A multi-institutional study has defined and established criteria for a new neurological disease closely resembling Alzheimer’s disease called primary age-related tauopathy (PART). Patients with PART develop cognitive impairment that can be indistinguishable from Alzheimer’s disease, but they lack amyloid plaques. Awareness of this neurological disease will help doctors diagnose and develop more effective treatments for patients with different types of memory impairment.
The study, co-led by Peter T. Nelson, MD, PhD, of the University of Kentucky’s Sanders-Brown Center on Aging, and John F. Crary, MD, PhD, of Pathology & Neuroscience with Mount Sinai Hospital, was published in the current issue of Acta Neuoropathologica.
“To make an Alzheimer’s diagnosis you need to see two things together in a patient’s brain: amyloid plaques and structures called neurofibrillary tangles composed of a protein called tau,” said Dr. Nelson, a professor of neuropathology at the University of Kentucky’s Sanders-Brown Center on Aging. “However, autopsy studies have demonstrated that some patients have tangles but no plaques and we’ve long wondered what condition these patients had.”
Plaques in the brain, formed from the accumulation of amyloid protein, are a hallmark of Alzheimer’s disease. Until now, researchers have considered cases with only tangles to be either very early-stage Alzheimer’s or a variant of the disease in which the plaques are harder to detect. However, previous in-depth biochemical and genetic studies have failed to reveal the presence of any abnormal amyloid in these patients. Although tangle-only patients can have memory complaints, the presence of plaques is a key requirement for an Alzheimer’s diagnosis.
In the current study, investigators from the United States (including five from Sanders-Brown), Canada, Europe, and Japan came together to formalize criteria for diagnosing this new neurological disorder. The study establishes that PART is a primary tauopathy, a disease directly caused by the tau protein in tangles. Many of the neurofibrillary tangles in Alzheimer’s brain, in contrast, are thought to arise secondarily to amyloid or some other stimuli. The researchers propose that individuals who have tangles resembling those found in Alzheimer’s but have no detectable amyloid plaques should now be classified as PART.
PART is most severe in patients of advanced age, but is generally mild in younger elderly individuals. The reason for this is currently unknown, but unlike Alzheimer’s disease, in which the tangles spread throughout the brain, in PART cases the tangles are restricted mainly to structures important for memory.
It is too early to tell how common PART is, but given that tangles are nearly universal in the brains of older individuals, it might be more widespread than generally recognized. While further studies are required, new diagnostic tests using brain scans and cerebrospinal fluid biomarkers for amyloid and tau are finding surprisingly high proportions of patients (as many as 25% in some studies) with mild cognitive impairment that are positive for tau but negative for amyloid.
“Until now, PART has been difficult to treat or even study because of lack of well-defined criteria,” said Dr. Nelson. “Now that the scientific community has come to a consensus on what the key features of PART are, this will help doctors diagnose different forms of memory impairment early. These advancements will have a big impact on our ability to recognize and develop effective treatments for brain diseases seen in older persons.”
Identifying the type of neurological disorder in the early stages of disease is critical if treatment is to begin before irreparable brain damage has occurred. However, in the absence of clear criteria, different forms of neurological disorders have been hard to distinguish. As a result, PART patients may have confounded clinical trials of amyloid-targeting drugs for Alzheimer’s disease as these treatments are unlikely to be effective against tangles. Along with the development of better biomarkers and genetic risk factors for dementia, the new diagnosis criteria will help PART patients to receive more targeted therapy and improve the accuracy of clinical trials for Alzheimer’s drugs.
