Primary Progressive Aphasia and Kindred Disorders

Chapter 54 Primary progressive aphasia and kindred disorders

MARSEL MESULAM* AND SANDRA WEINTRAUB

Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, USA

54.1. Introduction Bub, 1997; Kertesz et al., 2000, 2002; Hillis, 2002, 2004; Grossman and Moore, 2005). Terms such as The existence of progressive aphasias has been known progressive nonfluent aphasia (PNFA), semantic for more than 100 years. Pick (1892, 1904), Se´rieux dementia, aphasic variant of frontotemporal dementia (1893), Franceschi (1908), and Rosenfeld (1909) were (FTD), temporal variant of frontotemporal lobar among the first to report such patients. The current resur- degeneration (FTLD), Gogi aphasia and progressive gence of interest in this condition can be traced to a 1982 aphasia have been used, mostly implicitly, to denote report of six patients with a slowly progressive aphasia variants of PPA (Neary et al., 1998; Miller et al., and to the subsequent delineation of the primary progres- 1999). We prefer the PPA term as a root diagnosis sive aphasia (PPA) syndrome (Mesulam, 1982, 1987, for two reasons: not all progressive aphasias fulfill 2007; Mesulam and Weintraub, 1992). the PPA criteria and not all PPA cases are caused According to currently accepted criteria, the PPA by FTLD pathology. The word “primary” is a key diagnosis is made in any patient in whom a language descriptor that emphasizes the selective salience of impairment (aphasia), caused by a neurodegenerative the language disturbance and the relative preservation disease (progressive), constitutes the most salient aspect of other cognitive domains at initial stages. of the initial clinical picture (primary). The term lan- Acquired language disorders are known as aphasias. guage in this definition is used in its technical neurologi- Aphasias can be classified as being agrammatic, cal sense to refer to all component processes served by semantic, or anomic, depending on the specific aspect the left hemisphere language network, including phonol- of language that is most severely affected. Progressive ogy, morphology, syntax, semantics, naming, word- aphasias are not rare in neurological practice. Many finding, reading and spelling. The language impairment patients with Alzheimer’s disease (AD) eventually in PPA can be fluent or non-fluent and may or may not develop an aphasia. Aphasia can also arise in the interfere with word comprehension. Memory for recent course of motor neuron disease (MND), corticobasal events is preserved although memory scores obtained degenerations (CBD), behavioral variant of frontotem- in verbally mediated tests may be abnormal. The recog- poral dementia (bvFTD), and dementia associated with nition of familiar facts and objects is preserved (Adlam the posterior cortical atrophy (PCA) of Benson et al. et al., 2006). Minor changes in personality and behavior (1988). While all of these patients can be said to have may be present but are not the leading factors that bring progressive aphasias, the language impairment is not the patient to medical attention or that disrupt daily liv- “primary”, either because it is of lesser importance in ing activities. This selective clinical pattern is most con- comparison to other more salient deficits or because spicuous in the initial stages of the disease, covering an it is a late manifestation of the disease. interval of approximately 2 years after symptom onset. In a unique group of patients, a slowly progressive Hundreds of PPA cases have been reported and a aphasia arises in relative isolation, becomes the princi- sizable research literature on this topic has appeared pal cause of restrictions in daily living activities (Kertesz et al., 1994; Black, 1996; Westbury and (Wicklund et al., 2007), and remains the most salient

