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Brains With Medial Temporal Lobe Neurofibrillary Tangles But No Neuritic Amyloid Plaques Are a Diagnostic Dilemma But May Have Pathogenetic Aspects Distinct From Alzheimer Disease

Peter T. Nelson MD, PhD, Erin L. Abner MS, Frederick A. Schmitt PhD, Richard J. Kryscio PhD, Gregory A. Jicha MD, PhD, Karen Santacruz MD, Charles D. Smith MD, Ela Patel HT, William R. Markesbery MD
DOI: http://dx.doi.org/10.1097/NEN.0b013e3181aacbe9 774-784 First published online: 1 July 2009

Abstract

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP− cases, we analyzed 26 NFT+/NP− patient brains identified from the University of Kentucky AD Center autopsy cohort (n = 502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n = 5,108) and found 219 NFT+/NP− cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP− cases to encephalitis during childhood. We conclude that NFT+/NP− cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

Key Words
  • Alzheimer disease
  • Amyloid
  • CERAD
  • Neurofibrillary tangle
  • Postencephalitic
  • Tau

Introduction

The diagnostic and biological relevance of histopathological markers associated with Alzheimer disease (AD) has recently been called into question (1, 2). In view of the extreme complexity of age-related human brain diseases (3), a better understanding of the neuropathology of AD and of neurodegenerative diseases that overlap pathologically with AD is needed.

The distinct pathological hallmarks of AD are neurofibrillary tangles (NFTs) and neuritic amyloid plaques (NPs). Neurofibrillary tangles develop within neurons and are composed of filamentous tau protein polymers. As delineated by Braak and Braak (4), the numbers of NFTs generally increase in an anatomically predictable fashion as the disease progresses. The expanding distribution of NFTs in the brain is graded on a 0 to VI severity scale according to “Braak stages” (5). Braak stages 0-IV refer to NFT pathology that is mostly confined to the medial temporal lobe structures including the hippocampal formation and amygdala. The severity of neocortical NFT pathology correlates well with antemortem cognitive impairment in AD (3, 6, 7). Neurofibrillary tangles are, however, observed in other neurodegenerative conditions (8).

In contrast to NFTs, NPs are extracellular amyloid deposits that are specific to AD. Neuritic plaques contain Aβ-peptide polymers and are surrounded by degenerating neurites. The severity of NP pathology is scored according to a completely different neuropathological metric named after the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (9). The CERAD scoring system involves a 4-tiered semiquantitative scale of neocortical NP density; the earliest changes are usually found in the neocortex rather than in the medial temporal lobes. The density of NPs in medial temporal lobe structures is typically low (10), and the correlation between NP densities in these areas with antemortem cognitive impairment is relatively weak (11, 12).

The National Institute on Aging and Reagan Institute (NIARI) consensus criteria using both the Braak stages and the CERAD scales have been applied since 1997 for AD diagnosis (13). According to these guidelines, cases are parsed into “low,” “intermediate,” and “high likelihood” that clinical manifestations are due to AD. “Low” likelihood corresponds to CERAD “negative,” Braak stages 0-II; “intermediate likelihood” corresponds to CERAD “possible” or “probable,” Braak stages III or IV; “high likelihood” corresponds to CERAD “probable” or “definite,” Braak stages V or VI.

Most brains can be categorized readily among the NIARI diagnostic groups, but some cases defy those categories and are also difficult to reconcile with current theories of AD pathogenesis. For example, up to 6% of aged persons' brains contain relatively severe neurofibrillary pathology in the medial temporal lobes, corresponding to Braak stage III or IV, although no discernible NPs are detected elsewhere in the brains (14). We designate these cases as “NFT+/NP−” but stress that the “NFT+” refers to NFTs that are greater than 99% confined to the medial temporal lobe structures such as the hippocampal formation and amygdala. Cases of NFT+/NP− have been described previously (14-19), but many questions remain about their clinical and pathological context and the relationship to newer concepts such as the aberrant expression of thrombocytopenia and absent radius-DNA binding protein-43 (trans-activator regulatory DNA-binding protein 43) (20). We used patients from the University of Kentucky AD Center (UK ADC) cohort, the Nun Study, and pooled cases in the National Alzheimer's Coordinating Center (NACC) Registry to determine the clinical, demographic, and biological factors related to NFT+/NP− cases.