The study was supported by grants from: the Society for Supporting Research in Experimental Neurology, Vienna, Austria; the National Institutes of Health (P50AG08702, R01 AG037212, P01AG07232, P30 AG028383, P50 AG005138, P50 AG016574, U01 AG006786, R01 AG041851, R01 AG011378, P30 AG028383, P50 AG016574, P01 AG003949, P30 AG012300, P50 AG005146, P50 AG005136, P50 AG025688, P50 AG005138, P01 AG002219, P50 AG005133, P50 AG005681, P01 AG003991, R01 AG038651, P30 AG019610, P30 AG013854, P30 AG036453, P30 AG010124, AG005131, AG184440, AG008051); Medical Research Council (MRC, G0400074); National Institute for Health Research (NIHR, R:CH/ML/0712); the Dunhill Medical Trust (R173/1110); Alzheimer’s Research UK (ARUK), and the Alzheimer’s Society (AS-PG-2013-011), Louis V. Gerstner, Jr., Foundation; Alzheimer’s Association (NIRG-11-204450), FP7 EU Project Develage (No. 278486), Comprehensive Brain Research Network, Grant-in-Aid for Scientific Research (C; 26430060), and Daiwa Health Science Foundation, BrightFocus Foundation, Alzheimer’s Association NIRGD-12- 242642, Alzheimer Forschung Initiative (AFI # 13803) (DRT); German Ministry for Research and Education (BMBF) FTLD-Net, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation.
Contact: Laura Dawahare – University of Kentucky
Source: University of Kentucky press release
Image Source: The image is credited to Patho and is licensed Creative Commons Attribution Share-Alike 3.0 Unported
Original Research: Full open access research for “Primary age-related tauopathy (PART): a common pathology associated with human aging” by John F. Crary, John Q. Trojanowski, Julie A. Schneider, Jose F. Abisambra, Erin L. Abner, Irina Alafuzoff, Steven E. Arnold, Johannes Attems, Thomas G. Beach, Eileen H. Bigio, Nigel J. Cairns, Dennis W. Dickson, Marla Gearing, Lea T. Grinberg, Patrick R. Hof, Bradley T. Hyman, Kurt Jellinger, Gregory A. Jicha, Gabor G. Kovacs, David S. Knopman, Julia Kofler, Walter A. Kukull, Ian R. Mackenzie, Eliezer Masliah, Ann McKee, Thomas J. Montine, Melissa E. Murray, Janna H. Neltner, Ismael Santa-Maria, William W. Seeley, Alberto Serrano-Pozo, Michael L. Shelanski, Thor Stein, Masaki Takao, Dietmar R. Thal, Jonathan B. Toledo, Juan C. Troncoso, Jean Paul Vonsattel, Charles L. White 3rd, Thomas Wisniewski, Randall L. Woltjer, Masahito Yamada, and Peter T. Nelson in Acta Neuropathologica. Published online October 28 2014 doi:10.1007/s00401-014-1349-0
Primary age-related tauopathy (PART): a common pathology associated with human aging
We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
“Primary age-related tauopathy (PART): a common pathology associated with human aging” by John F. Crary, John Q. Trojanowski, Julie A. Schneider, Jose F. Abisambra, Erin L. Abner, Irina Alafuzoff, Steven E. Arnold, Johannes Attems, Thomas G. Beach, Eileen H. Bigio, Nigel J. Cairns, Dennis W. Dickson, Marla Gearing, Lea T. Grinberg, Patrick R. Hof, Bradley T. Hyman, Kurt Jellinger, Gregory A. Jicha, Gabor G. Kovacs, David S. Knopman, Julia Kofler, Walter A. Kukull, Ian R. Mackenzie, Eliezer Masliah, Ann McKee, Thomas J. Montine, Melissa E. Murray, Janna H. Neltner, Ismael Santa-Maria, William W. Seeley, Alberto Serrano-Pozo, Michael L. Shelanski, Thor Stein, Masaki Takao, Dietmar R. Thal, Jonathan B. Toledo, Juan C. Troncoso, Jean Paul Vonsattel, Charles L. White 3rd, Thomas Wisniewski, Randall L. Woltjer, Masahito Yamada, and Peter T. Nelson in Acta Neuropathologica. doi:10.1007/s00401-014-1349-0.
