MAPT) and FTDP-17 (PGRN

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NEUROLOGICAL REVIEW Refining Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17 Introducing FTDP-17 (MAPT) and FTDP-17 (PGRN)

Bradley F. Boeve, MD; Mike Hutton, PhD

rontotemporal dementia with parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65 years. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule-associated protein tau (MAPT; OMIM ϩ157140) onF chromosome 17 have been found in many kindreds with familial FTDP. Several other kindreds with FTDP had been linked to chromosome 17, but they had ubiquitin-positive inclusions rather than tauopathy pathology and no mutations in MAPT. This conundrum was solved in 2006 with the identification of mutations in the gene encoding progranulin (PGRN; OMIM *138945), which is only 1.7 Mb centromeric to MAPT on chromosome 17. In this review, we compare and contrast the demographic, clinical, radiologic, neuropathologic, genetic, and pathophysiologic features in patients with FTDP linked to mutations in MAPT and PGRN, highlighting the many similarities but also a few important differences. Our findings describe an intriguing oddity of nature in which 2 genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome. Arch Neurol. 2008;65(4):460-464

Frontotemporal dementia with parkin- ology of the varying disorders. The iden- sonism is one of the major degenerative tification of causative genes offers dementia syndromes (Table 1), particu- opportunities to quickly learn about the larly for those who begin experiencing pathophysiologic processes involved in cognitive, behavioral, or motor changes be- neurodegeneration, and drug testing can fore age 65 years. Advances in immuno- proceed relatively quickly using trans- cytochemistry and molecular genetics have genic mouse models that are designed to greatly expanded our knowledge of the dis- mimic the human disease. Several groups orders (and their associated dysfunc- of investigators have focused on families tional proteins) that can manifest as de- carrying mutations that cause FTDP. mentia with or without parkinsonism The hunt for causative genes in FTDP (Table 2). No disease-altering treat- was largely spearheaded by the first Fron- ment has been identified as yet for any of totemporal Dementia and Parkinsonism the neurodegenerative disorders that can Linked to Chromosome 17 Consensus manifest clinically as FTDP (Table 2). The Conference in Ann Arbor in 1996, for development of potential therapies re- which FTDP linked to chromosome 17 quires knowledge about the pathophysi- (FTDP-17) was the major focus.1 Soon thereafter in 1998, mutations in MAPT Author Affiliations: Divisions of Behavioral Neurology and Movement Disorders, were identified.2 During the 8 years since Department of Neurology, Mayo Clinic, Rochester, Minnesota (Dr Boeve); Mayo this discovery, 41 mutations in MAPT have Alzheimer’s Disease Research Center, and Robert H. and Clarice Smith and Abigail 3 Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, been found, and many other issues relat- Rochester, Minnesota, and Jacksonville, Florida (Drs Boeve and Hutton); and ing to FTDP-17 due to mutations in MAPT Neurogenetics Laboratory, Department of Neuroscience, Mayo Clinic, Jacksonville, have been characterized (Table 3).4 No Florida (Dr Hutton). sex predilection has been identified. The