Materials and Methods

Case Study Groups

Patients who came to autopsy from the UK ADC cohort (total n = 502) were the initial study group. Details of UK ADC institutional review board protocols, patient recruitment, and longitudinal follow-up have been described previously (12, 21). Briefly, nondemented subjects were contacted at 6-month intervals, had detailed annual mental status testing, and had neurological and physical examinations on at least a biannual basis. Mental status testing has been described previously (12, 21). Cases with frontotemporal dementia (n = 18) were excluded. All clinical diagnoses were documented by the clinicians at a consensus conference that included neurologists, neuropsychologists, and social workers. The Nun Study of the School Sisters of Notre Dame in the United States is a longitudinal study of 493 participants ranging in ages from 75 to 102 years (mean, 83 years) and has been described elsewhere (22, 23). Neuropathological evaluations were conducted by a single blinded neuropathologist (W.R.M.) who performed all gross and microscopic examinations.

Neuropathological Analysis

Detailed neuropathological studies were performed on both cohorts at the UK ADC as previously described (11, 12). Briefly, at least 24 samples were taken from each brain, including middle frontal gyrus (area 9), superior and middle temporal gyri (areas 21 and 22), inferior parietal lobule (areas 39 and 40), and occipital lobe including primary visual area (areas 17 and 18). Amyloid plaques were separated into diffuse plaques (plaques without neurites) and NPs in each region, as previously described (11, 12). An arithmetic mean was calculated from counts of diffuse plaques (number/2.35 mm2), NPs (number/2.35 mm2), and NFTs (number/0.586 mm2) for each region in the 5 fields that were subjectively determined to have the greatest involvement. As previously described (11), TDP-43 immunolabeling was performed.

Cases and Controls From the University of Kentucky AD Center

Cases of NFT+/NP− were selected from the UK ADC cohort who had Braak stage III or IV with CERAD score of “negative” (n = 26). As shown in Table 3, there were 2 control groups: Braak stage 0 with CERAD “negative” (n = 21; Control Group 1) and Braak stage III or IV but CERAD “definite” (n = 15; Control Group 2).

NACC Data

The NACC Registry contains detailed data from more than 30 different ADCs across the United States (24). Data from NACC were obtained by request according to the standard application methods. Cases with no Braak stage data, no CERAD data, or any subtype of frontotemporal dementia diagnosed by neuropathological criteria were excluded. Because the NIARI consensus guidelines were published in late 1997, only persons dying after 1997 were evaluated. Based on these criteria, 6,508 cases were excluded and 5,108 cases were included.

Results

We first evaluated data from the UK ADC (12) and the Nun Study (23, 25) to compare counts of NFTs and NPs from individual cases (Fig. 1). These data show that a subset of cases from both cohorts lack cortical NPs but have many NFTs in the medial limbic structures, that is, the hippocampus (CA1 field and subiculum), entorhinal cortex, and amygdala. In each cohort, however, there was not an appreciable subset of cases that lacked NPs and had many NFTs in the neocortex. One case had neocortical NFTs and lacked NPs but had bilateral chronic cerebral contusions (orange arrow, Fig. 1A).

FIGURE 1.

Data from the University of Kentucky Alzheimer Disease Center (UK ADC) (A, B) and the Nun Study (C, D), each blue diamond representing an individual patient. These data indicate that neurofibrillary tangles (NFTs) are often seen in medial limbic structures without amyloid plaques (B, D). By contrast, NFTs are almost never seen in neocortical areas without amyloid plaques (A, C). The exceptional case with a few plaques but with appreciable neocortical NFTs (orange arrow in A) also had chronic bilateral contusions. Neocortical lesion counts are totaled from parietal, occipital, superior midtemporal, and frontal cortices; medial limbic lesion counts refer to CA1, subiculum, amygdala, and entorhinal cortex. Cases with few amyloid plaques but with neocortical NFTs would be in the area indicated by red arrows (A, C), whereas these cases in medial limbic structures are indicated by light blue arrows (B, D).

