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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 11 NOVEMBER 2006 1025

STUART J. KANTER, DOSection of Geriatric Medicine, Department of

General Internal Medicine, Cleveland Clinic

RONAN M. FACTORA, MD*

Section of Geriatric Medicine, Department of

General Internal Medicine, Cleveland Clinic

Does this patient have primary

progressive aphasia?

REVIEW

ABSTRACT

Primary progressive aphasia (PPA) is a distinct clinicalentity in which the patient develops language deficitswhile other cognitive domains remain relatively preserveduntil late in the course of the illness. The diagnosis can be

relatively clear through an appropriate diagnosticapproach based on the history and physical examination.There is no cure, but speech therapy is beneficial in thisillness.

KEY POINTS

The differential diagnosis of PPA includes stroke, masslesion, and Alzheimer disease. Neuropsychiatric testing is

useful to help differentiate the cognitive deficits ofvarious dementing diseases.

Preliminary assessment of language can be done in theoffice.An example would be to ask the patient to identifygeometric shapes, parts of the body, or components ofcommon objects.

Laboratory testing is uninformative in PPA.

Electroencephography is normal in 75% of cases, andcomputed tomography and magnetic resonance imagingare normal in 50%.

N 81-YEAR-OLD WOMAN presents withcomplaints of word-finding problems

and difficulty finishing sentences that beganapproximately 4 years ago. Her daughter statesthat the patient starts a sentence without diffi-culty and is fluent to a point, but struggles to findwords. Her speech recognition, written languageskills, and memory are intact, as is her ability toperform basic and instrumental activities.

Her medical history includes hypertension,esophageal reflux, and mitral valve prolapse. Sheis a retired nurse, she smoked in the past but doesnot smoke now, and she rarely consumes alcohol.Her father died of Alzheimer disease at age 86.Her medications include verapamil (eg, Calan),famotidine (Pepcid), and a multivitamin.

Review of systems is notable for visiondeficits (corrected with glasses), occasional urgeincontinence, and feeling more melancholysince her husbands death 5 months ago.

The entire physical examination results,including vital signs, are within normal limits.On testing of mental status, she scores 30 (of apossible 30) on the Mini-Mental StateExamination (MMSE), she can draw a clock

face, and she scores 7 (of a possible 17) on theGeriatric Depression Scale (short form), indicat-ing depression. She has difficulty starting sen-tences and often cannot complete her thoughts.She states I know what I want to say but can-not say it.

Do the history, physical examination, andmental status testing support a diagnosis of pri-mary progressive aphasia (PPA)?

WHAT IS PPA?

PPA is clinically defined as a progressive lan-guage deficit that leads to the dissolution of

A

THEODORE T. SUH, MD, PhD, MHSc

Section of Geriatric Medicine, Department of General Internal

Medicine, Cleveland Clinic

*Dr. Factora has indicated that he owns stock in the Pfizer corporation and has received

honoraria from Pfizer for teaching and speaking.

Dr. Suh has indicated that he has received honoraria from the Pfizer corporation for teaching

and speaking.

CREDITCME

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1026 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 11 NOVEMBER 2006

almost all language functions, while other cog-nitive functions remain relatively preserveduntil late in the course of the disease.

Although controversy exists regarding thenomenclature of PPA, several subtypes havebeen recognized. PPA can be either fluent ornonfluent, and with or without repetition orimpairments in comprehension, reading, orwriting.1 PPA in which speech is nonfluentand agrammatical is known asprogressive non-

fluent aphasia. PPA with fluent speech but poorcomprehension is called semantic dementia.PPA with fluent aphasia is also called logopenic

progressive aphasia.Depending on the type of aphasia, specif-

ic areas of the brain are affected.2 Progressive

nonfluent aphasia is associated predominantlywith atrophy of both frontal lobes. Difficultyin naming and understanding words is associ-ated with involvement of the left parietotem-poral lobe. Difficulty with recognizing facesand objects is associated with involvement ofthe right temporal lobe.

Errors in speech may be semantic (wordchoice) or phonemic (sound-based). Speech

may also be described as telegraphic (usingabnormally short phrases). Examples ofsemantic errors in the sentence I will comemy house in your car and drive my car intoChicago include the inappropriate use ofmy and into Chicago instead of toChicago.3 The sentence For exercise I liketo runt and lit wastes demonstrates phonemicerrors in the substitution of runt for runand lit wastes for lift weights. Many ofthese errors can be identified during thepatient interview.

Although PPA can appear in people asyoung as 35, the mean age of onset is in the

6th decade, and it arises only rarely after age75. Patients experience isolated languageproblems for a median of 4.5 years (range115) before seeking medical attention.4

PPA is primarily a sporadic disorder, but itcan be inherited in an autosomal-dominantmanner. Familial PPA has been described, andthe disease has been linked to chromosomallocus 17q21.4 Early studies of apolipoprotein Egenotyping in PPA do not indicate a predispo-sition with the E4 allele, which has beenobserved in Alzheimer disease.5

Neuropathologic studies demonstratechanges consistent with Alzheimer disease in30% of PPA cases. In about 70%, the micro-scopic findings include focal spongiform

changes and focal neuronal degeneration,resembling the neuropathological findingsfound in frontal lobe dementia of the non-Alzheimer type. An additional 20% ofpatients with PPA have Pick disease, charac-terized by tau-positive spherical neuronalinclusions.3

PPA VS STROKE, MASS LESION,

ALZHEIMER DISEASE

The differential diagnosis of PPA includesstroke, mass lesion, and Alzheimer disease.

Dominant hemispheric stroke involvingthe language centers produces aphasia similarto the language deficits in PPA, but presentsacutely, making confusion with PPA unlikely.

