CHAPTER 2 Michael D. Geschwind and Caroline Racine Belkoura University of California, San Francisco, San Francisco, CA, USA The clinical presentation of atypical dementia varies widely and typically involves more than one symptom domain (e.g., cognition, motor function, behavior, autonomic function). This heterogeneity of presentation, in combination with the relative rarity of these disorders, can make accurate diagnosis difficult even for experienced clinicians. In our experience, the evaluation of individuals with suspected atypical dementia is optimal when conducted by a multidisciplinary team (e.g., neurology, neuropsychology, nursing, speech therapy, genetic counseling), allowing for a more comprehensive evaluation and the input of experts from several disciplines. Acquiring a thorough history is one of the most critical features of an atypical dementia evaluation. Because these disorders frequently present with symptoms affecting multiple systems (e.g., gastrointestinal, sleep, autonomic, higher cortical function, etc.), a broad review of systems (ROS) is necessary. A review of previous medical records and the input of family (and sometimes even friends and colleagues) is essential, as patients may not appreciate or be able to accurately report symptoms secondary to their cognitive deficits or lack of insight. Given that the patient has some cognitive impairment, the presence at the interview of an informant who knows the patient well, such as a family member, a close friend, or a caregiver, is very important. If they cannot be present, then the informant should be interviewed by telephone. When possible, try to leave time to interview the informant separately, such as when the patient is undergoing neuropsychological (cognitive) testing. This will allow the informant to discuss topics that might upset the patient or they do not feel comfortable discussing in front of the patient. Specific key elements to be included in the history are discussed in the following paragraphs. Determining the first symptom of a dementia is often the key to making the correct diagnosis. Encouraging family members to describe the earliest atypical behaviors or actions, even if only noted in retrospect, provides important information regarding the initial underlying neuroanatomy of their disease. For example, in a right-hander, early visuospatial problems might suggest right parietal involvement, early calculation difficulties might suggest left parietal dysfunction, and nonfluent speech might suggest left pre-Broca’s area frontal lobe involvement. These early symptom clusters can also assist with differential diagnosis. For example, profound changes in personality or behavior are seen early in behavioral variant frontotemporal dementia (bvFTD), whereas behavioral changes in the context of early falls are more typical of progressive supranuclear palsy (PSP). New-onset psychiatric symptoms (i.e., depression, anxiety, apathy) in someone without a psychiatric history are particularly noteworthy, although family members and patients might not realize they are an early symptom of the dementia. A change in employment status is sometimes an early sign that something is wrong but may initially be attributed to outside factors (e.g., downsizing) rather than patient issues. Determining the first symptoms of a disease is a critical step toward earlier detection, correct diagnosis, and, when available, appropriate treatment. Irrespective of what cognitive symptoms the patient presents with, a typical complaint might be, “I can’t remember things.” When evaluating a possible memory deficit, it is critical to determine if it is truly a primary memory problem. For example, semantic dementia (SD) patients might report, “I can’t remember words,” which actually reflects semantic loss rather than a primary memory problem. Similarly, posterior cortical atrophy (PCA) patients might describe, “I can’t remember where I put things,” reflecting their visual difficulties rather than impaired memory. Thus, detailed questioning during the history is required to determine the specific nature and etiology of presenting memory complaints. If it is a memory problem, then one must determine if it is an encoding or a retrieval problem. Many patients with frontal-executive deficits, such as due to ischemic vascular disease, report a primary memory problem, but often have problems with retrieval, but not encoding. Patients with frontal-executive function typically are aided in recall when given clues, whereas those with encoding deficits, such as occurs in Alzheimer’s disease (AD), usually are not. Other questions to ask the family and patient include “How are short-term and/or long-term memory affected, how long does it take for the patient to