. Risk factors for developing depression are familial or personal history of depressive disorder, female gender, and younger age (Lyketsos and Olin, 2002).

Anxiety is another early feature of AD. In the early stages, anxiety may be a manifestation of the patient’s subjective awareness of his/her cognitive decline, his or her increased dependency on others, and fear of the disease and its progression. In the moderate stages, anxiety over abandonment and fear of being left alone are common. Changes in the daily routine and the environment can trigger anxiety in the demented patient and could easily escalate to agitation and aggression.

Agitation and irritability frequently co-occur. Agitation is more common in males, those with later onset of dementia, and those of more advanced age. It encompasses disruptive, aggressive, and/or resistive behaviors and is related to changes in frontal cortex on functional imaging studies and postmortem examination (Cummings, 2003). Common sources of resentment and irritability are the patient’s inability to successfully accomplish tasks that were accomplished with ease in the past, or a feeling of being mistreated or ignored.

AD patients may show a whole host of psychotic features such as hallucinations, delusions, or delusional misidentifications. These typically occur in the moderate to severe stages in AD, whereas in DLB they can occur early on and even be the first manifestation of the disorder. Most hallucinations are in the visual modality. Delusions also tend to favor the later stages of the disorder and occur in 30% to 50% of patients. Most common are delusions of infidelity, theft, and paranoia. Delusions often co-occur with aggression, anxiety, and aberrant motor behavior (Cummings, 2003).

Attention to the neuropsychiatric features of dementia is important because they represent treatable components of excess morbidity and often have a profound impact on caregiver burden and prompt institutionalization (Kaufer et al., 1998).

Laboratory Studies

The evidence-based guidelines of the AAN for diagnostic evaluation of dementia (Knopman et al., 2001) recommend routine screening for vitamin B12 deficiency and hypothyroidism. Other blood tests, such as screening for syphilis, are also justifiable if a clinical suspicion for neurosyphilis is present, either because of high-risk behavior or because of location in an endemic region.

Genetic testing for the ApoE genotype is not recommended on a routine basis. A large multicenter study demonstrated that the presence of the ApoE E4 allele increased the positive predictive value of diagnosing AD by only 4% over diagnoses made on clinical grounds alone (90% versus 94%) (Mayeux et al., 1998).

The AAN guidelines noted that CSF tests for β-amyloid, tau, and neuropil thread protein (AD7C-NTP) gave insufficient data, demonstrating values above and beyond the relatively high sensitivity and specificity of the clinical diagnosis of AD (Knopman et al., 2001). New studies assessing the diagnostic or predictive capabilities of β-amyloid and tau or phosphorylated tau (phosphotau) in the CSF, however, suggest the possibility that they may have a role to play in difficult cases, confirmation of diagnosis, or prediction of development of AD in patients in the predementia stages (Mattsson et al., 2009). Low CSF β-amyloid (Aβ1-42) coupled with elevated tau or phosphotau increases the likelihood that the patient has AD-type pathology (Mattsson et al., 2009; Sunderland et al., 2003). However, it should also be kept in mind that some pathologically confirmed AD patients have shown normal CSF Aβ1-42 and tau levels prior to death (Brunnstrom et al., 2010). In the predementia stages, a CSF pattern suggestive of AD relates to a very high probability of developing AD in the next 5 years (Hansson et al., 2006).

Concentrations of CSF neurotransmitters, neuropeptides, amino acids, and trace elements are of no diagnostic value. Ubiquitin levels in CSF are increased in AD, but the levels are similar to those found in other neurodegenerative disorders. In blood, acute-phase proteins may be elevated but are not helpful in specific diagnosis.