Cases from the UK ADC database that were Braak stage III or IV but CERAD “negative” were defined as NFT+/NP− cases. Clinical and pathological features of these cases are presented in Tables 1 and 2. Comparisons with the 2 control groups are shown in Table 3. The incidence of apolipoprotein E2 alleles (7 alleles in the 26 NFT+/NP− cases) was relatively high but was similar to the other CERAD “negative” cases (Control Group 1). The NFT+/NP− cases tended to be relatively old (average age, >88 years); few had the diagnosis of a neurodegenerative disease or mild cognitive impairment (MCI) before death. The average final Mini-Mental State Examination score was 26.5 in this group. Patients in Control Group 2 (Braak stage III or IV and high NPs) had an average final Mini-Mental State Examination score of 22.1; this was not statistically different at p < 0.05 after Bonferroni correction.

View this table:
TABLE 1.
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TABLE 2.
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TABLE 3.

Cases of NFT+/NP− tended to have an apparent dropout of neurons in the cornu ammonis of the hippocampus, but there was not enough cell loss or astrocytosis for the designation of hippocampal sclerosis (Fig. 2). Most cases that were immunostained for TDP-43 did not show aberrant staining, but most of the cases with antemortem cognitive impairment (cases 9, 14, 18, 20, and 26; Tables 1 and 2) did have aberrant staining. This proportion of aberrant TDP-43 staining (more than half of cases with any degree of cognitive impairment including all with hippocampal sclerosis) is comparable with our prior studies of other cases (11); aspects of TDP-43 immunohistochemistry will be described in greater detail in a subsequent study. There was no consistent evidence of synucleinopathy, hippocampal sclerosis, or argyrophilic grains in the NFT+/NP− cases (Table 2).

FIGURE 2.

Neuropathological features of neurofibrillary tangle (NFT)-positive/neuritic plaque (NP)-negative cases from the University of Kentucky Alzheimer Disease Center. (A) Low-power section from CA1 of the hippocampus shows a low neuronal density but insufficient cell loss for the diagnosis of hippocampal sclerosis. (B) Preservation of neurons and NFTs is evident at higher magnification. (C) There are many NFTs in CA1 demonstrated by silver impregnation. (D) A case stained for amyloid Aβ peptide with NPs shows focal cerebral amyloid angiopathy (red arrow) but no extracellular parenchymal NPs. (E, F) Amyloid NPs are evident in the hippocampus in an Alzheimer disease (AD) case (green arrows, E), but only NFTs are present in the amygdala in an NFT+/NP− case (F). Scale bars = (A, D) 1 mm; (B) 100 μm; (C, E, F) 50 μm. (A, B) Hematoxylin and eosin (H&E); (C, E, F) Gallyas silver impregnation; (D) immunohistochemistry (IHC).

Eight of 23 NFT+/NP− cases that were assessed had immunohistochemical staining for phospho-tau antibody paired helical filament 1 (26) in the ventral midline of the medulla oblongata (Table 2; Fig. 3); the appropriate tissue blocks were not available in 3 NFT+/NP− cases. The stained cells had the histopathological appearances of glial tangles. This staining was also observed in 2 of 19 controls (p value vs NFT+/NP− cases <0.07 by χ2 test); another case with this finding had cerebellar and inferior olivary degeneration.

FIGURE 3.

Neurofibrillary pathology in the ventral medial medulla oblongata in a neurofibrillary tangle-positive/neuritic plaque-negative case. (A) Diagram indicates the area with aberrant phospho-tau (paired helical filament 1, PHF-1) immunoreactivity and Gallyas silver staining in red cross-hatching. (B) Low-power photomicrograph shows the distribution of PHF-1-immunoreactive cells (brown) on either side of the midline (blue asterisk). (C) Higher power demonstrates that the cells have the morphologic appearance of glial tangles. Scale bars = (B) 100 μm; (C) 20 μm.

We used cases from the NACC Registry to assess demographic indices of NFT+/NP− cases in a larger sample. Table 4 shows the relative representation of different cases stratified by Braak staging and CERAD scores. As in the UK ADC data, approximately 5% of cases are Braak stage III or IV although CERAD “negative". There were also cases with higher Braak stages (V and VI) that also were CERAD “negative” in the NACC data; these were not evaluated because they were not represented in the UK ADC or Nun Study data sets, and we were unsure what biological processes might underlie this pathology. We did not pursue detailed follow-up studies in the NACC data because of differences in neuropathological diagnostic approaches across ADCs; it has been shown that Braak staging can be different between individuals even in the best circumstances (27).

