Imaging Biomarkers for Familial Primary Progressive Aphasia

Murray Grossman, M.D.

University of Pennsylvania School of Medicine, Philadelphia, PA

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

June 2004, for 4 years

Funding Amount:

$100,000

Lay Summary

A Progressive Language Disorder May Reveal the Chromosomal Basis for Language

A genetic study may reveal the genetic basis for a language disability, and conversely, for the underlying capacity to develop and understand language. This is an imaging and genetic study of a subgroup of patients with a type of dementia that only produces a progressive language disorder, called primary progressive aphasia. Unlike the other patients afflicted with “frototemporal dementia,” who have other cognitive deficits in addition to progressive language problems, this subgroup of frontotemporal dementia patients have only language problems. Finding the defective gene that causes this language-only primary progressive aphasia, therefore, may reveal the genetic basis not only for the disorder, but also for the capacity to generate and use language.

This language-disordered subgroup of frontotemporal dementia patients differs from the dementia patients in another way. The dementia patients have a mutation on chromosome 17 that produces a defect in a brain protein called “tau.” The language-disordered subgroup has a normal chromosome 17, even though they have a defect in the brain tau protein. This evidence suggests that not only chromosome 17 has a mutation producing defective tau brain protein, but that some other chromosome has a similar mutation and that this mutation only affects language. If the investigators can identify this other chromosome, they will have located the genetic basis for the language disorder. Conversely, they also may have located the genetic basis for the underlying capacity to produce and use language and, as a result, the potential for normal language capacity.

The investigators will pursue their hypothesis by finding additional patients with frontotemporal dementia who have only the language deficit called primary progressive aphasia. Once identified, the researchers will collect three-generational medical histories of the patients’ families. Investigators then will image the patients and their three-generation families, using MRI and BOLD fMRI, to identify a “biomarker” in the brain that can be used to confirm the clinical diagnosis. This imaging technique will enable the investigators to quantify the anatomic and functional distribution of the disease in the brain. This analysis will define the familial form of the language disorder. Then the patients and their families will undergo genetic studies to identify the chromosomal basis for this progressive language disorder. This also may be the chromosome that, when functioning normally, is responsible for the capacity for language.

Significance: This study may lead to the identification of the chromosome(s) responsible for a genetically determined language disorder, providing a target for interventions to prevent this disorder. Identifying this chromosome also may lead in the future to determining how this chromosome, when functioning normally, produces the capacity to develop and use language.

Abstract

Imaging Biomarkers for Familial Primary Progressive Aphasia

Frontotemporal dementia (FTD) is a progressive neurodegenerative condition that presents with primary progressive aphasia (PPA) or a disorder of social comportment and executive functioning. FTD is a tauopathy, where the underlying histopathologic abnormality demonstrates a disorder of tau metabolism. About 6% of FTD patients have a defect in the q21-22 portion of chromosome 17 where the microtubule-associated protein tau gene is coded. All of these patients clinically show both aphasia and a social disorder. Careful family histories suggest an inherited cause of FTD in about 33% of patients. Our preliminary work identifies 6 of 38 FTD patients with pure PPA seen in the past year, where a three-generation family history strongly suggests an inherited form of FTD. However, examination of the tau coding region on chromosome 17 did not reveal a defect in these patients with familial PPA (fPPA).

We propose to use neurolinguistic and cognitive methods to identify PPA patients, to obtain three-generation family histories to determine their risk for an inherited disorder of tau metabolism, and to conduct imaging studies that will serve as a biomarker to confirm the clinical diagnosis and quantify the anatomic and functional distribution of disease. We hypothesize that neuroimaging can serve as a biomarker for identifying a subgroup of FTD patients with fPPA who are likely to have an inherited form of FTD that is not due to a defect on chromosome 17. Moreover, we hypothesize that imaging biomarkers will be more effective than other established biomarkers for identifying patients with an inherited neurodegenerative disease.

All patients will receive a complete medical and neurologic history, a detailed mental status evaluation, and a semi-structured neurologic exam to ensure that the proband has PPA, to rule out a social disorder, and to identify clinical features suggestive of non-FTD causes of PPA such as Alzheimer's disease (AD) or corticobasal degeneration (CBD). All families will be surveyed with a detailed, three-generation family history. Criteria will include at least 3 affected individuals in 2 generations with PPA or a similar disorder. Blood samples will be obtained from all patients for sequencing of tau coding regions, and for tau and apolipoprotein E (ApoE) haplotyping. DNA will be stored for later genotyping. CSF and urine samples will be collected for additional biomarker analyses such as tau and isoprostane levels. All patients will have a quantitative neuropsychological and neurolinguistic evaluation using well-established and validated techniques. Volumetric structural brain MRI will be obtained (voxel dimensions 0.85 x 0.85 x 1.0 mm). We will also obtain BOLD fMRI studies in PPA. We will recruit patients for autopsy, and histopathologic studies of FTD patients' brains will be performed in the future to demonstrate a disorder of tau.