*Correspondence to: M. Mesulam, 320 East Superior St, Chicago, IL 60611, USA. E-mail: [email protected], Tel: þ1-312-908-9339, Fax: þ1-312-908-8789. 574 M. MESULAM AND S. WEINTRAUB aspect of the clinical picture for several years. This among the presenting symptoms. Although the patient does not mean that all other cognitive and behavioral may forget names of people, word-finding during domains are intact, but that they are less severely conversation is usually not a major problem. In con- impaired than language. Such patients are said to have trast, the patient with PPA comes to medical attention a primary progressive aphasia or PPA. In contrast to because of word-finding difficulties, abnormal speech the clinical syndrome of probable Alzheimer’s disease patterns, or spelling errors of recent onset. Primary (PRAD), which designates a memory-based (amnestic) progressive aphasia is diagnosed when other mental dementia, or the behavioral variant of frontotemporal faculties such as memory for daily events, visuospatial dementia (bvFTD), which designates a behavior-based skills, face and object knowledge (assessed by the (comportmental) dementia, PPA designates a language- recognition of familiar faces and objects) and comport- based (aphasic) dementia. ment (assessed by history obtained from a third party) remain relatively intact; when language is the only area 54.2. Comments on the clinicopathological of major dysfunction early in the disease; and when nomenclature used in this chapter structural brain imaging does not reveal a specific lesion, other than atrophy, that can account for the There are currently no reliable in vivo markers for the language deficit (Mesulam and Weintraub, 1992; definitive identification of the underlying disease pro- Mesulam, 2001, 2003). cess in patients with non-familial neurodegenerative Standardized neuropsychological tests are helpful dementias. Furthermore, the same neuropathological for reaching an early diagnosis (Weintraub et al., entity can have multiple clinical manifestations depend- 1990; Weintraub and Mesulam, 1993, 1996). However, ing on its regional distribution in the brain. These are a strict reliance on neuropsychological tests, most of two reasons why nomenclature in this field can become which depend on verbal instructions, verbal responses, unusually confusing when the distinction between clini- or covert verbal reasoning, may occasionally lead to cal and neuropathological levels becomes blurred. the erroneous conclusion that areas other than language A physician can suspect that a dementia is caused by are also impaired. Scores on the Mini Mental Status Alzheimer’s disease or Pick’s disease but cannot confirm Examination (MMSE) (Folstein et al., 1975), for exam- this prediction until brain tissue is examined. This is of ple, can exaggerate the degree of disability. Although practical importance because the clinical patterns of the the language disorder in primary progressive aphasia two diseases can partially overlap despite differences in may interfere with the ability to memorize word lists the frequency of individual features (Weintraub and or solve reasoning tasks, the patient typically has no dif- Mesulam, 1993). This state of affairs makes it imperative ficulty recalling daily events or behaving with sound to distinguish clinical syndromes from neuropathological judgment, indicating that explicit memory, reasoning diagnoses. In this chapter, we will confine the use of acro- and social skills remain relatively intact. nyms such as PPA, bvFTD, and probable Alzheimer’s In some patients, the principal signs and symptoms disease (PRAD) to clinically identified syndromes of are confined to the area of language for as many as aphasic (Mesulam, 2003), amnestic (McKhann et al., 10–14 years. In others, impairments in other cognitive 1984) and comportmental (Neary et al., 1998)dementia, functions can emerge after the initial few years, but the respectively. The acronyms AD and FTLD will be re- language dysfunction remains the most salient feature served for neuropathological patterns identified by micro- and deteriorates most rapidly through many years scopy. Specifically, AD will refer to the presence of (Weintraub et al., 1990). Primary progressive aphasia amyloid plaques and neurofibrillary tangles in a certain is a form of dementia since it causes a gradual cogni- density and distribution (Hyman and Trojanowski, 1997), tive decline to the point where daily living functions whereas FTLD will refer to characteristic combinations become compromised. It is also an unusual dementia of focal neuronal loss with gliosis, superficial spongiosis, since core memory functions remain largely preserved. Pick bodies, other tau inclusions, and tau-negative ubi- In contrast to many patients with PRAD who tend to quitinated TDP-43 inclusions (McKhann et al., 2001; lose interest in recreational and social activities, some Neumann et al., 2006). patients with PPA maintain and even intensify their involvement in complex hobbies such as gardening, 54.3. Clinical features and diagnosis in carpentry, sculpting and painting. primary progressive aphasia Primary progressive aphasia should be differentiated from states of pure progressive dysarthria, speech The patient with PRAD comes to medical attention apraxia, or phonological disintegration where the for- because of forgetfulness. Misplacing personal objects, mation rather than usage of words becomes disrupted repeating questions, and forgetting recent events are (Broussolle et al., 1996). It should also be differentiated PRIMARY PROGRESSIVE APHASIA AND KINDRED DISORDERS 575 from PRAD and bvFTD where word-finding distur- 2 years. In many instances, the patient is the first to bances (anomia) or a paucity of speech output (economy detect a problem, usually in the form of word-finding of speech) may arise, but on a background of more sali- hesitations. These initial complaints are occasionally ent impairments of memory (in PRAD) and behavior (in attributed, by family members and even physicians, bvFTD). to stress or depression. No single type of language disorder is pathognomo- nic of PPA. The most common initial sign of primary 54.3.1. Core diagnostic features and progressive aphasia is a word-finding and naming confirmatory investigations impairment known as “anomia”. As the language impairment becomes established, it can be fluent (that The initial diagnostic criteria for PPA were descrip- is, with normal articulation, flow, and number of tive. We have subsequently proposed a cluster of core, words per utterance) or non-fluent (that is, with supportive, and exclusionary criteria for the diagnosis decreased mean length of utterance or slow output) of PPA. These criteria have been incorporated into and may or may not impair phonology, syntax or ver- the Uniform Data Set (UDS) used by the National Alz- bal semantics (comprehension of word meaning) heimer’s Disease Coordinating Center (NACC) of the (Mesulam, 1987; Mehler, 1988; Weintraub et al., National Institute on Aging (Morris et al., 2006). The 1990; Snowden et al., 1992; Thompson et al., 1997; salience of language impairments in the initial stages Otsuki et al., 1998). Written language may be less and the insidious onset and progression of symptoms impaired than spoken language but spelling errors over years are the two necessary core features (dysgraphia) are common. (Table 54.1). The early stages during which the lan- Further neuropsychological confirmation of the guage disorder remains the most salient symptom and aphasia can be obtained with instruments such as the the principal source of restrictions in daily activities Boston Diagnostic Aphasia Examination (BDAE: should have a minimum duration of approximately Goodglass et al., 2001), the Western Aphasia Battery

Table 54.1

Core, supportive and exclusionary criteria for primary progressive aphasia

Descriptive clinical profile: An aphasic dementia where the language impairment (aphasia) emerges in relative isolation and is the major determinant in the limitation of daily living activities. Perception, memory, personality are relatively preserved initially (usually 2 years or more). I. Core diagnostic features: These features are integral to the clinical syndrome. Both must be present for making the diagnosis. A. Insidious onset and gradual progression B. Early onset of aphasic disturbance (including any combination of the following): 1. Word-finding pauses 2. Word comprehension deficits 3. Naming impairments 4. Circumlocutious speech lacking specific nouns and verbs 5. Speech and/or writing that has impaired grammar and syntax 6. Syntactic comprehension deficits 7. Dysgraphia II. Supportive clinical features: These features are not present in all patients but their presence serves further to support the diagnosis. 8. Onset before the age of 65 9. Dysarthria 10. Ideomotor apraxia 11. Dyscalculia 12. Mild facial flattening on the side opposite the language-dominant hemisphere (usually right face) 13. Asymmetrical upper extremity posturing upon stressed gait on the side opposite the language-dominant hemisphere (usually right arm) 14. Mild rigidity on the side opposite the language-dominant hemisphere (usually right side of body)

(Continued) 576 M. MESULAM AND S. WEINTRAUB

Table 54.1

(Continued)

III. Investigations: The neuropsychological findings are present in all patients if the proper tests are used. The other test findings may not be present in all. 1. Neuropsychology: findings of aphasia in the absence of equally prominent amnesia, prosopagnosia, associative visual agnosia, apathy, disinhibition. 2. MRI or CT: perisylvian atrophy that can extend to parietal cortex and/or inferior temporal cortex on the side of language dominance (usually left) 3. PET or SPECT: asymmetrical hypometabolism in language-dominant hemisphere (usually left) 4. EEG: asymmetrical slowing in the temporal leads of the language-dominant hemisphere (usually left) IV. Exclusionary features 1. Abrupt onset 2. Brain imaging showing lesions other than focal atrophy that can account for the aphasia.