forget something they were told, and how has this changed over time?” In AD, short-term memory is often affected early by the illness, and only later is long-term memory (autobiographical and remote memory) affected. It is important to note how much of the history the patient can provide and in what level of detail, without relying on clues and hints provided by their family—thus, part of the neurological examination occurs during the history taking. It is sometimes necessary to explicitly tell family members (who might be used to speaking on behalf of the patient) to allow the patient to answer independently, assuring that they will have an opportunity to provide their input later. Asking about recent and more remote current major local, regional, national (e.g., “911,” “Hurricane Katrina,” etc.), or world events (e.g., who was the president during, or which countries were involved in, World War II) or family vacations provides additional opportunities to examine the patient’s recall abilities. Additional topics to discuss when asking about for memory difficulties include misplacing objects (e.g., keys, wallet, purse); being overly reliant on lists, post-it notes, or calendars; missing appointments; getting lost or disoriented in new (or old) environments; repeating oneself in conversation; and forgetting recent events (e.g., dinner with friends, movie recently seen). Word list learning tasks (e.g., California Verbal Learning Test-2nd Edition (CVLT-II) [1], Hopkins Verbal Learning Test-Revised (HVLT-R)) [2] are among the most common memory tasks used in neuropsychological testing and require the individual to recall a long series of words across multiple trials (learning) with recall tested again after a 20–30 min delay (delayed recall) followed by yes–no recognition. For younger and relatively high-functioning individuals, it is necessary to use a longer 16-item word list rather than a 9-item list, as ceiling effects are prominent and often mask subtle deficits. Story learning and recall tasks (e.g., Wechsler Memory Scale–4th Edition (WMS-IV) Logical Memory [3]) are also helpful tools. Story recall is less dependent on executive function in comparison to word list learning but is often difficult to interpret in the context of semantic and/or auditory comprehension difficulties. When interpreting the history and neuropsychological test results, it is helpful to think about the pattern of memory deficits, which suggests underlying neuroanatomy, thereby assisting with the differential diagnosis. A simplified view of memory deficits is that they are either hippocampal (medial temporal lobe (MTL)) or frontal executive in origin. Each anatomy generally has a different clinical pattern. Involvement of the MTL leads to anterograde amnesia (i.e., poor new learning and deficits in encoding) and the rapid forgetting of newly learned information. Associated clinical symptoms often include misplacing objects, repeating self in conversation, forgetting appointments, getting lost or disoriented in new environments, and poor memory for recent events. Neuropsychological testing typically reveals reduced learning, poor recall, and poor recognition (suggesting information was not appropriately stored or consolidated) even when provided with clues. These deficits are common in AD, SD (semantic variant (SV) frontotemporal dementia (FTD)), hippocampal sclerosis, limbic encephalopathy, and other disorders that affect MTL structures [4]. A frontal-subcortical pattern of memory loss, on the other hand, is associated with variable learning that is typically due to poor attention, difficulties with self-initiated recall (which typically improves with cues), and relatively spared recognition (suggesting information has been encoded in the MTL, but self-initiated access is difficult). These individuals tend to benefit from multiple learning trials and show progressive learning over time, whereas those with MTL involvement usually have flat learning curves. Clinical symptoms may be more variable (i.e., “he can remember if he pays attention”) and are often seen in combination with frontal-executive dysfunction on other tasks. Family members often will note that patients will recognize information when it is presented to them (i.e., “he remembered that we had gone to the movie as soon as I started talking about the plot”). These deficits are more typical of diseases that affect frontal-subcortical circuits, such as bvFTD and related disorders, Huntington’s disease (HD), Lewy body disorders, and white matter disorders [4, 5]. Many atypical dementias have accompanying motor features that help with differential diagnosis. For example, in AD, motor features typically occur very late, although there are motor presentations of