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Major Cognitive Impairment Table 3. Comparison Between Neurodegenerative and Dementia Syndromes Characteristics Associated With Mutations in MAPT and PGRN Genes Mild cognitive impairment Clinically probable Alzheimer disease Gene Dementia with Lewy bodies Parkinson disease with dementia Characteristic MAPT PGRN Frontotemporal dementia Frequency among individuals 65 Frontotemporal dementia with parkinsonism with FTD, % Progressive nonfluent aphasia Mode of inheritance AD AD Semantic dementia Penetrance, % Ͼ 95 90 by age 70 y Corticobasal syndrome Sex M=F M=F Posterior cortical atrophy Onset age, y 25-65 45-85 Duration of illness, y 3-10 1-15 Clinical features Personality/behavior changes ϩϩϩϩ ϩϩϩϩ Executive dysfunction ϩϩϩϩ ϩϩϩϩ Table 2. Specific Neurodegenerative Disorders Manifesting Language impairment ϩϩϩϩ ϩϩϩϩ as Dementia With or Without Parkinsonism and Their Memory impairment ϩϩ ϩϩ Associated Dysfunctional Proteins Visuospatial impairment ϩϩϩ Limb apraxia ϩϩϩ Parkinsonism ϩϩ ϩϩϩ Neurodegenerative Disorder (Dysfunctional Protein) Motor neuron disease ϩ 0 Amyloidopathies (Amyloid) Clinical syndromes Alzheimer diseasea FTD with or without ϩϩϩϩ ϩϩϩϩ Alzheimer disease associated with mutations in the genes encoding parkinsonism amyloid precursor protein (APP ), presenilin 1 (PSEN1), or Progressive nonfluent aphasia ϩϩ ϩϩϩ a presenilin 2 (PSEN2 ) Semantic dementia ϩϩ Down syndrome Amnestic mild cognitive ϩϩ Familial British dementia with mutations in the gene encoding the impairment integral membrane protein 2B (ITMP2B/BRI/FBD) Probable AD ϩϩϩ Familial Danish dementia with mutations in the gene encoding the Corticobasal syndrome ϩ ϩϩϩ integral membrane protein 2B (ITMP2B/BRI/FDD) Posterior cortical atrophy 0 0 Tauopathies (Tau) Parkinson disease 0 ϩ Pick diseasea Parkinson disease plus dementia 0 ϩ Corticobasal degenerationa Dementia with Lewy bodies 0 ϩ Progressive supranuclear palsya Amyotrophic lateral sclerosis ϩϩ 0 Argyrophilic grain diseasea Magnetic resonance imaging findings Multisystem tauopathya Frontal atrophy ϩϩϩϩ ϩϩϩϩ Frontotemporal dementia and parkinsonism linked to chromosome 17 Temporal atrophy ϩϩϩ ϩϩϩ associated with mutations in the gene encoding microtubule Parietal atrophy ϩϩϩ associated protein tau (MAPT)a Occipital atrophy 0 0 Alzheimer diseasea Parenchymal signal changes ϩϩϩ Pathologic findings Tardopathies (TDP-43) Tau-positive inclusions ϩϩϩϩ ϩ Frontotemporal lobar degeneration with ubiquitin-positive inclusionsa Ubiquitin-positive inclusions ϩ ϩϩϩϩ Frontotemporal lobar degeneration with motor neuron diseasea Mechanism of neurodegeneration Altered tau Loss of Frontotemporal dementia and parkinsonism linked to chromosome 17 progranulin with mutations in the gene encoding progranulin (PGRN )a Potential treatments Alter Replace or Inclusion body myopathy with early-onset Paget disease and protein-protein increase frontotemporal dementia associated with mutations in the gene interactions progranulin encoding valosin-containing protein (VCP )a Synucleinopathies (␣-Synuclein) Abbreviations: AD, Alzheimer disease; FTD, frontotemporal dementia; Lewy body disease manifesting as the syndromes of Parkinson M = F, men and women inherit mutation equally; 0, no definite cases reported disease, dementia with Lewy bodies, or Parkinson disease with to date; ϩ, extremely rare; ϩϩ, infrequently reported; ϩϩϩ, frequently dementiaa reported; ϩϩϩϩ, very frequently reported. Lewy body disease associated with mutations or duplications in the gene encoding ␣-synuclein (SNCA) Multiple system atrophy; rarely associated with dementia typical age of onset varies between 25 and 65 years. ␣-Internexinopathy (␣-Internexin) Penetrance appears to be close to 100%, though indi- Neurofilament inclusion body dementia,a also known as neuronal viduals living into old age without symptoms have been intermediate filament inclusion disease observed in families with at least 1 mutation (exon Unknown Dysfunctional Protein 10ϩ16).2 The duration of symptoms from onset to death Dementia lacking distinctive histopathologya is typically 3 to 10 years. Symptomatology usually in- Frontotemporal dementia associated with mutations in the gene a volves executive dysfunction and altered personality and encoding chromatin-modifying protein 2B (CHMP2B ) behavior, with aphasia and parkinsonism evolving in many Abbreviation: TDP-43, transactive response DNA–binding protein 43. individuals. Memory impairment occurs less frequently a Disorder that can manifest as frontotemporal dementia with or without as the primary presenting feature, and visuospatial im- parkinsonism. pairment and limb apraxia are quite rare. Motor neuron