(WAB; Kertesz, 1982), the Boston Naming Test (BNT; movements spontaneously when the need arises. Dys- Kaplan et al., 1983), the Token Test (De Renzi and calculia is very common, reflecting the anatomical Vignolo, 1962) and the F-A-S test of fluency (Benton proximity of the brain areas necessary for language and Hamsher, 1989). These can be supplemented by and calculations. In some patients, the dyscalculia additional tests to demonstrate the relative preservation emerges early and becomes as prominent as any other of other cognitive domains early in the course of the dis- of the aphasic impairments. A careful neurological ease, especially memory for recent events. Listening to examination can reveal subtle asymmetrical pyramidal the patient’s speech, obtaining a short writing sample, or extrapyramidal signs reflecting the dysfunction of assessing the comprehension of questions asked during the language-dominant (usually left) hemisphere. the examination, and supplementing these with the These signs include mild flattening of the nasolabial BNT and F-A-S offer a rapid survey of language function fold, widening of the palpebral fissure, asymmetrical that almost always reveals the presence of abnormalities. posturing of the hand while walking on the heels or In many, but not all patients, neurodiagnostic investiga- edge of the feet, and mild cogwheeling rigidity tions reveal asymmetric EEG slowing, hypoperfusion, induced when the other hand is engaged in repetitive hypometabolism and atrophy on the language-dominant tapping movements. (usually left) hemisphere (Fig. 54.1).

54.3.3. Exclusionary clinical and imaging criteria 54.3.2. Supportive features An abrupt onset of the aphasia excludes the diagnosis of In addition to the core diagnostic criteria, PPA patients PPA. Additional exclusionary criteria include the early display common features that support the diagnosis salience of motor deficits, amnesia, abnormal comport- without being necessary for it. Age of onset has ranged ment, associative agnosia, or visuospatial disorienta- from the 40s to 80s. However, the majority of patients tion. Patients with these features deserve a primary have had a presenile onset, before the age of 65. Dys- diagnosis of motor neuron disease (MND), corticobasal arthria can occasionally arise and becomes one of the degeneration (CBD), progressive supranuclear palsy factors undermining fluency. Ideomotor apraxia is (PSP), PRAD, bvFTD, or the syndrome of posterior cor- common. In some patients, it takes the form of “sym- tical atrophy (PCA), each accompanied by a non- pathetic dyspraxia” where the left hand cannot panto- primary progressive aphasia. In many cases, however, mime the movements related to the usage of the tool PPA patients may eventually display some features of mentioned by the examiner. A more frequent ocur- these syndromes, indicating the considerable clinical rence is the presence of an isolated buccofacial apraxia overlap among these entities. Brain imaging is neces- so that the commands to “cough” or “lick crumbs from sary, since any finding other than atrophy that can the lips” cannot be followed even though the patient account for the aphasia (such as neoplasm or ischemic understands the instructions and can perform the lesions) rules out the diagnosis of PPA. PRIMARY PROGRESSIVE APHASIA AND KINDRED DISORDERS 577

Fig. 54.1. Top: coronal sections of T1-weighted MRI obtained 6 years after disease onset in a patient who developed PPA at the age of 60. There is a high level of specificity in the distribution of atrophy. The left superior temporal gyrus (stg) is very atrophic and the left Sylvian cistern is enlarged. Bottom: horizontal sections of T1-weighted MRI obtained 1 and 4 years after onset in a patient who developed PPA at the age of 61. There is a clear progression of atrophy predominantly within the left perisylvian cortex (PSC). Reprinted from Mesulam, 2001, Ann Neurol 49: 425–432, with permission from Wiley. This is the sort of pattern seen in the agrammatic-dysfluent or logopenic PPA subtypes. In the semantic subtype, there can also be severe anterior and medial temporal atrophy.