AD, such as corticobasal syndrome (CBS) [6]. If the motor problems occur early, other diagnoses must also be considered. Early parkinsonism is a common feature of dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), PSP, and Creutzfeldt–Jakob disease (CJD). Some genetic forms of FTD (i.e., FTD-17) commonly present with parkinsonism. Axial rigidity and early falls are suggestive of PSP, whereas asymmetric progressive apraxia might suggest CBS. Myoclonus is frequently observed in DLB, CBD, CJD, and less commonly in late AD. Ataxia is often present in multiple system atrophy (MSA), fragile X-associated tremor/ataxia syndrome (FXTAS), spinocerebellar ataxias (SCAs), HD, prion disease, paraneoplastic disorders, and metabolic disorders such as Wernicke’s. Extraocular motor abnormalities occur in many neurodegenerative conditions and often are nonspecific, but some findings are helpful diagnostically. Gaze-evoked nystagmus is common in cerebellar degenerative disorders. Vertical supranuclear gaze palsy (limitations in downgaze) and slowed velocity of saccades are hallmark features of PSP. Breakdown of saccades can be observed in many disorders, particularly those that affect frontal-subcortical circuits including the frontal eye fields. Choreiform movements are commonly seen in HD, several HD-like syndromes (including some forms of genetic and variant prion disease, HDL2 due to junctophilin-3 gene mutations, and a few SCAs, particularly SCA17), other genetic disorders (e.g., dentatorubral-pallidoluysian atrophy (DRPLA), neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN), and chorea–acanthocytosis), and autoimmune/paraneoplastic conditions [7, 8]. Muscle wasting and fasciculations in combination with other upper/lower motor neuron signs are suggestive of amyotrophic lateral sclerosis (ALS) and when seen in combination with behavioral symptoms may suggest a combined FTD–ALS syndrome, although many conditions can mimic features of ALS [9]. Isolated, as well as concomitant, vascular disease is a frequent cause of motor symptoms and should always be considered. Most atypical dementias have prodromal states involving mood or behavior changes that are often recognized only in retrospect (i.e., depression and anxiety in DLB, depression and irritability in HD, apathy in bvFTD). Early changes in mood or behavior are frequently attributed to a psychiatric disorder or life stressors rather than an underlying neurodegenerative disease. A thorough review of the patient’s prior psychiatric history (e.g., depression, anxiety, suicidal ideation/attempt, mania) is essential in order to understand and differentiate new behaviors from those which are exacerbations of previous behaviors. Because patients may have limited insight into their own symptoms and behavior, it is crucial to obtain additional information from a reliable informant (i.e., spouse, relative, or close friend) who knows the person well. Important topics to cover in an interview include depression, anxiety, apathy, hallucinations, delusions, illusions, irritability/agitation, disinhibition, personality change, obsessions/compulsions, sleep disturbance, and appetite change; using an instrument such as The Neuropsychiatric Inventory can be helpful [10]. Certain conditions have neuropsychiatric symptoms that can greatly assist with differential diagnosis. Well-formed complex visual hallucinations (i.e., people at the dinner table or small animals) and delusions are common early in DLB but can also occur in late-stage AD. Depression is common in disorders with basal ganglia involvement (i.e., PSP, CBS, HD, vascular disease, and DLB), whereas anxiety is often seen in many disorders, including DLB, MSA, and HD. Sleep abnormalities such as REM sleep behavior disorder (RBD), restless legs syndrome (RLS), and periodic limb movements of sleep (PLMS) are also common in Lewy body disorders and other synucleinopathies and may predate the onset of the disorder by many years, if not decades [11]. Both central sleep apnea and obstructive sleep apnea (OSA) are relatively common in the general population and may contribute to cognitive deficits and depression if left untreated. The presence of sleep abnormalities should prompt a formal sleep evaluation, including polysomnography, to assess and adequately treat any underlying disorders. Profound personality changes, including early behavioral disinhibition, early apathy, early loss of empathy, and hyperorality, are hallmark features of bvFTD [12]. Many of these features, particularly apathy, increased appetite (particularly for sweets), and disinhibition, are also seen in SV where they are associated with right hemisphere atrophy [13–16]. Compulsions or obsessions (i.e., compulsive recycling, eating the same meal