Acta
NeuropathologicaPathology and Mechanisms of
Neurological Disease
© Springer-Verlag Berlin
Heidelberg 2014
10.1007/s00401-014-1349-0Consensus Paper
Primary age-related tauopathy (PART): a common pathology associated with human aging
John F. Crary1 , John Q. Trojanowski2,
Julie A. Schneider3, Jose F. Abisambra4, Erin L. Abner5, Irina Alafuzoff6,
Steven E. Arnold7, Johannes Attems8,
Thomas G. Beach9, Eileen H. Bigio10, Nigel J. Cairns11, Dennis W. Dickson12, Marla Gearing13,
Lea T. Grinberg14, 15,
Patrick R. Hof16, Bradley T. Hyman17, Kurt Jellinger18,
Gregory A. Jicha19, Gabor G. Kovacs20, David S. Knopman21, Julia Kofler22,
Walter A. Kukull23, Ian R. Mackenzie24, Eliezer Masliah25, Ann McKee26, Thomas J. Montine27, Melissa E. Murray12, Janna H. Neltner28, Ismael Santa-Maria1, William W. Seeley29, Alberto Serrano-Pozo30, Michael L. Shelanski1,
Thor Stein31, Masaki Takao32, Dietmar R. Thal33, Jonathan B. Toledo2, Juan C. Troncoso34, Jean Paul Vonsattel1,
Charles L. White3rd35, Thomas Wisniewski36, Randall L. Woltjer37,
Masahito Yamada38 and Peter T. Nelson39
(1)
Department of Pathology and Cell Biology and the
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia
University Medical Center, New York, NY 10032, USA
(2)
Department of Pathology, Division of
Neuropathology, University of Pennsylvania, Philadelphia, PA 19104,
USA
(3)
Departments of Pathology (Neuropathology) and
Neurological Sciences, Rush University Medical Center, Chicago, IL 60612,
USA
(4)
Department of Physiology and Sanders-Brown Center
on Aging, University of Kentucky, Lexington, KY 40536, USA
(5)
Department of Public Health and Sanders-Brown
Center on Aging, University of Kentucky, Lexington, KY 40536,
USA
(6)
Department of Immunology, Genetics and Pathology,
Uppsala University, SE-751 85 Uppsala, Sweden
(7)
Departments of Psychiatry and Neurology, University
of Pennsylvania, Philadelphia, PA 19104, USA
(8)
Institute for Ageing and Health, Newcastle
University, Newcastle upon Tyne, NE45PL, UK
(9)
Civin Laboratory for Neuropathology, Banner Sun
Health Research Institute, Sun City, AZ 85351, USA
(10)
Department of Pathology (Neuropathology),
Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern
University Feinberg School of Medicine, Chicago, IL 60611, USA
(11)
Department of Pathology and Immunology, Washington
University School of Medicine, St. Louis, MO 63110, USA
(12)
Department of Neuroscience, Mayo Clinic, 4500 San
Pablo Road, Jacksonville, FL 32224, USA
(13)
Department of Pathology and Laboratory Medicine
(Neuropathology), Emory University School of Medicine, Atlanta, GA 30322,
USA
(14)
Departments of Neurology and Pathology, UC, San
Francisco, CA 94110, USA
(15)
Department of Pathology, University of Sao Paulo,
Sao Paulo, Brazil
(16)
Fishberg Department of Neuroscience and Friedman
Brain Institute, Icahn School of Medicine at Mount Sinai, New York,
NY 10029, USA
(17)
Department of Neurology, Harvard Medical School and
Massachusetts General Hospital, Charlestown, MA 02129, USA
(18)
Institute of Clinical Neurobiology,
1070 Vienna, Austria
(19)
Department of Neurology and the Sanders-Brown
Center on Aging, University of Kentucky, Lexington, KY, USA
(20)
Institute of Neurology, Medical University Vienna,
1090 Vienna, Austria
(21)
Department of Neurology, Mayo Clinic, Rochester,
MN 55905, USA
(22)
Department of Pathology (Neuropathology),
University of Pittsburgh Medical Center, Pittsburgh, PA 15213,
USA
(23)
Department of Epidemiology, University of
Washington, Seattle, WA 98104, USA
(24)
Department of Pathology, University of British
Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada
(25)
Departments of Neurosciences and Pathology,
University of California, San Diego, La Jolla, CA 92093, USA
(26)
Department of Pathology (Neuropathology), Boston
University, Boston, MA 02118, USA
(27)
Department of Pathology, University of Washington,
Seattle, WA 98104, USA
(28)
Department of Pathology, University of Kentucky,
Lexington, KY 40536, USA
(29)
Departments of Neurology and Pathology, University
of California, San Francisco, CA 94143, USA
(30)
Department of Neurology, University of Iowa
Hospitals and Clinics, Iowa city, IA 52242, USA
(31)
Department of Pathology (Neuropathology), VA
Medical Center and Boston University School of Medicine, Boston, MA 02118,
USA
(32)
Department of Neuropathology, Tokyo Metropolitan
Geriatric Hospital, Tokyo 173-0015, Japan
(33)