54.3.4. The “PPA-plus” diagnosis selectivity of aphasia may no longer be ascertainable because of language comprehension deficits or Additional cognitive, behavioral and motor deficits that because deficits in other domains have emerged. In independently influence daily living activities arise in such cases, a structured interview with informants the middle or late stages of the disease. We have used can be used to establish whether the aphasia had in the descriptive term “PPA-plus” (PPAþ)todesignate fact emerged in relative isolation. A retrospective the fact that the patient had initially fulfilled the diag- diagnosis of PPAþ is made if such an interview con- nostic criteria for PPA but that the current clinical defi- firms that the diagnostic criteria had been met during cits are no longer confined to the aphasia. Personality an earlier phase of the disease in a patient who now changes (inappropriate familiarity, impaired problem- has other deficits as well. solving, blunted judgment) and extrapyramidal deficits reminiscent of CBD emerge quite commonly as the dis- 54.4. Subtyping and terminology in primary ease progresses and reflect the close anatomical associa- progressive aphasia tion of PPA-causing diseases with those causing bvFTD and CBD. The study of patients with cerebrovascular lesions has led to the delineation of several aphasia subtypes, each 54.3.5. Retrospective informant-based diagnosis characterized by a distinctive cluster of signs and symptoms linked to a preferred lesion site within the Diagnosing PPA is easiest when the patient is exam- language network. The clustering of deficits and their ined in early stages when core criteria can be fulfilled clinicopathological correlates are slightly different in explicitly. Occasionally, the clinician will see a patient PPA, perhaps because the lesions are selective for spe- at a more advanced clinical stage, at a time when the cific neuronal types and also indolently progressive, 578 M. MESULAM AND S. WEINTRAUB leading to more complex dissociations of function and The PNFA and semantic dementia subtypes do not some reorganization of cortical circuitry. account for all of PPA. The “logopenia” term intro- In contrast to stroke-induced syndromes where dys- duced in the initial 1982 paper on PPA (then known arthria is a frequent component of non-fluent apha- as slowly progressive aphasia) described a clinical sias, for example, the low fluency in PPA is usually state intermediate between non-fluent and fluent apha- due to word-finding pauses or to a characteristic non- sia (Mesulam, 1982). The most comprehensive recent dysarthric slow and labored output as if the patient development to take this “third” form of PPA into is struggling to form the word. In such patients single account is the work of Gorno-Tempini and colleagues syllables such as “pa”, “ta”, or “ka’” can each be who codified a “logopenic” variant of PPA (Gorno- repeated in rapid succession, but their combination into Tempini et al., 2004). “pataka” may not be possible, reflecting a high-order Based on these developments, we are now subdividing deficit in articulatory programming of phonological our cases into three variants: agrammatic-dysfluent, sequences. semantic and logopenic. In our clinical practice, the Components of language may dissociate in unusual agrammatic-dysfluent variant (representing a subset of ways. For example, a PPA patient may be non-fluent PNFA) is characterized by impairments of syntax and flu- but without the agrammatism that usually accompanies ency but preserved word comprehension; the semantic stroke-induced non-fluent aphasias. Conversely, the variant by poor word comprehension but preserved syn- agrammatism may be more pronounced and dramatic tax and fluency; and the logopenic variant by variable flu- than in any stroke-induced aphasic syndrome. In con- ency, frequent word-finding pauses and/or anomia but trast to patients with stroke-induced loss of fluency relatively intact syntax and word comprehension. who are consistently dysfluent, the impaired fluency in The steps we use in clinical diagnosis are listed PPA may be intermittent. Such patients can produce in Table 54.2. The practicing neurologist or psychiatrist fluent speech when allowed to engage in small talk may want to stop at the end of Step 1 after establishing and circumlocution, but become non-fluent because of the root diagnosis of PPA. This is the key step in differ- word-finding hesitations when forced to be precise. entiating the patient’s clinical picture from other major The neologism “logopenia” was coined to describe this dementia syndromes such as PRAD and bvFTD. The state of fluctuating fluency (Mesulam, 1982). The inter- further subtyping of PPA is a laborious exercise that mittent interruption of fluency in these patients also should probably be reserved for research purposes. shows that the fluent vs. nonfluent distinction, a gold standard for the classification of stroke-based aphasias, may be of more limited usefulness in the classification 54.4.1. PPA: agrammatic-dysfluent subtype of PPA. When present, comprehension deficits are usually confined to single words and rarely lead to the This variant is a subset of PNFA. It is characterized profoundly impaired comprehension of conversation by early and prominent agrammatism (in spoken and characteristic of Wernicke’s aphasia. These are some written language) in the absence of single word com- of the reasons why PPA patients do not easily lend prehension deficits. Output tends to be impoverished themselves to classification into traditional subtypes in function words but may be enriched in meaning- such as Broca’s, or Wernicke’s aphasia. appropriate nouns and verbs, giving speech a “tele- The progressive non-fluent aphasia (PNFA) of graphic” and pithy quality. Sentences display abnor- Neary et al. (1998) fulfills the PPA criteria and can mal word order (syntax) and the inappropriate be considered a PPA subtype. If the original Neary deployment of bound morphemes (word endings used et al. criteria for semantic dementia, namely the re- to denote tenses, possessives, or plurals). For example, quirement to have both poor word comprehension and the daughter of one of our patients first realized that also an associative agnosia, are interpreted literally, there was something wrong with her mother when semantic dementia does not fit the PPA criteria. How- she received the following e-mail: “I will come my ever, a revision of these criteria by the Cambridge house in your car and drive my car into Chicago ... group has led to a reformulation of semantic dementia You will back get your car and my car park in my dri- as a fluent form of PPA (Adlam et al., 2006). Accord- veway. Love, Mom.” Another patient who happened to ing to this reformulation, semantic dementia leads to be a nurse gave the following description of her diffi- recognition deficits only for unfamiliar faces and pic- culties: “Syntax errors and no articles.... Words in the tures. Since such patients would have a prominent flu- my head and cut up. Writing syntax errors. Edit my ent aphasia with poor comprehension and preserved work computer.” recognition of familiar faces and objects, they would Patients in this subgroup may also show a selective satisfy the criteria for a PPA diagnosis. comprehension deficit for grammatically complex sen- PRIMARY PROGRESSIVE APHASIA AND KINDRED DISORDERS 579 Table 54.2

The steps involved in the clinical diagnosis and subtyping of primary progressive aphasia

Step 1: Does the patient have an impairment in word-finding, object naming, syntax or word comprehension, caused by a neurodegenerative disease, and that initially constitutes the most salient aspect of the clinical picture? if yes, diagnose PPA and proceed to step 2 Step 2: Does the patient have word comprehension deficits and preserved fluency? if yes, classify as “PPA, semantic variant” if not, proceed to step 3 Step 3: Does the patient have consistently decreased fluency and selective impairments in the production and comprehesion of syntax? if yes, classify as “PPA, agrammatic-dysfluent variant” if not, proceed to step 4 Step 4: Does the patient have object naming deficits or intermittent dysfluency because of word-finding pauses? if yes, classify as “PPA, logopenic variant” if not, classify as “PPA, unspecified”