at the same time every day) become common in semantic variant primary progressive aphasia (svPPA) as the disease progresses [15]. Apathy is very common in PSP [17, 18], CBD [6], and frontal AD and tends to correlate with medial frontal and anterior cingulate involvement [19–21]. Frontal AD is often misdiagnosed as bvFTD because of prominent executive dysfunction and apathy; frontal AD, however, usually does not have prominent early disinhibition and loss of empathy [10, 16, 22]. Behavioral changes and neuropsychiatric symptoms can greatly affect quality of life, including difficulties maintaining employment and caregiver strain. In addition to assisting with diagnosis, the accurate assessment of neuropsychiatric symptoms allows the provider to intervene with appropriate treatment and also to better prepare the family for upcoming changes. A thorough evaluation of speech and language involves the assessment of motor speech symptoms (i.e., speech apraxia, dysarthria, swallowing) and language (i.e., reading, spelling, comprehension, repetition, fluency). Portions of the Western Aphasia Battery (WAB), the Boston Diagnostic Aphasia Examination (BDAE), the Boston Naming Test (BNT), the Boston Cookie Theft picture description, and the Pyramid and Palm Trees Test are useful in assessing language symptoms [13, 23, 24]. Most language disorders are affected by frequency and regularity effects, with high-frequency, short, and regular words being preserved until relatively late in the disease. Thus, it is very important to utilize relatively complex, unfamiliar, low-frequency stimuli in order to maximize the chance of detecting early, subtle language deficits. Word-finding difficulties are a common, but nonspecific, symptom associated with several neurodegenerative conditions, particularly progressive aphasias [25]. The types of errors made on naming tasks, however, can provide insight with respect to the underlying anatomy of disease. Patients with frontal deficits may make phonemic paraphasias (i.e., bread for bed) or have frank misarticulation errors but often benefit from phonemic cues and can select the appropriate answer from multiple-choice cues, whereas those with temporal involvement may make semantic paraphasias (i.e., dog for rhinoceros), do not typically benefit from phonemic cues, and may select incorrect answers on multiple-choice testing, suggesting frank semantic loss. Conversational speech should be examined for rate, rhythm, articulation errors, slurring, phonemic substitutions, word-finding pauses, circumlocution, and use of syntax. Verbal fluency tasks, including letter fluency (i.e., “State as many words starting with ‘D’ that you can think of”) and category prompts (i.e., “Tell me all the animals you can think of”), can be beneficial in determining underlying neuroanatomy, with frontal involvement usually leading to relative reductions in letter fluency but preserved category fluency (although as speech becomes more impaired, performance for both tasks declines) and temporal involvement leading to relative reduction in category fluency relative to letter fluency. Semantic knowledge can be tested with the Pyramid and Palm Trees Test, as well as asking general knowledge questions in several categories [23, 24]. There are three main subtypes of primary progressive aphasia. The nonfluent variant primary progressive aphasia (nvPPA) is associated with relative declines in left frontal function and presents with early motor speech abnormalities, including decreased speech output and reduced fluency (i.e., fewer words per minute, slow labored speech), dysarthria, and altered phoneme production, and also typically involves altered use of syntax (i.e., telegraphic speech or writing). Swallowing difficulties may also be present, particularly as the disease progresses, and most often these patients become mute within the first several years of the disorder. Reading, spelling, and comprehension tend to be relatively preserved, while writing may be noteworthy for syntactical errors and reduced output. Repetition may be impaired due to articulation deficits. nfvPPA is most often associated with CBD and PSP at autopsy [23, 26]. The semantic variant primary progressive aphasia (svPPA; formerly called SD) is associated with relative left temporal lobe atrophy and presents with fluent but empty speech, with the frequent use of generic words (i.e., thing, stuff) and relative omission of nouns. Patients may also ask for clarification regarding word meaning (i.e., “what do you mean by banister?”), and they often demonstrate frank difficulties on tasks requiring them to identify body parts (i.e., chin) or choose pictures representing single words (i.e., “primate” on Peabody Picture Vocabulary Test). Errors