Laboratory of Neuropathology, University of Ulm,
89081 Ulm, Germany
(34)
Department of Pathology and Laboratory Medicine,
Institute on Aging, Center for Neurodegenerative Disease Research, University of
Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104,
USA
(35)
Department of Pathology (Neuropathology),
University of Texas Southwestern Medical School, Dallas, TX 75390,
USA
(36)
Departments of Neurology, Pathology and Psychiatry,
New York University School of Medicine, New York, NY 10016, USA
(37)
Department of Pathology L113, Oregon Health
Sciences University, Portland, OR 97239, USA
(38)
Departments of Neurology & Neurobiology of
Aging, Kanazawa University Graduate School of Medical Sciences,
Kanazawa 920-8640, Japan
(39)
Department of Pathology (Neuropathology) and
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536,
USA
Received:
24 July 2014Revised: 26 September 2014Accepted: 28 September 2014Published online: 28 October 2014
Abstract
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.
Introduction
We propose a new term, “primary age-related tauopathy” (PART),
to describe a pathologic continuum ranging from focally distributed
neurofibrillary tangles (NFTs) observed in cognitively normal aged individuals,
through the pathology observed in persons with dementing illnesses that have
been referred to as “tangle-predominant senile dementia” (TPSD), “tangle-only
dementia”, “preferential development of NFT without senile plaques”, and “senile
dementia of the neurofibrillary tangle type” (SD-NFT), among other names. Here
we explain the need for introducing this term, reviewing the relevant studies in
the clinical and pathologic literature. We conclude with new proposed working
guidelines for the neuropathological classification of subjects with PART.
The main reasons for proposing this new terminology are to
provide a conceptual framework for studying PART, to facilitate communication
among pathologists, clinicians, and researchers, and to draw attention to this
entity, which is often overlooked. Another motivation, as with the recent National
Institute on Aging-Alzheimer’s Association diagnostic criteria for
Alzheimer’s disease (AD) [64,
102],
is to “disentangle” pathologic classification from clinical diagnosis for a
given patient. In the case of PART, the separation of clinical information from
the pathological diagnosis is especially necessary, because the term “dementia”,
as in “tangle-only dementia”, implies a multi-domain cognitive impairment with a
profound decrease in the ability to perform activities of daily living, both of
which are absent in the majority of persons with PART [65,
66,
107,
125,
142].
Practicing neuropathologists will benefit from the revised terminology because
many are reluctant to apply the clinical term “dementia” to a pathologic
diagnosis when dementia was not documented clinically or when knowledge of the
clinical history is limited. Also, there have been recommendations to lessen the
use of labels such as “dementia” and “senile” partly due to pejorative
implications [139]
and because the terms are considered to be imprecise [24].
Patients with mild-to-moderate AD-type neurofibrillary
degeneration in the medial temporal lobe, but lacking Aβ plaques, have been
described in European, Japanese, North and South American cohorts [2,
3,
14,
51,
52,
58,
69,
72,
79,
81,
82,
126,
142,
147,
149,
151].
NFTs are practically universal in older persons’ brains [22,
30,
108,
132],
and are also observed in a more limited distribution in many younger individuals
[30,
32,
42].
Cases at the more severe end of the pathologic spectrum (Braak stages III–IV)
lacking Aβ plaques were observed in 2–10 % of brains in large autopsy
series that included community-based sampling [89,
94,
107,
125].
These pathologic changes were more prevalent in a few autopsy series drawing
from memory disorder clinics [128,
129].
The theoretical and practical implications of these findings remain
controversial [9,
15,
29,
107].
Differences in nomenclature, study design (including cohort recruitment methods)
variable sensitivity in detecting pathologic changes, and conceptual
interpretations have fueled uncertainty. A more specific and ultimately useful
term for neuropathologic diagnoses is required, drawing from an expanding
research corpus.
Clinical features
Published data indicate that severe PART can be associated
with memory loss in aging [66,
107].