View this table:
TABLE 4.

When the years of birth of persons from the NACC Registry were compared across different groups, the NFT+/NP− cases had a statistically different distribution (p < 0.001 by the Kolmogorov-Smirnov statistic; Fig. 4). One possible explanation for this difference seemed to be the tendency for NFT+/NP− cases to have been born during the years 1911 and 1912. Results according to individual year of birth “bins” are shown in Table 5.

FIGURE 4.

Relative proportions of neurofibrillary tangle (NFT)-positive/neuritic plaque (NP)-negative (NFT+/NP−) cases (n = 212 between 1900 and 1930) and combined cases from the National Alzheimer's Coordinating Center from Braak stage III/IV andCERAD “definite,” or Braak stage 0and CERAD “negative"; n = 418) (controls [Ctrl]) by birth year. The NFT+/NP− cases tend to have a significantly different distribution (p < 0.001 by the Kolmogorov-Smirnov statistic) with an apparent peak in the years 1911-1912. The birth cohort with peak incidence of the 1918 to 1919 influenza pandemic is indicated by a green line. CERAD, Consortium to Establish a Registry for Alzheimer's Disease.

View this table:
TABLE 5.

Discussion

We used multiple data sets to characterize the demographic and neuropathological features of NFT+/NP− cases. Patients with extensive involvement of the cerebral neocortex by NFTs without concurrent NPs are extremely rare; there was only 1 case in our cohort that had bilateral chronic cortical contusions. By contrast, cases with NFTs mostly in medial temporal lobes represented approximately 5% of our cohort. Most of these patients lacked profound antemortem cognitive decline, and most of their brains showed no diffuse plaques, hippocampal sclerosis, synucleinopathy, or argyrophilic grains. A few cases with antemortem cognitive impairment also had aberrant TDP-43 staining, the significance of which is unclear; TDP-43 immunostaining is seen in a variety of conditions (11, 20, 28-30). There were also some differences in apolipoprotein E alleles between NFT+/NP− cases and controls, but this also is of unknown significance. There was also a tendency for some NFT+/NP− cases to exhibit neurofibrillary pathology in the medulla oblongata. These demographic and pathological features allow us to formulate a novel hypothesis about NFT+/NP− pathogenesis.

Previous studies have described brains from aged individuals with medial temporal lobe NFTs without any amyloid plaques (14, 15); the incidence in various series has ranged from 0 to approximately 6% (14-19, 31, 32). Notably, the neuroanatomical pattern of NFTs and the tau isoforms in this condition are similar to those in AD but are distinct from those in progressive supranuclear palsy, parkinsonism-dementia of Guam, corticobasal degeneration, and other tauopathies (14, 16, 31).

It is unclear how NFT+/NP− cases relate to AD. Most prior studies have assumed that NFT+/NP− cases represent a neurodegenerative disease separate from AD (14, 32), but it is possible that NFT+/NP− cases belong within the AD spectrum. From this perspective, the existence of these cases would argue against the amyloid cascade hypothesis (33) by indicating that NFTs do not develop downstream of amyloid plaques in AD. A number of authors have described NFT+/NP− cases in the context of “atypical AD” (34, 35) or a “variant"/"subgroup” of AD (36, 37), which can be considered a middle ground between the hypotheses that NFT+/NP− cases are separate from, or directly related to, all other AD cases.