in the reading and spelling of irregular words (e.g., yacht, gnaw) suggest surface dyslexia, in which a loss of semantic knowledge associated with temporal lobe involvement results in the application of phonetic rules (e.g., knight = kah-nih-ght). Frequency effects are typical, with low-frequency and irregular words being affected early in the disease, while knowledge about high-frequency words may be preserved until late in the disease course [23, 26]. The nfvPPA and svPPA are discussed in more detail in Chapter 5. The logopenic variant primary progressive aphasia (lvPPA) has relative left temporoparietal atrophy and presents with decreased short-term auditory storage (or echoic memory). These individuals have a reduction in digit span forward, being unable to maintain more than 3–4 bits of information in short-term storage rather than the 7±2 bits that is typical. This reduction affects the ability to comprehend lengthy sentences and also results in reduced sentence repetition, particularly for long, unfamiliar phrases. Speech tends to be slow with long pauses, “uh’s and um’s”; frequent word-finding difficulties; and circumlocution. This variant is often misdiagnosed as nfPPA because of these speech symptoms; however, relative to nfPPA, there are less frequent articulation errors (although there may be phonemic substitutions for complex words) and fewer syntactical errors in speech. Decreased reading, poor calculation skills, and left–right confusion are often observed in lvPPA due to left parietal involvement and help distinguish these individuals from nfPPA [23, 26]. Chapter 5 discusses lvPPA in more detail. Early visuospatial abnormalities are common in DLB and PCS (typically AD pathology) [27] as well as the Heidenhain variant of CJD [28]. Common complaints include difficulties finding specific objects among many (i.e., in the refrigerator or a messy desk), changes in driving (i.e., drifting within the lane, difficulties parallel parking, and recent accidents), getting lost or disoriented in unfamiliar environments, and complaints about vision despite adequate visual acuity. Complex visual-constructional copy tasks (i.e., three-dimensional cube, Rey–Osterrieth Complex Figure, Benson Figure) are typically impaired early in these disorders. Decreased interest in reading and difficulty maintaining one’s place while reading or working on the computer (especially common in PSP) might be early symptoms. Difficulties with face or object perception suggest alterations in the ventral visual processing stream within the temporal lobe, whereas difficulties with spatial orientation and location suggest alterations in the dorsal visual processing stream within the parietal lobe [29]. Due to bilateral superior parietal involvement, individuals with PCA often exhibit some degree of Balint’s syndrome, including optic ataxia (difficulties integrating visual and motor movements, i.e., reaching for a cup), oculomotor apraxia (volitional eye movements), and simultagnosia (ability to pay attention to more than one item in the visual field) [27, 30]. In DLB, in addition to visuospatial difficulties, visual illusions or hallucinations are common [31]. Individuals with PSP may also report early visual difficulties, although upon testing it becomes obvious that this is secondary to restricted eye movements rather than visual perception per se. Visuospatial difficulties should prompt an evaluation of driving skills, with appropriate restrictions made (i.e., no night driving, limited freeway use) and, if necessary, early voluntary cessation from driving. In some states, health-care professionals are mandated to report individuals who are diagnosed with dementia or otherwise thought to be unsafe to drive. A home safety evaluation might also be warranted. Executive function is an umbrella term representing many subabilities that allow one to pursue goal-directed action (i.e., working memory, inhibition, organization, rapid processing, multitasking, set-shifting, planning, goal maintenance, and judgment). Patients may have reductions in specific aspects of executive function (i.e., working memory), whereas other aspects remain intact (i.e., inhibition). Executive function is usually associated with the frontal lobe and its links to circuits in the basal ganglia (i.e., frontal-striatal circuits) [32, 33]. Cerebellar dysfunction, however, can also lead to executive function impairment due to connections between the cerebellum and frontal lobe via the thalamus [34].
The multidisciplinary evaluation of the atypical dementia patient
Introduction
History
First symptoms
Memory
Motor
Behavior and neuropsychiatric symptoms
Speech and language
Visuospatial
Executive function
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