However, the high prevalence of comorbid brain diseases in elderly individuals
make clinicopathologic correlations challenging in this population [76,
80,
108,
109,
117,
125],
and the entire clinicopathologic spectrum of PART has yet to be systematically
characterized. Most relevant prior studies have either focused on the most
severe cases with TPSD or have investigated the associations between medial
temporal lobe or brainstem tau pathology related to AD [5,
6,
11,
12,
19,
48,
49,
55,
56,
79,
133,
134,
144].
A subset of patients with PART (previously referred to as SD-NFT, TPSD, etc.)
displays marked clinical impairment in the absence of any other recognizable
substrate for dementia [14,
21,
39,
60,
66,
72,
99,
142].
The average age of death is generally higher for these patients than those with
AD pathology [37,
79,
107].
Whereas cognitively impaired subjects with PART often carry a clinical diagnosis
of possible or probable AD [115],
the coexistence of PART and AD in aging is an inevitable complicating factor
[153].
A recent analysis of the National Alzheimer’s Coordinating Center (NACC) autopsy
database [16]
found that ~14 % of subjects clinically diagnosed with mild-to-moderate
probable AD had no or sparse neuritic plaques [128].
Here we provide additional data from the NACC database that underscore
characteristics of PART: the pathology is common and Braak stage “0” is
relatively unusual in older individuals; there is an absence of an association
between PART and APOE genotype; and, the more severe PART
pathology is associated with a higher age of death and lower scores on cognitive
tests (Table 1).
Table 1
Clinical features of primary age-related tauopathy
(PART)
Amyloid plaque density |
Braak stage | |||||
---|---|---|---|---|---|---|
0 |
I |
II |
III |
IV | ||
Number of subjects | ||||||
PART, definite |
None |
11 |
22 |
25 |
15 |
15 |
PART, possible |
Low |
4 |
16 |
27 |
16 |
31 |
– |
Mod |
2 |
11 |
15 |
32 |
50 |
– |
High |
3 |
7 |
10 |
39 |
83 |
Age at death (average) | ||||||
PART, definite |
None |
81.3 |
82.4 |
88.5 |
88.4* |
92.0*, ** |
PART, possible |
Low |
88.4 |
80.4 |
84.7 |
89.7* |
87.6* |
– |
Mod |
89.0 |
80.2 |
87.4* |
84.9 |
86.5 |
– |
High |
77.0 |
84.9 |
86.7 |
85.3 |
84.6 |
Final MMSE scores | ||||||
PART, definite |
None |
28.0 |
28.4 |
26.5 |
25.1*** |
24.3*** |
PART, possible |
Low |
28.5 |
25.8 |
24.4 |
24.6 |
21.9* |
– |
Mod |
26.5 |
26.8 |
27.3 |
23.2* |
19.8* |
– |
High |
25.5* |
24.5 |
27.9* |
21.2* |
18.8*, ** |
APOE ε4 positive (%) | ||||||
PART, definite |
None |
9.1 |
13.6 |
0.0 |
20.0 |
13.3 |
PART, possible |
Low |
25.0 |
12.5 |
14.8 |
37.5 |
35.5* |
– |
Mod |
0.0 |
36.4 |
13.3 |
34.4* |
50.0* |
– |
High |
66.7* |
28.6 |
50.0* |
33.3* |
56.6*, ** |
The application of imaging and CSF biomarkers has given a
novel perspective on the prevalence and associated clinical features of
neurodegenerative processes that undoubtedly include PART. Biomarker-based
clinical research supports the claim, initially made based on the autopsy
studies of putatively cognitively intact people [36,
88]
and of persons with mild cognitive impairment (MCI) [83,
93,
113],
that tauopathy in the absence of Aβ-type amyloidosis is common. Reported
biomarkers include CSF Aβ(1–42) or positron emission tomography (PET) imaging
for Aβ pathology and CSF tau or phospho-tau, structural MRI, and PET (including
fluorodeoxyglucose PET) for neurodegeneration. The abnormalities of the
neurodegeneration biomarkers have generally been defined relative to levels seen
in AD. It appears that roughly a quarter of cognitively normal elderly
individuals have abnormal neurodegeneration biomarkers in the absence of
abnormal brain amyloidosis [86,
87,
143,
145].
This clinical cohort’s status has been termed “suspected non-Alzheimer
pathophysiology” (SNAP) to distinguish it from persons with Aβ-type amyloidosis
[75,
87].
