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Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Frontotemporal lobar degeneration with τ pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick’s disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8 % of non-diseased controls, we found grains, coiled bodies, and/or τ-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.

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Acknowledgments

The brain material studied was received from FTLDc-Net Brain Banks in Munich and Ulm (Germany) and the Newcastle Brain Tissue Resource (UK), which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. The authors thank Professor Heiko Braak and Dr. Kelly Del Tredici (Ulm/Germany) for providing stained and unstained sections of some cases of their collection for inclusion into this study. This study was supported by the BMBF—(ministry of science and technology) Grant FTLDc and Alzheimer Forschung Initiative (AFI) Grant #13803; and NIA AG12411. Part of the research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-related disease and the Biomedical Research Unit for Lewy body dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (R:CH/ML/0712). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Conflict of interest

DRT received consultant honorary from Simon Kucher and Partners, GE-Healthcare, and Covance Laboratories, speaker honorary from GE-Healthcare and collaborated with Novartis Pharma AG. CAFvA received honoraria from serving on the scientific advisory board of Nutricia GmbH and has received funding for travel and speaker honoraria from Nutricia GmbH, Novartis Pharma GmbH, Lilly Deutschland GmbH, Desitin Arzneimittel GmbH and Dr. Willmar Schwabe GmbH &Co. KG and has received research support from Roche Diagnostics GmbH, Biologische Heilmittel Heel GmbH and ViaMed GmbH.

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Authors and Affiliations

  1. Laboratory of Neuropathology, Institute of Pathology, Center for Clinical Research, Ulm University, Ulm, Germany

    Dietmar Rudolf Thal

  2. Department of Neurology, Ulm University, Ulm, Germany

    Christine A. F. von Arnim

  3. Donald W. Reynolds Center on Aging, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA

    W. Sue T. Griffin

  4. Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center, Little Rock, AR, USA

    W. Sue T. Griffin

  5. Department of Pathology, University of Toledo, Toledo, OH, USA

    Robert E. Mrak

  6. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    Lauren Walker & Johannes Attems

  7. Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany

    Thomas Arzberger

  8. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany

    Thomas Arzberger

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  1. Dietmar Rudolf Thal
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  2. Christine A. F. von Arnim
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  3. W. Sue T. Griffin
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Correspondence to Dietmar Rudolf Thal.

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Thal, D.R., von Arnim, C.A.F., Griffin, W.S.T. et al. Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. J Neural Transm 122, 1007–1018 (2015). https://doi.org/10.1007/s00702-014-1360-6

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