In sum, neuroimaging will serve as a biomarker to define a familial form of primary progressive aphasia that is an excellent candidate group for a genome-wide scan. This will allow us to discover other causes of impaired tau metabolism. Language is a uniquely human cognitive skill, and studies of fPPA will help us identify the genetic basis for language. Imaging work in these patients also will improve out understanding of the neural basis for language.

Hypothesis

Hypothesis:
A multidimensional diagnostic procedure can identify a narrowly defined cohort of patients with an inherited form of aphasia in order to understand the genetic basis of language. Specifically, we hypothesize that neuroimaging can serve as a biomarker for identifying patients with a familial form of progressive aphasia who are likely to have an inherited form of frontotemporal dementia that is not due to a defect on chromosome 17. Moreover, we hypothesize that imaging biomarkers will be more effective than other established biomarkers for identifying patients with an inherited neurodegenerative disease.

Goals:
We propose to use neurolinguistic and cognitive methods to identify patients with Primary Progressive Aphasia (PPA), to obtain three-generation family histories to determine their risk for an inherited disorder of tau metabolism, and to conduct imaging studies that will serve as a biomarker to confirm the clinical diagnosis and quantify the anatomic and functional distribution of disease.

Methods:
All patients will receive a complete medical and neurologic history, a detailed mental status evaluation, and a semi-structured neurologic exam to ensure that the proband has PPA, to rule out a social disorder, and to identify clinical features suggestive of non-FTD causes of PPA such as Alzheimer's disease (AD) or corticobasal degeneration (CBD). All families will be surveyed with a detailed, three-generation family history. Criteria will include at least 3 affected individuals in 2 generations with PPA or a similar disorder. Blood samples will be obtained from all patients for sequencing of tau coding regions, and for tau and apolipoprotein E (ApoE) haplotyping. DNA will be stored for later genotyping. CSF and urine samples will be collected for additional biomarker analyses such as tau and isoprostane levels. All patients will have a quantitative neuropsychological and neurolinguistic evaluation using well-established and validated techniques. Volumetric structural brain MRI will be obtained (voxel dimensions 0.85 x 0.85 x 1.0 mm). We will also obtain BOLD fMRI studies in PPA that include measures of single word and sentence comprehension. We will recruit patients for autopsy, and histopathologic studies of FTD patients' brains will be performed to demonstrate a disorder of tau.

Scientific Results:
This past summer, two seminal reports announced the association of progranulin (PGRN) mutations with frontotemporal dementia (Baker et al 2006, Cruts et al 2006). In our cohort, we identified 8 families with a mutation of PGRN. With the support of the Dana Foundation, we describe the index patients (2 from the same family), and contrast their clinical and pathological characteristics with patients who have the identical pathology without a PGRN mutation (Van Deerlin et al 2007). We find a language complaint at presentation in 4 (44%) of these 9 cases, but only 2 (25%) of 8 patients with a FTD spectrum phenotype have a form of primary progressive aphasia. An equal number of these cases presents with an executive complaint, and 6 (67%) of the 9 cases present with a social disorder. A statistical analysis reveals less severe language difficulty in the patients with a PGRN mutation than in the patients with matched pathology but no PGRN mutation. Histopathologic examination reveals less pathologic burden in the PGRN patients than the patients without a PGRN mutation. We are now studying in detail one PGRN family where language difficulty is present. This includes lumbar punctures and imaging data on two generations of affected individuals, and similar studies on several non-affected individuals in the third generation.

