Check Your Diagnosis — Patient 35

George M. Ringholz, M.D., Ph.D.

Diagnosis

Progressive Non-fluent Aphasia (formerly Primary Progressive Aphasia)

Clinical Summary and Discussion

This patient's condition began with dysnomia and progressed to a severe expressive language disorder over the course of approximately five years. His current status also reflects early deficits in frontal lobe executive functioning (maintenance of task set and planning and execution of complex drawings). There is relative preservation of visuospatial skills. The deficits in memory seen affect both verbal and non-verbal domains. However, the patient does not show global memory impairment in terms of his orientation to time. There is relative preservation of personality and no history of socially inappropriate behavior, apathy, restricted affect, or amimia. These findings are suggestive of a primary progressive aphasia that has begun to involve the frontal lobes.

Progressive nonfluent aphasia (PA) is currently conceptualized as one of three prototypic clinical syndromes of frontotemporal lobar degeneration (FTLD), the other two being frontotemporal dementia (FTD) and semantic dementia (SD). FTLD is the third most common cause of cortical dementia - after Alzheimer's disease and Dementia with Lewy bodies. There are two major pathologic substrates associated with these three different clinical syndromes: prominent microvacuolar change without specific histologic features (frontal lobe degeneration type) and severe astrocytic gliosis with or without ballooned cells and inclusion bodies (Pick type). The associated clinical syndromes are determined by the distribution of the pathology. A consensus statement on clinical diagnostic criteria for the subtypes of FTLD was recently advanced. According to these criteria, PA has as its dominant feature, a disorder of expressive language that is present at the onset of the condition and remains throughout the disease course. Other aspects of cognition are intact or relatively well preserved. Core diagnostic features include an insidious onset with gradual progression, and nonfluent spontaneous speech marked by agrammatism, phonemic paraphasias, or anomia. Supportive diagnostic speech and language features include stuttering or oral apraxia, impaired repetition, and alexia with agraphia. Early in the disease, word meanings are preserved. Mutism occurs as a late feature. Social skills are preserved early in the course of the disease. However, late behavioral changes similar to FTD (rigidity and inflexibility, distractibility and impersistence, and perseverative and stereotyped behavior) are seen. Other supportive features include onset before age 65. There is a positive family history of a similar disorder in a first-degree relative in as many as 50% of patients. The development of motor neuron disease in a patient presenting with a primary language disorder strongly supports a clinical diagnosis of PA.

A familial form of frontotemporal dementia with parkinsonism (FTDP-17) also has been identified. Clinical features include personality changes, hyperorality, nonfluent aphasia, bradykinesia, rigidity, and impairment of executive functions. The inheritance is autosomal dominant with a pathological locus mapped to a 2 cM interval on 17q21-22. The gene for the microtubule-associated protein tau is located in this region, and tau-positive neuronal inclusions have been demonstrated in many of these family members. More than 10 exonic and intronic mutations in the tau gene have been identified in patients with familial FTDP-17. Missense mutations including P301L, V337M, and R406W have been shown to disrupt cytoskeletal networks of microtubules and/or result in an accelerated aggregation of tau into filaments.

Early in the course of the disease, the neurological examination is typically normal. However, late physical signs such as contralateral primitive reflexes, akinesia, rigidity, and tremor are common. Neuropsychological testing shows a nonfluent aphasia in the absence of severe amnesia or perceptuospatial disorder. The electroencephalogram is usually normal, but minor asymmetric slowing may be seen. Structural or functional imaging may likewise show an asymmetric abnormality affecting the dominant hemisphere.

Diagnostic exclusion features include abrupt onset with ictal events, head trauma related to onset, early severe amnesia, spatial disorientation, logoclonic and festinant speech with loss of train of thought, myoclonus, corticospinal weakness, cerebellar ataxia, or choreoathetosis.

As noted above the course of the disease is typically slowly progressive; however, rapidly progressive cases have been documented. There is currently no known effective treatment. Careful monitoring of functional skills, application of appropriate supportive therapies (patient and care-giver), symptomatic treatment, and alternative communication devices provide the best opportunities at the present time for maintaining quality of life.

References

  1. The Lund and Manchester Groups. Clinical and neuro-pathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry. 1994;57(4):416-8.
  2. Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol. 1982;11(6):592-8.
  3. Weintraub S, Rubin NP, Mesulam MM. Primary progressive aphasia: longitudinal course, neuropsychological profile and language features. Arch Neurol. 1990;47(12):1329-35.
  4. Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702-5.
  5. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43(6):815-25.
  6. Brown J, Ashworth A, Gydesen S, et al. Familial nonspecific dementia maps to chromosome 3. Hum Mol Genet. 1995;4(9):1625-8.
  7. Caselli RJ, Windebank AJ, Petersen RC, et al. Rapidly progressive aphasic dementia and motor neuron disease. Ann Neurol. 1993;33(2):200-7.

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