Genetics

A family history of AD is a major risk factor. Familial AD (FAD) has two forms: early-onset autosomal dominant and late-onset familial AD. The latter seems to show a complex polygenic pattern but has increased frequency in families. The former is associated with mutations in one of three genes: the amyloid precursor protein (APP), and the presenilin 1 (PSEN1) and 2 (PSEN2) genes. Early-onset autosomal dominant families in the world have been identified with PS1, accounting for the vast majority of cases. PS1 likely encodes a protein from the γ-secretase complex, an enzyme complex responsible for the cleavage of the APP molecule to β-amyloid. Consideration of genetic testing for mutations requires appropriate pretest advice and counseling, because positive results have deterministic implications for the family. All three genetic mutations—in APP, PSEN1, and PSEN2—increase brain and blood levels of β-amyloid.

Some but not all late-onset FAD pedigrees are associated with inheritance of the E4 allele of ApoE. In addition to the late-onset familial cases, ApoE also contributes to sporadic disease. Increased amyloid load and earlier age at onset are related to ApoE4 gene dosage (Mayeux et al., 1998). The apoE4 genotype is, however, only a risk factor, being neither sufficient nor necessary for disease development, and this is why it is not used routinely in clinical evaluations.

The search in the human genome for other gene variants that may affect risk of AD is ongoing. Genetic variations (polymorphisms) generally have been sought in proteins or lipoproteins related to the pathogenesis of AD (e.g., amyloid metabolism, inflammation, oxidative stress). Numerous genetic risk factors have been proposed, including allelic variants in sortilin-related receptor L (SORL1), clusterin (CLU, also known as ApoJ), phosphatidylinositol binding clathrin assembly protein (PICALM), and many others. To date, only the ApoE4 gene has been consistently confirmed as a “risk gene.” New searches for risk genes in AD use genome scans to look for candidate regions, and loci on several chromosomes are under investigation.

Neuroimaging

The AAN dementia practice parameter guidelines state that at least one unenhanced CT or MRI scan should be performed in patients with cognitive decline to rule out unexpected structural lesions and also to provide information about potential silent vascular injury (Knopman et al., 2001). MRI, with its improved resolution, allows better quantification of cerebral structures and better discrimination of normal from mildly affected patients with AD than is possible with CT. Noninvasive neuroimaging has greatly aided the accurate diagnosis of AD; structural lesions such as tumors, hydrocephalus, subdural hemorrhage, and strokes are identified easily. MRI and to a lesser extent CT aid in identification of vascular lesions that may be primary causes of dementia or contributory to cognitive decline in cases of mixed AD/vascular dementia.

Mesial temporal atrophy including the entorhinal cortex, hippocampus, and amygdala are considered typical for the prodromal AD stages (Apostolova et al., 2006, 2009; Jack et al., 2004) (Fig. 66.1). In the dementia stage, global brain atrophy—more striking in the temporoparietal than in the frontal regions—and ventricular enlargement are also pronounced (Apostolova et al., 2007; Thompson et al., 2003) (Fig. 66.2). A gradient-echo sequence on MRI could reveal cortico-subcortical microhemorrhages suggestive of the presence of vascular amyloidosis.

New and advanced methodologies provide unique opportunities to study the earliest changes in the hippocampal structure. Some studies have documented subtle atrophy present as early as 3 years prior to MCI and 6 years prior to the dementia stages of AD (Apostolova et al., 2010b) (Fig. 66.3). Imaging biomarkers are presently being developed as diagnostic and prognostic biomarkers as well as surrogate biomarkers for clinical trials, with hippocampal atrophy, the most validated structural biomarker, already being accepted as a biomarker criterion for AD presence in the prodromal AD stages (Dubois et al., 2007).

Functional brain imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) can identify disease-specific patterns such as temporoparietal abnormalities in AD, frontal or anterior temporal abnormalities in FTD, and temporo-parieto-occipital abnormalities in DLB (O’Brien, 2007) (Fig. 66.4). SPECT findings of blood-flow abnormalities in a temporoparietal distribution may aid in confirmation of AD, especially in cases without significant atrophy. PET using [18

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