The histopathologic abnormality in these patients is the accumulation of ubiquitin-positive but tau-negative inclusions in gray matter and white matter. Recent work from collaborators at the University of Pennsylvania, including members of our lab supported by the Dana Foundation, described the abnormal protein accumulating in these patients – TDP-43 (Neumann et al 2006). A target for etiologically-driven therapy in these patients thus has been identified. A manuscript under review characterizes the clinical and pathological characteristics of these patients (Grossman et al 2007b). There are three conformational forms of TDP-43, and each has its own morphologic appearance and anatomic location. Mutations of PGRN are associated exclusively with FTLD-U3, the form of TDP-43 with neuronal intracytoplasmic inclusions, neurites, and neuronal intranuclear inclusions. Two (33%) of these 6 individuals has progressive non-fluent aphasia. Although these patients were not obviously demented (mean MMSE = 24.8), they had significant difficulty (p<0.01, relative to 25 age- and education-matched controls) on measures of confrontation naming (z = -2.61), category naming fluency (z = -2.57), reverse digit span (z = -2.38) and verbal memory recognition (z = -2.35). The overall histopathologic burden of disease in these patients did not differ from patients with other TDP-43 conformations. FTLD-U3 patients had denser pathology in lateral temporal and prefrontal regions, but less disease burden in medial temporal structures.

In another study supported in part by the Dana Foundation, we outline the range of studies that we are obtaining in 61 patients with pathologically-confirmed disease who presented with a FTD spectrum clinical disorder (Grossman et al 2007a). This work shows distinct clinical and cognitive profiles in FTD patients with tau-negative disease due to FTLD-U, including significant language and social deficits, significant frontal and temporal cortical atrophy on MRI, and significant frontal and temporal histopathologic disease. In FTD patients with tau-positive disease, by comparison, we find significant visual perceptual-spatial difficulties associated with frontal and parietal cortical atrophy on MRI, and significant histopathologic disease in frontal and parietal regions. Previous work described the cerebrospinal fluid profile of proteins in these patients (Grossman et al 2005). In two papers about to be submitted, we characterize the cerebrospinal fluid profiles of autopsy-confirmed cases with tau-positive and tau-negative FTD, and relate the cerebrospinal fluid profiles of clinically diagnosed FTD patients to their clinical and neuropsychological characteristics.

These findings emphasize that familial FTD is a heterogeneous condition that does not preferentially compromise language functioning. Patients with tau-negative disease such as FTLD-U nevertheless tend to have a phenotype that preferentially compromises language functioning, and there are specific families with this presentation who have FTD due to a mutation of PGRN that present with a form of primary progressive aphasia.

Selected Publications

Grossman M., Libon D.J., Forman M.S., Massimo L., Wood E., Moore P., Anderson C., Farmer J., Chatterjee A., Clark C.M., Coslett H.B., Hurtig H.I., Lee V.M.Y., and Trojanowski J.Q. Distinct antemortem profiles in pathologically deffined patients with frontotemporal dementia. Arch Neurol. 2007 Nov;64(11):1601-9.

Grossman M., Wood E.M., Moore P., Neumann M., Kwong L., Forman M.S., Clark C.M., McCluskey L.F., Miller B.L., Lee V.M., and Trojanowski J.Q. TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. Arch Neurol. 2007 Oct;64(10):1449-54.

Van Deerlin V.M.D., Wood E.M., Moore P., Yuan W., Forman M.S., Clark C.M., Neumann M., Kwong L.K., Trojanowski J.Q., Lee V.M.Y., and Grossman M. Clinical, genetic, and pathological characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol. 2007 Aug;64(8):1148-53.

Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micseny M.C., Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M., McCluskey L.F., Miller B.L., Masliah E., Mackenzie I.R., Feldman H., Feiden W., Kretzschmar H.A., and Trojanowski J.Q., and Lee V.M.Y. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3.

Baker M., Mackenzie I.R., Pickering-Brown S.M., Gass J., Rademakers R., Lindholm C., Snowden J., Adamson J., Sadovnick A.D., Rollinson S., Cannon A., Dwosh E., Neary D., Melquist S., Richardson A., Dickson D., Berger Z., Eriksen J., Robinson T., Zehr C., Dickey C.A., Crook R., McGowan E., Mann D., Boeve B., Feldman H., and Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9.

Cruts M., Gijselinck I., van der Zee J., Engelborghs S., Wils H., Pirici D., Rademakers R., Vandenberghe R., Dermaut B., Martin J.J., van Duijn C., Peeters K., Sciot R., Santens P., De Pooter T., Mattheijssens M., van den Broeck M., Cuijt I., Vennekens K., de Deyn P.P., Kumar-Singh S., and van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006 Aug 24;442(7105):920-4.

Grossman M., Farmer J., Leight S., Work M., Moore P., Van Deerlin V.M.D., Pratico D., Clark C.M., Coslett H.B., Chatterjee A., Gee J.C., Trojanowski J.Q., and Lee V.M.Y. Cerebrospinal fluid profile distinguishes frontotemporal dementia from Alzheimer’s disease. Ann Neurol. 2005 May;57(5):721-9.