In persons with amnestic MCI, remarkably, about the same proportion of SNAP
cases is found [112,
114].
Although autopsy experience is limited so far in cases with biomarker-defined
SNAP, the prominent involvement of the medial temporal lobe in reported SNAP
cases suggests that PART-type pathologic changes may underlie at least a subset
of persons with the SNAP biomarker profile in the broader population. A more
specific diagnostic classification enables terminology that parallels the
recently adopted nomenclature for AD, with a biomarker-positive presymptomatic
stage and a symptomatic stage where both biomarkers and clinical phenotype are
present [74].
There are ongoing and potential future clinical trials that target either Aβ- or
tau-related pathogenic mechanisms. PART and AD may well respond differently to
those therapeutic interventions [23],
which underscore the importance of harmonizing clinical decisions with data that
were previously obtained in high-quality autopsy series.
Neuropathologic changes
Gross examination of the brain of subjects with PART may show
no obvious differences from those deemed “normal for age”. In other individuals
with PART, there may be mild-to-moderate diffuse atrophy of the neocortex, and
medial temporal lobe atrophy may be pronounced in persons with dementia
(Fig. 1)
[110,
122].
Immunohistochemistry
reveals telencephalic NFTs emerging most consistently in the medial temporal
lobe, particularly the hippocampal formation and adjacent regions
(Fig. 1b–d).
Abnormal tau-immunoreactive inclusions are most prominent in neurons
(Fig. 2).
Subcortical NFTs can be observed even in teenage years in the locus coeruleus
[9,
30,
41,
42,
131],
so this process is not necessarily limited to individuals of advanced age. NFTs
may also be seen in the amygdala, nucleus basalis of Meynert, nucleus accumbens,
hypothalamus, thalamus, olfactory system (bulb and cortex), dorsal raphé
nucleus, and medulla oblongata [7,
8,
53,
107,
141].
While NFTs at all stages of evolution can be seen in PART, individuals with
cognitive impairment often have abundant extracellular, so-called “ghost”,
tangles [110,
122].
Fig. 1
Primary age-related tauopathy (PART): gross pathology
and low-power photomicrographs. a A
formalin-fixed left hemisphere from a 103-year-old woman reveals enlargement of
the inferior horn of lateral ventricle and severe medial temporal atrophy. Only
mild neocortical atrophy is present. b A
Luxol fast blue-counterstained
hematoxylin–eosin section (LHE) shows atrophy of the medial temporal lobe. c Phospho-tau (p-tau; AT8)-immunolabeled
sections highlight marked tauopathic changes predominantly in the hippocampus
and entorhinal cortex. d For comparison, a
case with advanced AD demonstrates a more severe tauopathy extending into the
temporal neocortex
Fig. 2
Primary age-related tauopathy (PART): histopathology.
The neuropathology corresponds to Braak stages I–IV, with involvement of the
hippocampal formation (a–c
are nearly serial sections from the hippocampus of the same patient) as shown
with Luxol fast blue-counterstained
hematoxylin–eosin (LHE) (a), and p-tau
(AT8) immunohistochemistry (b). However,
unlike cases with AD, Aβ immunohistochemistry (c) shows minimal or no staining. Gallyas silver
impregnation reveals many “ghost tangles” in the hippocampal formation (d), here without amyloid plaques. A key
difference between AD and PART pathology is that, by definition, advanced AD
(e) shows extensive hyperphosphorylated
tau (p-tau) in neocortical areas such as the prefrontal cortex (Brodmann area
9), whereas PART pathology spares the neocortex (f). Scale
bar in a 1 mm for (a–c),
scale bar in d
100 µm, and scale bar in e 5 mm for (e, f).
CA1-4 denote the hippocampal subfields,
DG dentate gyrus
The only existing grading system that applies to PART is Braak
neurofibrillary staging [26,
28,
32].
The pathologic continuum of PART includes pretangle or cortical pretangle (up to
Stage Ib), entorhinal (I–II), or limbic (III–IV) Braak stages [25,
27,
28].
Theoretically, given experimental findings that tau pathology might be
propagated trans-synaptically [34,
35,
38,
46,
47,
57,
91],
it is notable that PART-type pathology generally does not progress to the
isocortical Braak stages (i.e., V–VI), remaining relatively restricted
neuroanatomically even in the oldest-old subjects with limited extension beyond
the temporal neocortex to other neocortical regions [73,
148].
The neurofibrillary changes in PART resemble those in AD
brains (Fig. 3).
