Chronic Traumatic Encephalopathy: Where Are We and Where Are We Going?

Chronic traumatic encephalopathy (CTE, previously called punch drunk and dementia pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research.     

Evolving concepts of chronic traumatic encephalopathy as a neuropathological entity

Chronic traumatic encephalopathy (CTE) is a long‐term neurodegenerative consequence of repetitive head impacts which can only be definitively diagnosed in post‐mortem. Recently, the consensus neuropathological criteria for the diagnosis of CTE was published requiring the presence of the accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in an irregular pattern as the mandatory features. The clinical diagnosis and antemortem prediction of CTE pathology remain challenging if not impossible due to the common co‐existing underlying neurodegenerative pathologies and the lack of specific clinical pointers and reliable biomarkers. This review summarizes the historical evolution of CTE as a neuropathological entity and highlights the latest advances and future directions of research studies on the topic of CTE.     

Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postu-lated that rosiglitazone may ameliorate diffuse axonal injuryvia its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone signiifcantly reduced the levels ofamyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser404 (p-tau (S404)), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S404) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.     

Total and phosphorylated tau proteins: evaluation as core biomarker candidates in frontotemporal dementia

An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer's disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231)) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau(181)) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau(231) levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks.     

Chronic Traumatic Encephalopathy: The cellular sequela to repetitive brain injury

This review aims to integrate current literature on the pathogenic mechanisms of Chronic Traumatic Encephalopathy (CTE) to create a multifactorial understanding of the disease. CTE is a progressive neurodegenerative disease, classed as a tauopathy, although it appears the pathogenic mechanisms are more complex than this. It affects those with a history of repetitive mild traumatic brain injury. Currently, there are no treatments for CTE and the disease can only be affirmatively diagnosed in post mortem. Understanding the pathogenesis of the disease will provide an avenue to explore possible treatment and diagnostic modalities. The pathological hallmarks of CTE have been well characterised and have been linked to the pathophysiologic mechanisms in this review. Human studies are limited due to ethical implications of exposing subjects to head trauma. Phosphorylation of tau, microglial activation, TAR DNA-binding protein 43 and diffuse axonal injury have all been implicated in the pathogenesis of CTE. The neuronal loss and axonal dysfunction mediated by these pathognomonic mechanisms lead to the broad psycho-cognitive symptoms seen in CTE.     

Pathological heterogeneity in progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative disorders of late adult life. Focal asymmetric cortical atrophy with ballooned neurons, nigral degeneration, and tau‐positive neuronal and glial lesions in both the gray and white matter, especially astrocytic plaques in the affected cerebral cortex, are characteristic features of CBD. While cortical involvement may occur in PSP, ballooned neurons are sparse and limited to the limbic system, and tufted astrocytes are abundant in the precentral gyrus and striatum. The present findings suggest that PSP and CBD are distinct pathological entities. However, there exist ‘atypical’ cases of PSP and CBD. Severe cortical involvement or asymmetric cortical atrophy can be seen in PSP. Ballooned neurons are sparse or difficult to detect in some cases of CBD, in spite of typical cortical tau pathology. Cortical symptoms are absent or only mild in ‘minimal change’ CBD. Moreover, several neurodegenerative disorders can underlie CBD. This pathological heterogeneity leads to difficulty in the clinical and pathological diagnosis of both disorders.     

额叶型痴呆的临床和病理

目的　证实一种少见的伴有痴呆的神经系统变性疾病———额叶型痴呆。方法　对 1例因并发肺炎而死亡的 46岁进行性痴呆患者 ,进行脑部剖检 ,经系列的组织染色及PrP ,tau蛋白等免疫组织化学染色。结果　该例患者有 :(1)进行性神经、精神症状 ,病程为 3年 ;(2 )头部CT示双侧额叶灰质萎缩 ,脑电图呈阵发性全导联 ,长间歇期 (>2s)的高波幅慢波 ;(3)脑重 10 5 0g ,脑萎缩仅限于额叶 ,未累及颞叶 ;(4)额叶灰质从第二层开始神经细胞大量脱失伴明显胶质增生 ,而锥体细胞相对完好。Beilschowsky及Gallyas染色无异常发现 ;(5 )神经细胞及胶质细胞内未发现任何包涵体 ;(6 )PrP、tau蛋白免疫组织化学染色呈阴性反应。结论　该病例为典型额叶型痴呆 ,今后在分析伴有痴呆的神经系统变性疾病时 ,应想到此类型痴呆。     