tences such as those with passive voice, possessives, be abnormal in these patients, as in nearly all cases and embedded clauses. For example, when looking at of PPA. a pair of pictures, one of a girl chasing a boy, and the other of a boy chasing a girl, the patient correctly 54.4.2. PPA: semantic subtype points to “boy chasing the girl” but frequently gets confused when asked to point to the “girl chased by This subtype fits the criteria for semantic dementia as the boy”. In general, these patients have no difficulty redefined by Adlam et al. (2006). The core feature is understanding casual conversation or single words. the early onset of prominent word comprehension def- Some patients in this group display the remarkable icits in the absence of major agrammatism (Hodges finding of grammatical alexia: they can read nouns et al., 1992; Mesulam, 2001; Gorno-Tempini et al., such as “alligator” or “house” but not pronouns such 2004). Fluency is usually preserved when the patient as “he” or “it”. is allowed to produce circumlocutions and simplifica- Fluency, as determined by word outflow per minute tions but word-finding pauses may emerge as the or by mean length of utterance, is consistently decreased patient struggles to retrieve a word. At the initial and speech may be halting, labored and effortful but stages, the patient may follow most conversation not necessarily dysarthric. Speech apraxia and phono- except for an intermittent inability to interpret indivi- logical disintegration may distort speech. Frequent dual words. In the course of an otherwise uneventful word-finding pauses may emerge and naming is more conversation, for example, the patient may suddenly impaired for verbs than nouns (Hillis et al., 2004). The assume a perplexed expression and ask: “school? critical findings for this subtype include low fluency What does ‘school’ mean?” Many of the naming def- and agrammatism in the presence of preserved compre- icits at this stage are “two-way” so that the patient can hension for single words and sentences with canonical neither name an object nor point to it when the exam- syntax (Mesulam, 2001; Hillis et al., 2002; Gorno- iner provides the name. This represents a state where Tempini et al., 2004). the semantic “knowledge” related to the object cannot Neuropsychological instruments useful for identi- be accessed through the verbal route. In contrast, fying this PPA subtype include tests of speech produc- the knowledge related to the same object can be tion (Wertz et al., 1984; Duffy, 1995), the Token Test accessed through the visuoperceptual route since the for assessing grammatical comprehension (De Renzi patient can successfully subgroup objects they cannot and Vignolo, 1962), subtests of the WAB (Kertesz, name into appropriate semantic categories and since 1982) and the Curtiss-Yamada Comprehensive Lan- they experience no difficulty (until late in the disease) guage Evaluation (Curtiss and Yamada, unpublished using the objects they cannot name. Nonetheless, results; Gorno-Tempini et al., 2004). The BNT can such patients may display recognition deficits when 580 M. MESULAM AND S. WEINTRAUB shown unfamiliar faces or objects (Adlam et al., 2006). one depicted in the Cookie Theft) where objects need In time, even the most common words fail to be to be named. Comprehension is preserved well into understood and the comprehension of sentences during the middle and late stages. The BNT is abnormal in conversation becomes impossible. Reading and writing patients with extrinsic anomia but may be normal in are frequently impaired but may initially remain some patients with a predominantly intrinsic anomia. relatively more preserved than spoken language. This is almost always a one-way deficit so that the The WAB (Kertesz, 1982) contains naming and word patient cannot name the object but can point to it when comprehension subtests that can be used to test whether the name is given by the examiner. Spelling errors are naming alone is impaired or whether the patient is also common. unable to comprehend the spoken words for objects, numbers, colors, and geometric shapes. Performance in the Pyramids and Palm Trees (Howard and Patterson, 54.4.4. Other subtypes 1992) can be used to assess semantic associations and is usually abnormal in this PPA subtype, at least in part Some patients will fulfill criteria for PPA but will not because it relies on extensive verbal processing. fit into the semantic, agrammatic-dysfluent or logope- The Regularity and Reading subtest of the Psycholinguis- nic subtypes. For example, some patients may have tic Assessment of Language Processing in Aphasia agrammatism or loss of fluency together with compre- (PALPA) (Kay, 1992) can be used to demonstrate the sur- hension deficits, others a loss of comprehension for face dyslexia characteristic of these patients. This PPA spoken but not written words. These patients can be subtype is associated with the most severe abnormalities classified as having “mixed” or “word-deaf” subtypes on the BNT. A distinctive feature is the failure to point to of PPA. Still other patterns may exist, illustrating the an object named by the examiner, a process that is pre- complexity of the language network and the heteroge- served in the other PPA subtypes. These are the most neity of its response to the underlying neurodegenera- challenging patients to evaluate since the inability to tive disease. comprehend questions may give the mistaken impression of global cognitive deficits. 54.4.5. Varieties of naming impairments and paradoxical priming in PPA 54.4.3. PPA: logopenic-anomic subtype Anomia is one of the most common deficits in PPA. The core features of this subtype include an anomia A rich and bewildering variety of naming deficits can without early agrammatism or comprehension deficits. be encountered in PPA. Some patients may name The anomia can be intrinsic, in which case the patient objects but not actions; others may be able to write cannot find the word to express the intended verb or the name of objects they cannot name verbally; still noun, leading to halting but syntactically correct others can display dissociations in the naming of living speech interspersed with word-finding pauses, or versus non-living objects. Psycholinguistic experi- extrinsic, in which case the major difficulty is in nam- ments in neurologically intact subjects show that brief ing objects and actions perceived by the patient. These exposure to a word may speed up the subsequent nam- two types of anomia can be dissociated from each ing of a picture depicting a semantically related object. other. Extrinsic anomia is diagnosed by poor perfor- This process is known as priming. In PPA, priming mance on naming tests such as the BNT. Intrinsic with a semantically related word causes the subsequent anomia is characterized by word-finding pauses during picture naming to be slower than when primed by spontaneous speech. Patients with intrinsic anomia a semantically unrelated word (Vandenberghe et al., learn to circumvent the use of words they cannot 2005). This phenomenon of semantic interference was retrieve and can produce fluent but circumlocutious not seen in controls or PRAD patients tested with the and simplified sentences lacking in verbs and nouns same task. In order to explain this paradoxical effect, (for example, a patient who says “the thing that you we postulated that PPA interferes with the discrimin- use to put it in” instead of “hammer”). When asked ability of semantically related words during naming. to be specific (for example, about the details of their According to this scenario, the prime activates the occupation) paraphasias and word-finding pauses proper semantic field but paradoxically slows the nam- emerge and the patient becomes non-fluent. Conver- ing of related objects because the correct choice sely, patients with an extrinsic anomia may be quite becomes embedded in a field of semantically related fluent when describing complex ideas but may become nouns. This phenomenon resembles the gradual slow- non-fluent when asked to describe a scene (such as the ing of target detection in a spatial attention task as PRIMARY PROGRESSIVE APHASIA AND KINDRED DISORDERS 581 distracters look more and more like the target. A basic severe comprehension deficits and usually a severe mechanism for the logopenia and anomia in PPA may loss of fluency. Output becomes limited to single thus be a deterioration of the signal to noise ratio dur- words, palilalic syllables, or grunts. In others with flu- ing lexical retrieval. In keeping with this finding, ent onset, speech deteriorates into meaningless logor- PPA patients showed abnormalities in recognizing rhea. Behavior may range from apathy to severe previously encountered words mostly because of false agitation. positive identification of semantically related distracters (Rogalski et al., 2007). 54.6. Non-PPA progressive aphasias

