Deep clinical and neuropathological phenotyping of Pick disease
Corresponding Author
David J. Irwin MD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Address correspondence to Dr Irwin, Frontotemporal Degeneration Center/Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Hospital of the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104. E-mail: [email protected]Search for more papers by this authorJohannes Brettschneider MD
Department of Neurology, Herford Hospital, Herford, Germany
Search for more papers by this authorCorey T. McMillan PhD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorFelicia Cooper MS
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorChristopher Olm MS
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorSteven E. Arnold MD
Brain-Behavior Laboratory, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorVivianna M. Van Deerlin MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorWilliam W. Seeley MD
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorBruce L. Miller MD
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorEdward B. Lee MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Translational Neuropathology Research Laboratory, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorVirginia M.-Y. Lee PhD, MBA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorMurray Grossman MD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorJohn Q. Trojanowski MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorCorresponding Author
David J. Irwin MD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Address correspondence to Dr Irwin, Frontotemporal Degeneration Center/Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Hospital of the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104. E-mail: [email protected]Search for more papers by this authorJohannes Brettschneider MD
Department of Neurology, Herford Hospital, Herford, Germany
Search for more papers by this authorCorey T. McMillan PhD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorFelicia Cooper MS
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorChristopher Olm MS
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorSteven E. Arnold MD
Brain-Behavior Laboratory, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorVivianna M. Van Deerlin MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorWilliam W. Seeley MD
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorBruce L. Miller MD
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorEdward B. Lee MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Translational Neuropathology Research Laboratory, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorVirginia M.-Y. Lee PhD, MBA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorMurray Grossman MD
University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorJohn Q. Trojanowski MD, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorAbstract
Objective
To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease.
Methods
Detailed neuropathological examination using 70μm and traditional 6μm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity.
Results
Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau–positive and 4R tau–negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions.
Interpretation
Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration. Ann Neurol 2016;79:272–287
Supporting Information
Additional supporting information can be found in the online version of this article.
| Filename | Description |
|---|---|
| ana24559-sup-0001-suppinfo01.docx95.6 KB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Pick A. Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prag Med Wochenschr 1892; 17: 165–167.
- 2 Kertesz A. Pick complex—historical introduction. Alzheimer Dis Assoc Disord 2007; 21: S5–S7.
- 3 Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010; 119: 1–4.
- 4 Yokota O, Tsuchiya K, Arai T, et al. Clinicopathological characterization of Pick's disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions. Acta Neuropathol 2009; 117: 429–444.
- 5 Piguet O, Halliday GM, Reid WG, et al. Clinical phenotypes in autopsy-confirmed Pick disease. Neurology 2011; 76: 253–259.
- 6 Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134(pt 9): 2456–2477.
- 7 Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–1014.
- 8 D Dickson, ed. Sporadic tauopaties: Pick's disease, corticobasal degeneration, progressive supranuclear palsy and argyrophilic grain disease. 2nd ed. New York, NY: Cambridge University Press, 2004.
- 9 Toledo JB, Van Deerlin VM, Lee EB, et al. A platform for discovery: the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Alzheimers Dement 2014; 10: 477–484.
- 10 Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 2012; 123: 1–11.
- 11 Van Deerlin VM, Forman MS, Farmer JM, et al. Biochemical and pathological characterization of frontotemporal dementia due to a Leu266Val mutation in microtubule-associated protein tau in an African American individual. Acta Neuropathol 2007; 113: 471–479.
- 12 Hogg M, Grujic ZM, Baker M, et al. The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathol 2003; 106: 323–336.
- 13 Feldengut S, Del Tredici K, Braak H. Paraffin sections of 70-100 μm: a novel technique and its benefits for studying the nervous system. J Neurosci Methods 2013; 215: 241–244.
- 14 Mercken M, Vandermeeren M, Lubke U, et al. Monoclonal antibodies with selective specificity for Alzheimer Tau are directed against phosphatase-sensitive epitopes. Acta Neuropathol 1992; 84: 265–272.
- 15 Brettschneider J, Del Tredici K, Irwin DJ, et al. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol 2014; 127: 423–439.
- 16 Seubert P, Mawal-Dewan M, Barbour R, et al. Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau. J Biol Chem 1995; 270: 18917–18922.