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DNA A A C G T G A A G G C T C G A T C C T G C G A G A A G G A A G T G G T C T C T Protein N V K A R S C E K E V V S Codon 489 490 491 492 493 494 495 496 497 498 499 500 501

DNA A A C G T G A A G G C T Y G A T C C T G C G A G A A G G A A G T G G T C T C T Protein N V K A X Codon 489 490 491 492 493

Figure. Sequence chromatograms of exon 11 of the progranulin gene (PGRN ) from a control individual (A) and a patient with frontotemporal dementia carrying the common c.1477CϾT mutation (B). Below each chromatogram is the predicted amino acid sequence of progranulin including codon numbering. The arrow denotes the position of the mutation in the chromatogram. The PGRN c.1477CϾT mutation results in a premature termination of the coding sequence at codon 493, inducing the degradation of mutant PGRN RNA by nonsense-mediated decay and loss of progranulin (haploinsufficiency).

disease is also infrequent, though several cases have been sive supranuclear palsy, argyrophilic grain disease, or reported. Most patients carry 1 or more of the syn- Pick disease if the presence of an MAPT mutation was dromic diagnoses listed in Table 1, particularly fronto- not known. temporal dementia (FTD) with or without parkinson- The mutations presumably cause disease either through ism, progressive nonfluent aphasia, or primary progressive disrupting the alternative splicing of MAPT exon 10 and aphasia. Rarely, the syndromes of mild cognitive impair- thereby altering the relative levels of tau isoforms with ment, probable Alzheimer disease, semantic dementia, 4 or 3 microtubule binding repeats, or they directly de- or corticobasal syndrome are manifested. Few cases have crease the ability of tau to bind to and promote micro- been diagnosed with amyotrophic lateral sclerosis (ALS), tubule assembly and/or increase tau-filament forma- and there are no reports of patients with mutations in tion. No disease-altering treatments exist yet for the MAPT who were diagnosed with posterior cortical atro- tauopathies, though kinase inhibitors and microtubule phy or dementia with Lewy bodies. Over time, most pa- tau stabilizers have shown promise in in vitro and ani- tients develop other clinical features such that 2 or more mal model studies.8,9 syndromes can be applied, reflecting the progressively A significant minority of patients with FTDP-17— expanding involvement of other brain regions.5 many of whom were the focus of discussion at the meet- Structural neuroimaging studies show frontal and/or ing in Ann Arbor in 1996—had no identifiable muta- temporal atrophy, either symmetric or asymmetric6; tions in MAPT, nor did they have any tau-positive parenchymal signal changes on magnetic resonance inclusions at autopsy.10-13 The recent identification of imaging are either absent or very mild.7 A similar topog- mutations in PGRN in all of these remaining chromo- raphy of abnormalities is typically seen on single- some 17–linked families and in many other kindreds photon emission computed tomography and positron (Figure)14-27 has now solved this decade-long conun- emission tomography scans, often with basal ganglia drum, a few atypical FTDP phenotypes have been rede- and/or thalamic hypoperfusion or hypometabolism. fined, and an amazing freak of nature has been realized. Pathologically, cortical atrophy is as indicated on The PGRN gene is only 1.7 Mb centromeric to MAPT on imaging studies, with the maximally affected cortical chromosome 17, demonstrating an intriguing example gyri sometimes described as having a “knife edge” of how 2 apparently different genes can cause a very simi- appearance. Tau-positive inclusions in neurons (eg, lar phenotype and reside so near to each other on the same neurofibrillary tangles, neuronal threads, and Pick bod- chromosome.27 ies) and/or glia (eg, astrocytic plaques and oligoden- With closer inspection, how similar are the clinical droglial coiled bodies) are always present on histologic phenotypes associated with mutations in MAPT and examination, sometimes accompanied by argyrophilic PGRN? While our knowledge of the full spectrum of clini- grains. These tau-positive inclusions are often in a dis- cal, radiologic, and pathologic issues in FTDP associ- tribution such that patients would be pathologically ated with mutations in PGRN is still evolving, interest- identified as having corticobasal degeneration, progres- ing findings have already emerged that allow comparisons