Unlike in our series where most cases were not cognitively impaired, clinical and pathological series have referred to “NFT-predominant dementia,” “limbic NFT dementia,” “senile dementia of the NFT type,” “senile dementia with tangles,” and “tangle-predominant senile dementia” (14, 16, 31, 37, 38). In the UK ADC autopsy cohort, only 4 cases had clinical diagnosis of AD, and one had the diagnosis of MCI. Similar cases have been reported in the context of clinicopathological case series with MCI (17-19); this is more expected because Braak stages III and IV are not usually substrates for severe cognitive impairment (3); there are no UK ADC cases with higher Braak stages and no NPs. We note that the NACC data contain a few dozen Braak stage V or VI cases that are CERAD “negative"; however, prior studies seem to refute the presence of these cases (14), and we are uncertain about the clinicopathological features of these cases because we have not studied them ourselves. In contrast to NFT+/NP− cases, virtually all Braak stage VI cases have many NPs and diffuse plaques. Moreover, NPs do not develop in response to tauopathies. Furthermore, the NFT+/NP− patients are quite old; thus, there are reasons to suggest that NFT+/NP− cases are unlikely to represent “pre-clinical” stages of AD. We and others have hypothesized that NFTs and/or their precursor tau protein elements are injurious to neurons in AD and across many different conditions (3, 36, 39-45). Aside from the “tauopathies,” NFTs are seen in brains in association with a variety of developmental, neoplastic, traumatic, and prion diseases including Niemann-Pick disease type C, pantothenate kinase-associated neurodegeneration, myotonic dystrophy, chronic traumatic encephalopathy, gangliogliomas, and Gerstmann Sträussler Scheinker disease (3, 8, 46-48). There are many subtypes of neurodegeneration without NFTs, but there is no condition characterized by widespread neocortical NFTs without cognitive impairment and neuron loss. In addition, there are at least 2 viral illnesses characterized by brain NFTs: subacute sclerosing panencephalitis and postencephalitic parkinsonism (PEP) (47, 49-51).

The clinical and pathological features of PEP deserve special note. Postencephalitic parkinsonism occurred in individuals who survived encephalitis lethargica (von Economo encephalitis, or the “sleeping sickness"), which was linked to the 1918 to 1919 influenza pandemic. The influenza pandemic affected ∼30% of Americans and killed approximately 20 to 40 million worldwide (52, 53), and encephalitis lethargica killed as many as 500,000 Americans (54). Clinically, PEP refers to a spectrum of extrapyramidal movement dysfunction. Pathology was mostly subcortical, but cortical changes could include hippocampal NFTs (involving the same tau protein isoforms as AD) but no amyloid plaques (51, 55-57). The disease was progressive over decades, and incidence of PEP peaked in the 1950s, more than 30 years after the pandemic started.

Even outside encephalitis lethargica, the influenza virus can induce profound stress on the human central nervous system (58). Furthermore, widespread behavioral sequelae from encephalitis lethargica were more pronounced than generally thought, affecting children differently from adults (54, 59). To the best of our knowledge, however, there has not been a systematic clinical or pathological study of survivors of the 1918 to 1919 pandemic who did not have encephalitis lethargica or frank PEP. Notably, the age group with peak incidence of illness from the 1918 to 1919 influenza pandemic in the United States was those born between 1909 and 1914 (52, 53). This group also coincides with the lowest mortality rate from the disease (52, 53); hence, many individuals survived from this birth cohort.

We found that NFT+/NP− cases had a greater tendency than controls to be in the abovementioned high-risk birth cohort for infection during the 1918 to 1919 influenza pandemic (Table 5). This provides circumstantial evidence to support a novel hypothesis that the NFT+/NP− pattern might occur in individuals infected during the pandemic. According to this hypothesis (Fig. 5), there was a relatively “short” (∼30-year) lag time to autopsy for the individuals affected by encephalitis lethargica and PEP, with commensurately dramatic clinical and pathological disease. For persons affected differently by the influenza virus, however, there might be a longer subclinical phase, and patients may be very long-lived and manifest far milder NFT+/NP− pathology. European studies performed over a decade ago provided a similar age range for tangle-predominant dementia cases as in the current series (15, 60). It should be noted, however, that the cognitive impairment seen in those studies seemed more severe that in our cohort, which could indicate that milder cases survived longer with cognition more intact.

FIGURE 5.

Hypothesis on the pathogenesis of neurofibrillary tangle (NFT)-positive/neuritic plaque (NP)-negative cases. Postencephalitic parkinsonism (PEP) is a progressive neurodegenerative disease caused by encephalitis lethargica and linked to the 1918 to 1919 influenza pandemic that affected up to 40% of many Western populations. The brains of PEP patients may have hippocampal NFTs without NPs. Postencephalitic parkinsonism incidence peaked by the early 1950s (purple line), but it is not known what happened to individuals who were affected by influenza and/or encephalitis lethargica before 1920 but did not develop PEP. We hypothesize that in some patients with a milder prodrome and/or different host factors, there was a longer subclinical phase (orange line) and that the disease became manifest as many NFTs in medial temporal lobe structures. Patients that were not otherwise destined to develop Alzheimer disease did not develop NPs. If this hypothesis is valid, the incidence of NFT+/NP− cases would decline as this birth cohort passes.