Immunohistochemical and biochemical studies have found that NFTs in PART, as in
AD, contains accumulation of both 3-repeat (3R) and 4-repeat (4R) tau isoforms
(Fig. 3a–c)
[70,
79,
122,
130].
In AD NFTs, electron microscopy has revealed predominantly paired helical
filaments (PHFs), which are considered a disease hallmark [85,
119,
146].
The tau fibrils in brains with PART pathology also display a typical PHF
morphology (Fig. 3d)
[67,
72,
122].
These observations are not unique to PART and the pathologic overlap requires
further consideration.
Fig. 3
The NFTs of PART resemble those of AD by
immunohistochemistry, biochemistry, and ultrastructure. a,
b NFTs in PART reveal immunoreactivity
with both 3R and 4R anti-tau monoclonal antisera (RD3 and RD4, respectively).
Scale bar 200 μm for a,
b. c
Immunoblot using polyclonal antisera targeting
total tau (tau C) shows a banding pattern similar to that in AD (from Ref.
[122]
with permission). d The tau fibrils
(paired helical filaments) in PART show similar ultrastructural features and
periodicity as in AD. Scale bar
100 nm
Differentiating PART from other neurodegenerative diseases
A synthesis of previously reported observations exposes an
apparent paradox: the NFT is one of the two defining pathological hallmarks of
AD, the other is the Aβ plaque. However, AD-type NFTs are almost ubiquitously
observed in older persons’ brains, even in the absence of Aβ plaques or features
of other classifiable tauopathies. Because there are pathologic features in
common with AD, some investigators may consider PART a subset of AD or an early
stage of AD. Indeed, NFTs in the brainstem of younger adults show features in
common with the pathological processes of AD [31].
Yet clinically and pathologically salient features may differ despite the
overlap in pathologies. In comparison to AD, current data suggest that PART
typically has a far more limited impact on cognition and develops in persons
without Aβ plaques or biochemical evidence of elevated Aβ [122].
A diagnosis of AD neuropathologic changes requires at least a minimum threshold
level of Aβ deposition [64,
102].
This criterion is supported by extensive genetic and clinicopathologic
observations [108].
There is an accumulating body of evidence suggesting that medial temporal lobe
NFTs are involved in at least two common processes, an AD-related process, and a
non-AD aging-related process [103,
107].
Supportive evidence comes from genetic studies that show an association between
PART and the microtubule-associated protein tau gene (MAPT)
H1 haplotype [76,
122],
whereas there is an absence of an association between PART and the strongest
risk factor for AD, the APOE ε4 allele [13,
67,
70,
122,
150,
151].
PART cases have likely been reported in autopsy series of
SD-NFT, TPSD, tangle-predominant dementia or tangle-only dementia [10,
14,
17,
43,
79,
98,
106,
110,
122].
These proposed pathologic entities may have included some cases that would now
be considered frontotemporal lobar degeneration (FTLD). TPSD has previously been
grouped among FTLD subtypes [33]
and there are presumably FTLD-tau subtypes that may overlap with the spectrum of
PART even if the pathogenesis is distinct. For example, individuals with
germline MAPT R406W mutation may present
as a temporal lobe predominant tauopathy with similar features to TPSD [63],
but the presence of NFTs in the globus pallidus, subthalamic nucleus, substantia
nigra, and pons in such cases is reminiscent of PSP. The pattern of tau isoform
accumulation associated with PART pathology can also be seen in other
tauopathies, including amyotrophic lateral sclerosis/Parkinsonism dementia
complex of Guam
[61,
111,
123,
124],
which, like AD, may also show α-synuclein and TDP-43 pathology [50,
140].
By contrast, PSP and CBD display a predominance of 4-repeat tau isoforms, and Pick
disease shows predominantly 3-repeat tau isoforms [4,
44,
79,
90,
138,
152].
Also commonly seen in brains from individuals of advanced age are
tau-immunoreactive argyrophilic grains. However, argyrophilic grain disease is a
4R tauopathy featuring CA2 pretangles and dentate granule cell involvement, all
acetylated tau-negative, and none of these features are seen in AD/PART
[54,
71,
84,
107,
120,
136,
138].
Future studies and unanswered questions
Additional studies are necessary to refine our understanding
of PART in the complicated context of the aged human brain. Most fundamentally,
the exact clinicopathologic spectrum of PART remains to be definitively
characterized. Additional topical questions relate to the “boundary zone”
between PART and other tauopathies, especially AD. The precise threshold of Aβ
deposition below which a diagnosis of definite PART is appropriate, and the
relative importance of diffuse amyloid and neuritic plaques, require further
study. In addition, there is a growing appreciation, not yet incorporated into
consensus-based guidelines, that the neuropathology of AD is heterogeneous
[2,
18,
20,
59,
62,
76–78,
92,
104,
105,
118,
151].