Occasionally, patients with otherwise typical motor 54.5. Longitudinal course neuron disease (MND) may display anomia and other 53.5.1. Early-stage primary progressive aphasia: features of aphasia (Caselli et al., 1993; Rakowicz and Hodges, 1998; Strong et al., 1999). In some The distinctive features characteristic of the PPA sub- patients, the earliest stages will raise the suspicion of types are most clearly identified in the early stages of PPA but signs of motor neuron disease will soon the disease, usually within the first 2 years after symp- emerge, usually within the first year, and dominate tom onset. This is the stage at which the predominance the clinical picture. This is the one group of progres- of the aphasia is most obvious. Even at these early sive aphasics where a rapidly progressive course lead- stages, however, all other domains need not be abso- ing to death within a few years may be encountered. lutely normal. On occasion, patients with early PPA Asymmetry of pathology is common in corticobasal may also show mild ideomotor (usually buccofacial) degeneration (CBD). When the disease targets the left apraxia, dyscalculia, disinhibition, and constructional hemisphere, right-sided motor deficits can be accom- deficits. These additional signs reflect a spread of dys- panied by prominent and progressive aphasic distur- function to prefrontal and parietal cortices immedi- bances (Frattali et al., 2000; Kertesz et al., 2000). ately adjacent to the language network. However, Patients who fit the diagnostic criteria for PRAD, deficits in non-language domains, if present, are minor bvFTD, and posterior cortical atrophy (PCA) can also relative to the language impairment and do not contri- develop aphasias. However, the language disturbance bute to the limitations of daily living activities in any in these patients either emerges late in the course of major way. the disease or does not represent the most salient aspect of the clinical picture. These patients can be 54.5.2. Mid-stage primary progressive aphasia designated as having a progressive aphasia in addition to the relevant primary diagnosis. As the symptomatology progresses, more pronounced In PRAD the language disorder usually takes the deficits in other domains may emerge. The most form of a fluent aphasia with or without comprehen- common are in the areas of executive function and sion deficits (Weintraub et al., 1990; Price et al., comportment. Some of our patients develop apathy, 1993), in bvFTD the language disorder is characterized start to show signs of poor judgment, excessive jovial- by an economy of expression and occasional agramma- ity, inappropriate conviviality, and blunted foresight. tism, in CBD the aphasia is usually dysfluent, and in Others may show memory deficits for recent events. MND the aphasia may be associated with dysarthria or Still others may develop recognition deficits even for dysphonia. familiar faces and objects. In the majority of our patients these non-language deficits have been less 54.7. Functional and structural neuroanatomy salient than the aphasia, progressed less rapidly, and had a lesser impact on daily living activities. Mild pyr- The vast majority of patients with PPA display focal amidal and extrapyramidal deficits on the side of the atrophy, EEG slowing, hypoperfusion (measured by body contralateral to the hemisphere dominant for lan- SPECT) and hypometabolism (measured by PET) cen- guage (usually left) may tend to emerge. This is the tered in the perisylvian region of the language-dominant stage at which the diagnosis of PPAþ may be consid- hemisphere (usually left) where the core components of ered as described above. the language network are located. These structural and physiological abnormalities frequently extend into the 54.5.3. End-stage primary progressive aphasia adjacent frontal, insular, temporal, and parietal components of the language network (Chawluk et al., 1986; As the end-stages are reached, all patients gravitate Kempler et al., 1990; Tyrrell et al., 1990; Mesulam toward a state of global aphasia characterized by and Weintraub, 1992). Two voxel-based morphometry 582 M. MESULAM AND S. WEINTRAUB studies, involving a total of 42 patients, have confirmed ing Wernicke’s area (Gorno-Tempini et al., 2004; that PPA is characterized by strongly asymmetrical Adlam et al., 2006). atrophy revolving around the left perisylvian cortex but also extending into neighboring areas (Sonty et al., 54.8. Neuropathology 2003; Gorno-Tempini et al., 2004). Other parts of the brain, including the entire right hemisphere, may Is PPA a single disease linked to a unitary neuro- remain relatively intact well into the middle and late pathology or is it a syndrome arising from a common stages of the disease (Chawluk et al., 1986; Tyrrell anatomical distribution of multiple disease entities? et al., 1990). In the rare patients with right hemi- This question has not yet been resolved. Despite the sphere dominance for language, the atrophy is centered tendency to rely on the post-mortem examination as in the right perisylvian region (Mesulam et al., 2005). the final arbiter, it is necessary to consider the possibi- The clinical focality of PPA is thus matched by the anato- lity that the cellular changes noted at death, 10–15 years mical selectivity of the underlying pathological process after symptom onset, may not necessarily reflect the for components of the language network. initiating cellular changes that triggered the distinctive Abnormalities of blood flow and metabolism may clinical picture in the beginning. emerge prior to the detectable atrophy. SPECT or PET may therefore provide more sensitive diagnostic 54.8.1. PPA and the FTLD spectrum of information than structural MRI or CT scans. When neuropathology asked to identify homonyms or synonyms in the course of functional MRI experiments, PPA patients and age- More than 100 patients with the clinical syndrome of matched controls activate the same components of the PPA have yielded neuropathological information language network, including Broca’s and Wernicke’s (Mesulam and Weintraub, 1992; Chin et al., 1994; areas (Sonty et al., 2003). However, the functional Harasty et al., 1996; Turner et al., 1996; Kertesz connectivity between these two major nodes of the lan- et al., 2005; Knibb et al., 2006). The single most com- guage network becomes disrupted (Sonty et al., 2007). mon neuropathological picture associated with PPA, It appears, therefore, that disrupted language proces- seen in 60–70% of the patients, is one that fits the sing in PPA may reflect an impairment of