Our finding of neurofibrillary pathology in the medulla oblongata in NFT+/NP− brains may also support the hypothesis of a connection with PEP, which was characterized by subcortical NFTs without extracellular amyloid (55, 57, 61). The appearance of this pathology in NFT+/NP− brains was not statistically different from the comparison group, although a trend was noted (8/23 NFT+/NP− cases, versus 2/19 cases in the control group; p < 0.07), perhaps because some cases that also have AD pathology show some of the features of this process too. Notably, Rub et al (62) looked carefully for medulla oblongata neurofibrillary pathology in the earliest stages of AD using sensitive tau antibodies and did not report this pattern of staining.

Testing the hypothesis that NFT+/NP− pathology is linked to the 1918 to 1919 influenza pandemic would be extremely challenging. Unfortunately, reliable personal recollections or medical records are not adequate to perform a retrospective correlation study. Moreover, prior studies that have tried to isolate evidence of viral nucleic acid in PEP brains were unsuccessful (63-65). Therefore, we cannot address the question using current molecular techniques. If this hypothesis is valid, however, it would predict that the incidence of NFT+/NP− persons coming to autopsy would decrease in coming years with the passing of the members of this birth cohort. There is also debate about the causative link between influenza and encephalitis lethargica (61, 66). This concern would not obviate the point that long-term neuropathological sequelae may be associated with the influenza pandemic of 1918 to 1919, or, alternatively, with whatever induced PEP.

In summary, we cannot yet prove the lack of a direct relationship between AD and NFT+/NP− cases because the tau protein isoforms and anatomical distribution of NFTs in these cases are essentially identical to those in early AD (14). Furthermore, there is suggestion from human A-beta vaccination studies that amyloid-negative NFT-positive cases can progress to end-stage AD (67). We note that approximately one fifth of the cases with NFT+/NP− pathology in our autopsy cohort were born after 1919 so that the birth cohort effect is not absolute. Hence, it is quite possible that NFT+/NP− cases are not due to a viral illness or other environmental effect and are instead directly relevant to AD pathogenesis. Even if the early pathogenesis of neurofibrillary pathology in NFT+/NP− cases is notably different from what occurs in AD brains, because some pathways must be relevant to both, the study of these cases may provide important clues about how AD develops.

From a diagnostic standpoint, it is notable that most NFT+/NP− cases in the UK ADC cohort had a high cognitive status. We propose that Braak stage III or IV cases that are CERAD “negative” should still fall in the NIARI “low likelihood” category in terms of AD, as so designated in prior studies (18, 19). Even if the brain shows no other contributing pathologies and the patient was profoundly cognitively impaired, we agree with Jellinger and Attems (14) in recommending a diagnosis of some version of non-AD dementia.

Limitations to this study include the challenges inherent in studying an uncommon, sporadic, human-specific disease process that requires expert neuropathological evaluation for detection. Most of the conclusions that we draw are based on correlations that will require validation from other data sets. The UK ADC is limited mostly to relatively well-educated whites without Parkinson disease or neuropsychiatric disorders, and it is difficult to generalize beyond these data. It should be emphasized that interrater reliability for diagnosing Braak stages also is imperfect, even in the best circumstances (27). Finally, because an association with NFT+/NP− pathology was seen in both the 1903 to 1908 and 1909 to 1914 birth cohorts who likely represent the oldest subjects autopsied in this study population, an additional possibility is that this pathology is associated with extreme age, independent of exposure to influenza. We look forward to further studies from other data sets of patients with extensive medial limbic NFTs without appreciable amyloid plaque pathology.

Acknowledgments

We are deeply grateful to all of the participants in our longitudinal aging study and to the patients in our Alzheimer's Disease Center's research clinic. We thank Ann Tudor, Paula Thomason, Dr Huaichen Liu, and Sonya Anderson for the technical support; Gregory Cooper, MD, PhD; Nancy Stiles, MD; and Allison Caban-Holt, PhD, for the clinical evaluations; and Daron Davis, MD, for pathological evaluations. We also thank Leslie E. Phillips, MS, for help with NACC data.

Footnotes

  • This study was supported by grants R01 NS061933, K08 NS050110, and P30-AG028383 from the National Institutes of Health, Bethesda, MD.

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