It is possible that brains with hypothesized hippocampal “localized” [100,
101]
or “limbic-predominant” [76,
104,
105,
151]
AD subtypes are along a common continuum with PART [76,
79,
105].
The rationale for including extracortical tau pathology in PART is that the
pathologies commonly coexist and that brainstem NFTs, if they represent the same
process, appear to occur even earlier in human aging [30–32,
53].
In this context, it is also not known whether spinal cord tauopathy is related
to PART [40].
More studies will be needed to determine whether there are distinct subtypes of
extracortical tauopathy and how these changes relate to AD as well as PART.
There are other conditions besides AD that overlap pathologically with PART. For
example, it is notable that chronic traumatic encephalopathy generally presents
pathologically as a non-Aβ tauopathy with features that overlap pathologically
with PART [95],
and in the future markers may be developed to better discriminate between
disorders in which NFTs develop in similar brain areas. Tau-immunoreactive glial
pathology is also frequently seen in advanced old age [1,
44,
65,
68,
89,
90,
127].
It is unknown whether the age-related glial tauopathy is associated with
mechanisms that also cause PART pathology, but PART appears to be a
predominantly neuronal pathology. To enable future studies aimed at addressing
the extant unresolved questions, a working diagnostic guideline is
required.
Neuropathologic criteria
New criteria are proposed to classify patients with PART for
research and potential future clinical purposes (Table 2).
PART is defined by AD-type neurofibrillary changes without, or with few, Aβ
plaques as described below. PART can be designated as “Definite” or “Possible”
depending on the presence of coexisting neuropathology and many cases will not
be gradable due to comorbid pathology. Specifically, neurofibrillary changes may
correspond to subcortical pretangle or cortical pretangle (up to Ib), entorhinal
(I–II), or limbic (III–IV) Braak stages [25,
27,
28].
In keeping with the current guidelines for AD [64,
102],
mild Aβ plaques defined using the Thal grading system [116,
135,
137],
consistent with low AD neuropathologic changes, preclude the diagnosis of
“Definite” PART. Some pathologists may prefer the CERAD system for grading
neuritic plaque density [96],
but the method used must be indicated as it would alter the classification of
some subjects. Possible wording for the pathologic diagnoses is provided
(Table 2).
If both early AD pathology and “Possible” PART pathology are observed, both may
be reported diagnostically. The presence of few or moderate argyrophilic grains
as assessed with established staging methods [45,
121]
does not rule out PART. We emphasize that a pathologic diagnosis of PART does
not necessarily indicate that a functional deficit was detected clinically. We
also note that Braak stage IV pathology without Aβ plaques is unusual and in
these cases the possibility of a FTLD-tau condition should be considered.
Table 2
Primary age-related tauopathy (PART): working
classification
1. Requires | ||
NFTs present with Braak stage ≤IV (usually
III or lower) | ||
2. Then subclassify as follows | ||
Category |
Thal Aβ Phasea |
Other disease associated with NFTb
|
Definite |
0 |
Absent |
Possible |
1–2 |
Absent |
Examples | ||
Primary age-related tauopathy (PART),
Definite, Braak stage II | ||
Primary age-related tauopathy (PART),
Possible, Braak stage III, Thal Aβ phase 2 | ||
3. Ancillary studies (not required) | ||
Immunohistochemistry:
3R and 4R tau-positive | ||
Electron microscopy: paired helical
filaments present | ||
Genetics: absence of pathogenic FTLD-tau
mutation |
Summary
PART is a common brain pathology relevant to researchers,
clinicians, and the broader public. Despite the high prevalence in published
brain autopsy series, PART has been difficult to categorize because of the
absence of a well-accepted nosology. We expect that the study of tau biomarkers
will broaden the recognition of PART, and improve our understanding of a
condition currently known mostly from neuropathologic studies. More studies are
needed to better understand the pathogenesis of PART, its relation to other
neurodegenerative disorders, and the full clinical spectrum of this common brain
disease of aging.
Acknowledgments
We are extremely grateful to the patients, clinicians,
and fellow researchers that made this effort possible. We also acknowledge the
following funding sources: the Society for Supporting Research in Experimental
Neurology, Vienna, Austria, National Institutes of Health Grants 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.
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