information FTLD spectrum of diseases (McKhann et al., 2001). transfer within the language network rather than a fail- These patients do not have plaques and neurofibrillary ure of activation within the network nodes. In compari- tangles in quantities that warrant a diagnosis of AD. In son to neurologically intact subjects, the PPA patients some, the findings are confined to a focal (lobar) also displayed additional aberrant activations within degeneration characterized by neuronal loss, gliosis, regions of the brain outside the classic language network and mild spongiform change within superficial cortical (Sonty et al., 2003). It is not yet clear whether these layers. This pattern was once known as nonspecific aberrant activations reflect compensatory processes focal atrophy or dementia lacking distinctive histol- or abnormal disinhibition. The latter possibility is sup- ogy. In other cases, the cerebral cortex may contain ported by the fact that the intensity of the aberrant acti- ballooned neurons filled with phosphorylated neurofi- vations is inversely correlated with performance on a lament protein, tau-positive Pick bodies, CBD- or naming test (Sonty et al., 2003). PSP-like tau inclusions, or tau-negative but TDP-43- Non-fluent patients with intact comprehension tend immunoreactive and ubiquitinated inclusions (Lippa to have atrophy and metabolic dysfunction within the et al., 1991; Mesulam and Weintraub, 1992; Kertesz frontal and perisylvian components of language areas, et al., 1994, 2000; Ikeda et al., 1996; Kinoshita et al., whereas fluent patients with comprehension deficits 1996; Turner et al., 1996; Molina et al., 1998; Rossor tend to have atrophy and dysfunction also in the tem- et al., 2000; McKhann et al., 2001; Boeve et al., poral parts of the language network (Abe et al., 2003; Neumann et al., 2006). The tau-negative ubiqui- 1997; Rosen et al., 2002). According to voxel-based tin/TDP-43 inclusion pattern is also known as FTLD- morphometry, the agrammatic-dysfluent subtype is U or FTLD-MND type. most closely associated with atrophy in the anterior parts of the language network, including Broca’s area; 54.8.2. PPA and AD neuropathology the semantic subtype with atrophy in the middle and anterior temporal cortices bordering the perisylvian The frontotemporal family of neuropathologies does region as well as the inferior temporal lobe; and the not seem to account for all cases of PPA. Approxi- logopenic-anomic subtype with atrophy in the tempor- mately 30–40% of PPA patients who have been exam- oparietal component of the language network, includ- ined post mortem have shown the pathology of AD PRIMARY PROGRESSIVE APHASIA AND KINDRED DISORDERS 583 ( Mesulam and Weintraub, 1992; Kni bb ).et al.,in 2006conj unction with Creutzfe ldt-Jakob disease . How- A very small numb er of the patients in thisever, group the havecours e is so rapid that deat h usually occur s neuro patholog ical featur es that are n ot seenbefore in thetypical criteri a of appro ximatel y 2 y ears of indo- AD, such as neurofibri llary tangle distrib utionslently favor- progress ive isolated aphasia can be ful filled ing neocorti cal rather than limbic areas (Mandeand thell et al.,). 1989 absen ce of seni le Galtonplaqu eset ( al., ).2000 How - ever , the currently cited 30–40 % frequenc y54.9. of GeneticsAD in and risk factors of PPA PPA may overemp hasize the importanc e of this rela- tionshi p sinc e the neuropat hologica l examinProgressive ation isaphasia can be seen in patient s with auto- usually perform ed many year s after dise asesomal onset dominan , at t d ementias linked to chromos ome 17 an age whe n the plaq ues and tangles of (BaAD sunare etende- al., 1997; Bird et al., 1 997; Lendon et al., mic. In fact, the primary neuro path ological 1998;diag nosisMurrel l et al.,). In1999 som e kindreds , this of AD in a p atient with the clinical picturehas been of called PPA familial dysphasic dementia, or heredi- and a limbic concentrat ion of neuro fibrillarytary tang dysphasic les disinhibition dementia. There is also a typical of AD should be met with skeptic uniqueism autosomalsince dominant disorder, linked to chro- such a diagnosi s woul d have faile d to estmosome ablish 9,a wherecred inclusion- body myopathy and ible clinicopathol ogical correl ation. So me Paget’sof diseasethe are seen in conjunction with a progres- patients in this group may have had anothersive aphasianeuro- (Kovach et al., 2001). However, the early path ological proce ss that may have been emergenceresponsi ble of prominent memory, behavior, and motor for the clinical pictur e of progress ive aphasiaimpairments but that in these familial cases differs from the coul d have been overlooke d in the presencepattern of seen the in typical PPA. more conspi cuous age- related plaq ues and Intang two les recently reported kindreds, three of four (Mun oz et al., 2007). The nosol ogical distinctsiblings ion (in theof PPA1 kindred) and two of three sib- PPA from AD is suppor ted by the observationlings (in that the PPA3 kindred) developed typical PPA patients with PPA have differ ent patterns of( Mesulamapol ipo- et al., 2007). In both kindreds, a mutation protei n E and prion protein genot ypes thanin thepatients progranulin gene (PGRN) on chromosome 17 with the PRAD syndromeMesu (lam et al., 1997;was Li found to segregate with the presence of PPA. Neu- et al., 2005). Howeve r, the possi bility that thereropathological is a evaluations in affected siblings showed disti nct subgroup of PPA caused by an atypicacharacteristic l mani- left perisylvian atrophy and ubiquinated festatio n of AD cannot be dismisse d. intracellular and intranuclear inclusions characteristic of the FTLD-U pattern. Investigations in larger groups 54.8.3. Relat ionship of PPA subtype to of patients show that PPA is a major clinical manifes- neuropat hology and differen tiating AD fromtation FTLD of PGRN mutations (Gass et al., 2006). Such mutations can also be encountered in PPA patients In non-fam ilial cases, some auto psy series showwith nothat known the family history (Davion et al., 2007). dysfluen t subt ypes are mor e closel y associatedIn some with families with PGRN mutations, one family tauo pathy and the semantic subtyp es with memberFTLD-U may have PPA, and another bvFTD (Van der ( Knibb et al., ).2006 Howeve r, there is considerZee able et al., 2006). How can the same mutation target overlap. Furthermor e, in famili al cases FTLD-the U languagepathol- network in one family member and the ogy is more closely associated with the dysfluenprefrontal t rather cortex in another? The common denomina- than the semantic variantsVan der( Zee et al.,). 