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 between MAPT’s and PGRN’s mutation-associated char- sufficiency.14,16,18 This disease mechanism may allow a acteristics (based on published findings to date and un- more straightforward approach for treatment by either published data from our group) (Table 3). The fre- replacing progranulin or using drugs to increase produc- quency of mutations in PGRN in FTD series is similar to tion or secretion of progranulin from the remaining nor- that in MAPT.18 With at least 35 mutations identified to mal PGRN allele. date,3 almost as many mutations in PGRN have been dis- The net effect of 2 genes linked not only by proxim- covered in less than 1 year than in the 8 years since the ity but also by most overlapping and expanding features initial identification of mutations in MAPT. The mode of requires refinements in our conceptual framework and inheritance follows an autosomal dominant pattern but nomenclature in FTDP. An obvious solution to this prob- with reduced penetrance (only 90% of carriers develop lem is to simply refine the term by including reference symptoms by age 70 years).18 There are multiple known to the genetic cause of the disease in each case, and thus PGRN mutation carriers who are asymptomatic in their FTDP-17 could be subdivided into FTDP-17 (MAPT) and 70s, and at least 1 known affected individual developed FTDP-17 (PGRN). This approach has the advantage of symptoms after age 80 years. The clinical features and employing a now widely used, if not always completely particularly the syndromic diagnoses have been more vari- appropriate, clinical terminology, refining it to reflect that able than in MAPT mutation carriers, with not only be- ultimately these conditions are defined by their genetics havioral and cognitive features commonly present, but rather than their clinical or pathological phenotypes. The also memory impairment, limb apraxia, parkinsonism, scientific community has clearly just begun to expand and visuospatial dysfunction, leading to cases being di- the characterization and refine the nomenclature of fa- agnosed with mild cognitive impairment, Alzheimer dis- milial disorders linked to chromosome 17. ease, Parkinson disease, Parkinson disease with dementia, and dementia with Lewy bodies in addition to FTD Accepted for Publication: January 14, 2007. with or without parkinsonism and 1 of the progressive Correspondence: Bradley F. Boeve, MD, Department of aphasia syndromes.25 The diagnosis of corticobasal syn- Neurology, Mayo Clinic, 200 First St SW, Rochester, MN drome has also been particularly frequent in the cases 55905 ([email protected]). reported thus far, while no patient with a definite patho- Author Contributions: Study concept and design: Boeve genic PGRN mutation has been reported to date with an and Hutton. Acquisition of data: Boeve and Hutton. Analy- ALS phenotype. sis and interpretation of data: Boeve and Hutton. Drafting As one would expect, based on the clinical features of the manuscript: Boeve and Hutton. Administrative, tech- of apraxia and visuospatial dysfunction, greater parietal nical, and material support: Boeve and Hutton. involvement is clearly present in many PGRN mutation Financial Disclosure: None reported. cases, which