Association of total tau and phosphorylated tau 181 protein levels in cerebrospinal fluid with cerebral atrophy in mild cognitive impairment and Alzheimer disease

Background

We sought to examine the association of levels of total tau (t-tau) and phosphorylated tau 181 (p-tau181) protein with brain morphology in mild cognitive impairment, as defined by the concept of aging-associated cognitive decline (AACD) and Alzheimer disease.

Methods

Twenty-three participants with AACD, 16 with Alzheimer disease and 15 healthy controls underwent magnetic resonance imaging and lumbar puncture. We performed voxel-based morphometry to investigate the association between tau levels in cerebrospinal fluid (CSF) and cerebral grey matter density throughout the entire brain.

Results

Voxel-based morphometry revealed that both elevated t-tau and p-tau181 concentrations were associated with reduced grey matter density in temporal, parietal and frontal regions. Among participants with AACD, elevated levels of p-tau181 (but not t-tau) in CSF were correlated with a pronounced atrophy in the right hippocampus.

Limitations

Our study was limited by the small sample, especially with respect to the analysis comprising the AACD subgroups. Moreover, we did not correct our voxel-based morphometry analyses for multiple dependent comparisons, therefore they harbour a risk of false-positive results.

Conclusion

Elevated levels of t-tau and p-tau181 in CSF reflect degenerative processes in the cortical regions typically affected in Alzheimer disease. Our findings in participants with AACD support the hypothesis that p-tau181 might be more specifically related to neurodegenerative changes in early Alzheimer disease.     

Advances in the development of biomarkers for Alzheimer’s disease: from CSF total tau and Aβ1–42 proteins to phosphorylated tau protein

Advances have been made to establish biological markers of Alzheimer’s disease (AD). Measurement of total tau (t-tau) and beta-amyloid_1–42 (Aβ_1–42) in the cerebrospinal fluid (CSF) seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. New immunoassays to detect different phosphorylated tau epitopes (p-tau) have recently been developed. P-tau phosphorylated at threonine 231 (p-tau₂₃₁) showed improvements compared to t-tau in the early detection of AD in subjects with mild cognitive impairment. As p-tau₂₃₁ declined during the course of AD, it may have potential to track disease progression. Additionally, p-tau₂₃₁ improved differential diagnosis between AD, frontotemporal dementia, and geriatric major depression. P-tau phosphorylated at threonine 181 improved diagnostic accuracy between AD and dementia with Lewy bodies. P-tau phosphorylated at serine 199 demonstrated high discriminative power between AD and non-Alzheimer’s dementia. P-tau phosphorylated at serine 306/serine 404 improved differential diagnosis between AD and vascular dementia. A comparative study of the different p-tau epitopes is currently under way.In summary, first clinical multi-center studies suggest that measurement of phosphorylated tau proteins may significantly improve early and differential diagnosis and may come close to fulfilling proposed criteria of a biological marker for AD.     

The CSF levels of total-tau and phosphotau in patients with relapsing-remitting multiple sclerosis

Summary. Total-tau protein is considered the marker of axon damage whereas the abnormally phosphorylated tau forms are mainly associated with Alzheimer’s disease. An increase in total-tau levels was observed in neurodegenerative diseases, including multiple sclerosis (MS). In order to find out whether the phosphorylated tau forms occur in MS patients and to evaluate their clinical significance, the levels of total-tau (t-tau) and tau phosphorylated at Thr 181 (p-tau) were determined in 60 MS patients (40 during relapse including 18 with the first relapse and 20 stable) and in 18 age-matched controls. The determinations were conducted in the cerebrospinal fluid (CSF) using the ELISA method. The levels of t-tau and p-tau were higher in MS patients than in controls; however, increased levels were not related to the clinical activity of the disease. In CSF of the patients with the first relapse the level of t-tau was significantly increased whilst the level of p-tau was not elevated.     