2006tor may not be the nature of the molecular/cellular pro- Some autopsy series have suggeste d that the cessnon-flue but ant selective vulnerability of the language forms (PNFA) have a partic ularly high frequencnetwork y of that AD makes it a locus of least resistance. Such path ologyKnibb ( et al., ),2006 others that the assocselective ia- vulnerabilities may be genetic or acquired. tion is mostly with the logop enicGorno- subty peFor example,( we reported that learning disabilities, Temp ini et al., ). 2004Our exper ience tend s toincluding favor dyslexia, were overrepresented in patients the latt er. Conceivabl y, CSF biomar kers orwith amyloid- PPA and their first-degree relatives when com- binding PET ligands may assist in dete rminingpared whethe with controlsr and AD patients (Mesulam and PPA is cause d by AD or FTLD . Weintraub, 1992; Rogalski et al., in press). In some of these families, the concentration of dyslexia was 54.8.4. PPA and Creutzfel dt-Ja kob neu ropathostriking, logy affecting the majority of children or siblings. Furthermore, two patients with PPA onset in their A rapi dly progress ive lang uage diso rder 60swith were all found the to have left hemi-craniosynostosis, a initial characterist ics of PPA has also been milddescr developmental ibed abnormality that interferes with 584 M. MESULAM AND S. WEINTRAUB the normal growth of the underlying cortex. In these two Other degenerative diseases can also eventually lead patients, the left hemisphere hypoplasia was function- to language disturbances but the resultant aphasias ally compensated throughout most adulthood but are not “primary” because they are neither the most appears to have provided the neural background for salient feature of the clinical picture nor early in onset. the emergence of PPA in the 7th decade of life (Alberca Primary progressive aphasia has a broad spectrum of et al., 2004). Such tardive manifestations of remote clinical manifestations. Early in the course of the dis- vulnerabilities are not unknown in neurology. One ease, agrammatic-dysfluent, semantic, logopenic var- study, for example, showed that patients who had recov- iants can be identified. ered from childhood hemiplegia reported the progres- The manifestations of primary progressive aphasia sive emergence of hemiparkinsonism later in life on are distinctly different from those of PRAD. Different the side of the original weakness (Klawans, 1981). aspects of daily living activities are impaired and These observations have led us to wonder whether require different sorts of intervention. Some patients PPA could represent the tardive manifestation of can learn sign language, others find it useful to carry genetic or acquired vulnerabilities of the language net- laminated cards with specific messages, still others work that remain functionally compensated during benefit from voice synthesizers or laptops containing most of adulthood but that become the locus of least digitally stored words and phrases. An evaluation by resistance for the distribution of neurodegeneration. a speech therapist is useful for exploring alternative In other patients with a different set of prior vulner- communication strategies. In contrast to PRAD, where abilities the same neurodegenerative process may have new information cannot be retained in memory, the a different distribution and therefore different clinical recall and evaluation of recent events remains intact manifestations. although the patient may not be able to express this Additional risk factors for PPA have also been sug- knowledge verbally. Explaining this phenomenon to gested. The H1/H1 haplotype of tau may be overrepre- the family and offering an objective assessment of how sented in PPA (Sobrido et al., 2003). Furthermore, the the aphasia interferes with verbal expression and lan- MV polymorphism in codon 129 of the prion protein guage comprehension tends to help the family cope with gene is more prevalent in PPA than in normals or the patient’s impairments. We find that psychosocial AD (Li et al., 2005). This does not imply that PPA is interventions, support groups and targeted educational a prion disease, but that polymorphisms in the prion programs are necessary components of a comprehensive protein may influence the anatomical distribution of approach to patients and families (Weintraub and susceptibility to degeneration, as they do in fatal Morhardt, 2005). familial insomnia and familial Creutzfeld-Jacob dis- The epidemiology of PPA is largely unknown. ease (Parchi et al., 1996; Hauw et al., 2000). The pos- Hundreds of patients have been reported in the litera- sibility that the language network has a unique and ture and many thousands are likely to be receiving identifiable molecular fingerprint that would make it care in clinics around the world. There is currently the target of selective vulnerability in some genetic no effective pharmacological treatment for this condi- backgrounds but not in others is not as implausible tion but clinical trials with potentially promising drugs as it may sound, especially in view of observations are being initiated. A controlled bromocriptine trial did on the KE family, where speech and language distur- not yield positive results (Reed et al., 2004). A trial bances are linked to a FOXP2 gene mutation (Fisher with memantine in our clinic is nearing completion et al., 1998). In men with PPA, the frequency of but is unlikely to yield promising results. Transcranial vasec tomy was found to be Weintraubincr eased magnetic( stimulation of the left prefrontal cortex et al., 2006). As a possibl e under lying mec appearshanism tofor have led to improvement in one patient this association it was pointed out that sperm and brain (Finocchiar o et al., 2006). Discov ering effect ive phar- tissue share some common antigens and that the macological treatments constitutes the most critical hypothesized vasectomy-related neurodegeneration challenge facing this field. may have an autoimmune basis similar to that of para- While we await the appearance of effective thera- neoplastic diseases. The E4 allele of apolipoprotein E, pies, PPA offers a unique experiment of nature for a major risk factor for AD, is not overrepresented in exploring the molecular fingerprints that make the lan- PPA (Mesulam et al., 1997). guage network a primary disease target and for prob- ing the cognitive architecture of human language as 54.10. Conclusions and patient care it undergoes a slow but relentless dissolution. 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