- 17 Hasegawa M, Fujiwara H, Nonaka T, et al. Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 2002; 277: 49071–49076.
- 18 de Silva R, Lashley T, Gibb G, et al. Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol 2003; 29: 288–302.
- 19 Dan A, Takahashi M, Masuda-Suzukake M, et al. Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer's disease brain. Acta Neuropathol Commun 2013; 1: 54.
- 20 Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, et al. Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease. Neurobiol Aging 2005; 26: 1015–1022.
- 21 Irwin DJ, Cohen TJ, Grossman M, et al. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am J Pathol 2013; 183: 344–351.
- 22 Irwin DJ, Cohen TJ, Grossman M, et al. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies. Brain 2012; 135(pt 3): 807–818.
- 23 Igaz LM, Kwong LK, Lee EB, et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 2011; 121: 726–738.
- 24 Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011; 72: 57–71.
- 25 Montine TJ, Monsell SE, Beach TG, et al. Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease. Alzheimers Dement (in press).
- 26 Uchihara T, Tsuchiya K. Neuropathology of Pick body disease. Handb Clin Neurol 2008; 89: 415–430.
- 27 McMillan C, Irwin D, Avants B, et al. White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry 2013; 84: 949–955.
- 28 Mori S, Oishi K, Jiang H, et al. Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. Neuroimage 2008; 40: 570–582.
- 29 Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol 1996; 55: 53–67.
- 30 Zhukareva V, Mann D, Pickering-Brown S, et al. Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 2002; 51: 730–739.
- 31 Probst A, Tolnay M, Langui D, et al. Pick's disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol 1996; 92: 588–596.
- 32 Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013; 80: 496–503.
- 33 Berry RW, Sweet AP, Clark FA, et al. Tau epitope display in progressive supranuclear palsy and corticobasal degeneration. J Neurocytol 2004; 33: 287–295.
- 34 Guillozet-Bongaarts AL, Glajch KE, Libson EG, et al. Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol 2007; 113: 513–520.
- 35 Schmidt ML, Schuck T, Sheridan S, et al. The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse beta-pleated sheet structures in postmortem human neurodegenerative disease brains. Am J Pathol 2001; 159: 937–943.
- 36 Miki Y, Mori F, Tanji K, et al. An autopsy case of incipient Pick's disease: immunohistochemical profile of early-stage Pick body formation. Neuropathology 2014; 34: 386–391.
- 37 Hornberger M, Piguet O. Episodic memory in frontotemporal dementia: a critical review. Brain 2012; 135(pt 3): 678–692.
- 38 Towfighi J. Early Pick's disease. A light and ultrastructural study. Acta Neuropathol 1972; 21: 224–231.
- 39 Sparks DL, Danner FW, Davis DG, et al. Neurochemical and histopathologic alterations characteristic of Pick's disease in a non-demented individual. Journal of neuropathology and experimental neurology 1994; 53: 37–42.
- 40 Mimuro M, Yoshida M, Miyao S, Harada T, Ishiguro K, Hashizume Y. Neuronal and glial tau pathology in early frontotemporal lobar degeneration-tau, Pick's disease subtype. J Neurol Sci 2010; 290: 177–182.
- 41 Seeley WW, Crawford R, Rascovsky K, et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol 2008; 65: 249–255.
- 42 Kim EJ, Sidhu M, Gaus SE, et al. Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cereb Cortex 2012; 22: 251–259.
- 43 Seeley WW, Carlin DA, Allman JM, et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol 2006; 60: 660–667.
- 44 Arai T, Ikeda K, Akiyama H, et al. Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 2001; 101: 167–173.
- 45 Kersaitis C, Halliday GM, Kril JJ. Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies. Acta Neuropathol 2004; 108: 515–523.
- 46 Whitwell JL, Josephs KA, Rossor MN, et al. Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia. Arch Neurol 2005; 62: 1402–1408.
- 47 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.
- 48 Brettschneider J, Del Tredici K, Toledo JB, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 2013; 74: 20–38.
- 49 Kovacs GG, Rozemuller AJ, van Swieten JC, et al. Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium. Neuropathol Appl Neurobiol 2013; 39: 166–178.
- 50 Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013; 79: 1094–1108.
Citing Literature