is also reflected on imaging and pathologic Funding/Support: This study was supported by grants studies. In some cases, rather striking signal changes on AG06786, AG16574, AG11378, and AG07216 from the magnetic resonance imaging are present,25 which is National Institute on Aging; by the Robert H. and Clarice rarely seen in MAPT mutation carriers. Another curious Smith and Abigail Van Buren Alzheimer’s Disease Re- observation is the tendency in some kindreds for the search Program of the Mayo Foundation; and by the Fund same cerebral hemisphere to be maximally involved in for Scientific Research–Flanders. most or all affected members of a family, such as a pro- Additional Contributions: We thank our many collabo- gressive aphasia syndrome with maximal left hemi- rators within and outside the Mayo Foundation, particu- sphere involvement22,26,28 and the corticobasal syndrome larly Rosa Rademakers, PhD, for her critical review of this with or without FTD features with maximal right hemi- paper, and her and Matt Baker’s assistance in providing sphere involvement25,29; to our knowledge, this ten- the sequence chromatograms for Figure 1. We thank the dency has not been noted among any kindreds with staff of the Mayo Clinic Alzheimer’s Disease Research Cen- MAPT mutations. ter for their assistance in characterizing participants, and On histologic examination, the consistent finding is we particularly thank the members of the many kin- FTLD with ubiquitin-positive inclusions with neuronal dreds with MAPT and PGRN mutations for participating intranuclear inclusions.14,16-18,20-26 Immunostaining di- in neurodegenerative disease research. rected against progranulin stain normal structures within neurons and activated microglia. However, the ubiqui- REFERENCES tinated inclusions are not progranulin immunoreactive; rather, transactive response DNA–binding protein 43 was 1. Foster NL, Wilhelmsen K, Sima A, Jones MZ, D’Amato CJ, Gilman S. Frontotem- very recently discovered to be a major ubiquitinated pro- poral dementia and parkinsonism linked to chromosome 17: a consensus tein in both neuronal cytoplasmic and intranuclear in- conference. Ann Neurol. 1997;41(6):706-715. clusions in PGRN mutation cases.30 Moreover, transac- 2. Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5Ј-splice-site tive response DNA–binding protein 43 is also present in mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686): 702-705. neuronal ubiquitin-positive inclusions in FTLD with ubiq- 3. Alzheimer Disease & Frontotemporal Dementia Mutation Database. http://www uitin-positive inclusions, FTLD with motor neuron dis- .molgen.ua.ac.be/FTDmutations/. Accessed February 14, 2007. ease, and idiopathic ALS.31 4. Poorkaj P, Grossman M, Steinbart E, et al. Frequency of tau gene mutations in Also contrasting with MAPT is the mechanism of dis- familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001; 58(3):383-387. ease with PGRN mutations—all PGRN mutations iden- 5. Kertesz A. Pick’s complex and FTDP-17. Mov Disord. 2003;18(suppl 6): tified thus far create functional null alleles that cause a S57-S62. partial reduction in progranulin production or haploin- 6. Boeve BF, Tremont-Lukats I, Waclawik A, et al. Longitudinal characterization of two