A slow-growing mass in the language cen-ter could also produce aphasia, but an imagingstudy would exclude this possibility.

Aphasia is common in Alzheimer diseasebut is almost invariably is associated with earlymemory loss or other cognitive impairment.

She states

I know what Iwant to say

but I cant

say it

PRIMARY PROGRESSIVE APHASIA KANTER AND COLLEAGUES

Cognitive domains affected by PPA,Alzheimer disease, and vascular dementia

LANGUAGE MEMORY MEMORY EXECUTIVEEXPRESSION REGISTRATION RECOGNITION FUNCTION

Primary progressive aphasia Very impaired No change No change No change

Alzheimer disease Impaired Impaired Very impaired Impaired

Vascular dementia Impaired Impaired Impaired Very impaired

T A B L E 1

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Vascular dementia may have language prob-

lems associated with it, but cognitive deficitsinvolving memory and executive function aremore pronounced. TABLE 1 shows areas of cog-nition characteristically affected by PPA,Alzheimer disease, and vascular dementia.

DIAGNOSIS IS CLINICAL

The diagnosis of PPA is based primarily on the

history and physical examination. Laboratorytesting is uninformative. Electroencephalo-graphy can demonstrate left-hemisphere slow-ing or, less commonly, diffuse abnormalities,but findings are normal in 75% of cases.

Computed tomography (CT) or magneticresonance imaging (MRI) can show left tem-poral lobe atrophy, but these imaging studiesare normal in 50% of cases. Functional neu-roimaging with positron emission tomographyand single-photon emission computed tomog-raphy (SPECT) can demonstrate left tempo-ral hypometabolism. A recent study indicatesthat perfusion deficits demonstrated bySPECT precede morphological abnormalitiesidentified by MRI or CT.6

Neuropsychiatric testing is useful to helpdifferentiate the cognitive deficits of variousdementing diseases. This battery of testing is

more sensitive and specific for identifying cog-nitive deficits than the MMSE. It is also moreprecise in identifying what realms of cognitionare decreased in function,7 especially languagedeficits, in which the MMSE is particularlyweak. Prior to referral for neuropsychiatricevaluation, preliminary assessment of lan-guage can be done in the office. An examplewould be to ask the patient to identify geo-

metric shapes, parts of the body, or compo-nents of common objects.3

NO CURE,

BUT SPEECH THERAPY CAN HELP

PPA is a degenerative disorder, and patientseventually develop severe dementia. Languageimpairment and functional communicationcan be positively and significantly influencedby speech therapy, regardless of whether theaphasia is chronic or acute and independent ofthe diagnostic type of aphasia or severity of

deficit at start of care.8,9

CASE REVISITED: DIAGNOSTIC WORKUP,TREATMENT, AND FOLLOW-UP

At the initial evaluation we thought the diag-nosis of PPA to be likely. We obtained a thy-roid-stimulating hormone level, completeblood cell count, basic metabolic panel, andvitamin B

12

level to rule out potentiallyreversible causes of cognitive impairment.Depression was suspected, and a trial of citalo-pram (Celexa) was started.

MRI of the brain demonstrated periven-tricular and subcortical leukoencephalopathyalso involving the pons and mild global atro-phy, changes that are not unusual for thepatients age. Electroencephalography wasnormal without focal or epilepiform activity.

Neuropsychiatric testing evaluation supporteda diagnosis of PPA.

Her mood improved with citalopramtherapy. She was referred to a speech thera-pist, and she had objective improvement after16 visits. At a later follow-up appointment,her family noted a further decline in speechbut no other cognitive decline. The familywas instructed to monitor her mood, and the

patient was scheduled to undergo repeatedneuropsychiatric testing.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 11 NOVEMBER 2006 1027

Neuro-

psychiatrictesting helps

differentiate

various

dementing

diseases

REFERENCES

1. Schwarz M, De Bleser R, Poeck K, Weis J. A case of primary progressiveaphasia. A 14-year follow-up study with neuropathological findings. Brain1998; 121:115126.

2. Gorno-Tempini M, Dronkers NF, Rankin KP, et al. Cognition and anatomy inthree variants of primary progressive aphasia. Ann Neurol 2004;55:335346.

3. Mesulam MM. Primary progressive aphasiaa language-based dementia.N Engl J Med 2003; 349:15351542.

4. Burke JR. Other neurodegenerative disorders. Primary progressive aphasia.In: Hazzard WR, et al, editors. Principles of Geriatric Medicine andGerontology, 4th ed. New York: McGraw-Hill, 1999:12861287.

5. Mesulam MM, Johnson N, Grujic Z, Weintraub S. Apolipoprotein E geno-types in primary progressive aphasia. Neurology 1997; 49:5155.

6. Sonty SP, Mesulam MM, Thompson CK, et al. Primary progressive aphasia:

PPA and the language network. Ann Neurol 2003; 53:3549.

7. Looi JC, Sachdev PS. Differentiation of vascular dementia from AD on neu-

ropsychological tests. Neurology 1999; 53:670678.

8. Aftonomos LB, Appelbaum JS, Steele RD. Improving outcomes for persons

with aphasia in advanced community-based treatment programs. Stroke

1999; 30:13701379.

9. Kiran S, Thompson CK. The role of semantic complexity in treatment of

naming deficits: training semantic categories in fluent aphasia by control-

ling exemplar typicality. J Speech Lang Hear Res 2003; 46:608622.

ADDRESS: Theodore T. Suh, MD, PhD, MHSc, Department of Geriatric

Medicine, A91, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195;

e-mail suht@ccf.org.