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 dementia patients with a Progranulin mutation. Ann Neurol. 2006;60(3): associated with the S305N tau mutation. Brain. 2005;128(pt 4):752-772. 374-380. 7. Frank AR, Wszolek ZK, Jack CR Jr, Boeve BF. Distinctive MRI findings in pal- 20. Mackenzie IR, Baker M, Pickering-Brown S, et al. The neuropathology of fron- lidopontonigral degeneration (PPND). Neurology. 2007;68(8):620-621. totemporal lobar degeneration caused by mutations in the progranulin gene. Brain. 8. Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium 2006;129(pt 11):3081-3090. correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci 21. Masellis M, Momeni P, Meschino W, et al. Novel splicing mutation in the pro- USA. 2005;102(19):6990-6995. granulin gene causing familial corticobasal syndrome. Brain. 2006;129(pt 11): 9. Zhang B, Maiti A, Shively S, et al. Microtubule-binding drugs offset tau seques- 3115-3123. tration by stabilizing microtubules and reversing fast axonal transport deficits in 22. Mukherjee O, Pastor P, Cairns NJ, et al. HDDD2 is a familial frontotemporal lo- a tauopathy model. Proc Natl Acad Sci U S A. 2005;102(1):227-231. bar degeneration with ubiquitin-positive, tau-negative inclusions caused by a mis- 10. Lendon CL, Lynch T, Norton J, et al. Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. Neurology. 1998;50(6): sense mutation in the signal peptide of progranulin. Ann Neurol. 2006;60(3): 1546-1555. 314-322. 11. Rademakers R, Cruts M, Dermaut B, et al. Tau negative frontal lobe dementia at 23. Pickering-Brown SM, Baker M, Gass J, et al. Mutations in progranulin explain 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol atypical phenotypes with variants in MAPT. Brain. 2006;129(pt 11):3124-3126. Psychiatry. 2002;7(10):1064-1074. 24. Snowden JS, Pickering-Brown S, Mackenzie I, et al. Progranulin gene muta- 12. van der Zee J, Rademakers R, Engelborghs S, et al. A Belgian ancestral haplo- tions associated with frontotemporal dementia and progressive non-fluent aphasia. type harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain. 2006;129(pt 11):3091-3102. Brain. 2006;129(pt 4):841-852. 25. Kelley BJ, Haidar W, Boeve BF, et al. Prominent phenotypic variability associ- 13. Mackenzie IR, Baker M, West G, et al. A family with tau-negative frontotemporal ated with mutations in Progranulin [published online ahead of print October 18, dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain. 2007]. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2007.08.022. 2006;129(pt 4):853-867. 26. Mesulam M, Johnson N, Krefft T, et al. Progranulin mutations in primary pro- 14. Baker M, Mackenzie I, Pickering-Brown S, et al. Mutations in progranulin cause gressive aphasia: the PPA1 and PPA3 families. Arch Neurol. 2007;64(1): tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006; 43-47. 442(7105):916-919. 27. Rosenberg RN. Progranulin and tau gene mutations both as cause for demen- 15. Benussi L, Binetti G, Sina E, et al. A novel deletion in progranulin gene is asso- tia: 17q21 finally defined. Arch Neurol. 2007;64(1):18-19. ciated with FTDP-17 and CBS [published online ahead of print December 5, 2006]. 28. Krefft TA, Graff-Radford N, Dickson D, et al. Familial primary progressive aphasia. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2006.10.028. Alzheimer Dis Assoc Disord. 2003;17(2):106-112. 16. Boeve BF, Baker M, Dickson D, et al. Frontotemporal dementia and parkinson- 29. Boeve BF, Maraganore DM, Parisi JE, et al. Corticobasal degeneration and fron- ism associated with the IVS1ϩ1G-ϾA mutation in progranulin: a clinicopatho- logic study. Brain. 2006;129(pt 11):3103-3114. totemporal dementia presentations in a kindred with nonspecific histopathology. 17. Cruts M, Gijselinck I, van der Zee J, et al. Null mutations in progranulin cause Dement Geriatr Cogn Disord. 2002;13(2):80-90. ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature. 30. Josephs KA, Ahmed Z, Katsuse O, et al. Neuropathologic features of frontotem- 2006;442(7105):920-924. poral lobar degeneration with ubiquitin-positive inclusions with progranulin gene 18. Gass J, Cannon A, Mackenzie I, et al. Mutations in progranulin are a major cause (PGRN) mutations. J Neuropathol Exp Neurol. 2007;66(2):142-151. of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006; 31. Neumann M, Sampathu D, Kwong L, et al. Ubiquitinated TDP-43 in frontotem- 15(20):2988-3001. poral lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 19. Huey ED, Grafman J, Wassermann EM, et al. Characteristics of frontotemporal 314(5796):130-133.

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