Chronic traumatic encephalopathy – neuropathology in athletes and war veterans

Abstract

Objective: The neuropathologic findings of chronic traumatic encephalopathy (CTE) were first described almost 40 years after the first clinical reports. We reviewed the literature and describe the neuropathological findings seen primarily in professional athletes and more recently, in war veterans.

Methods: We reviewed the literature of CTE concentrating on references that focused on the correlation of clinical findings with the neuropathologic changes. The pathobiology and proposed mechanisms of injury are described. Diagnostic modalities and various diagnostic criteria of CTE are reviewed.

Results: We are beginning to understand the neuropathologic basis of CTE, which appears to be a consequence of repetitive mild brain injuries. There appear to be reproducible criteria for the post-mortem diagnosis of CTE and the neuropathologic findings are becoming more widely accepted. More research is required to elucidate the risk factors that predispose athletes and war veterans to CTE. There is also a need for more diagnostic markers and a method to assess CTE in patients prior to death. The neuropathologic findings of a progressive tauopathy including the presence of numerous neurofibrillary tangles (NFTs), rare neuritic plaques, and widespread expression of TDP-43 (transactive response [TAR] DNA binding protein 43) also require further study.

Discussion: The potential prevalence of CTE, as well as the vulnerable populations involved, makes research into this topic crucial. Currently, a comprehensive neurological exam, neuropsychiatric assessment, and standard radiographic techniques such as conventional MRI are the mainstay of diagnosis. There is a pressing need for the prevention of CTE and the development of non-invasive diagnostic tests in order to develop therapies that may be of clinical use to athletes and blast injury veterans during their lifetimes.     

Advances in the development of biomarkers for Alzheimer's disease: from CSF total tau and Abeta(1-42) proteins to phosphorylated tau protein

Advances have been made to establish biological markers of Alzheimer's disease (AD). Measurement of total tau (t-tau) and beta-amyloid(1-42) (Abeta(1-42)) in the cerebrospinal fluid (CSF) seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. New immunoassays to detect different phosphorylated tau epitopes (p-tau) have recently been developed. P-tau phosphorylated at threonine 231 (p-tau(231)) showed improvements compared to t-tau in the early detection of AD in subjects with mild cognitive impairment. As p-tau(231) declined during the course of AD, it may have potential to track disease progression. Additionally, p-tau(231) improved differential diagnosis between AD, frontotemporal dementia, and geriatric major depression. P-tau phosphorylated at threonine 181 improved diagnostic accuracy between AD and dementia with Lewy bodies. P-tau phosphorylated at serine 199 demonstrated high discriminative power between AD and non-Alzheimer's dementia. P-tau phosphorylated at serine 306/serine 404 improved differential diagnosis between AD and vascular dementia. A comparative study of the different p-tau epitopes is currently under way.In summary, first clinical multi-center studies suggest that measurement of phosphorylated tau proteins may significantly improve early and differential diagnosis and may come close to fulfilling proposed criteria of a biological marker for AD.     

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β₄₂ (Aβ₄₂), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD.MethodsWe retrospectively analyzed concentrations of MHPG, Aβ₄₂, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters.ResultsThe currently used combination of Aβ₄₂, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia.ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.     

Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.     

Neuroimaging Biomarkers of Chronic Traumatic Encephalopathy: Targets for the Academic Memory Disorders Clinic

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, such as those from contact sports. The pathognomonic lesion for CTE is the perivascular accumulation of hyper-phosphorylated tau in neurons and other cell process at the depths of sulci. CTE cannot be diagnosed during life at this time, limiting research on risk factors, mechanisms, epidemiology, and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders. Neuroimaging is an integral component of the clinical evaluation of neurodegenerative diseases and will likely aid in diagnosing CTE during life. In this qualitative review, we present the current evidence on neuroimaging biomarkers for CTE with a focus on molecular, structural, and functional modalities routinely used as part of a dementia evaluation. Supporting imaging-pathological correlation studies are also presented. We targeted neuroimaging studies of living participants at high risk for CTE (e.g., aging former elite American football players, fighters). We conclude that an optimal tau PET radiotracer with high affinity for the 3R/4R neurofibrillary tangles in CTE has not yet been identified. Amyloid PET scans have tended to be negative. Converging structural and functional imaging evidence together with neuropathological evidence show frontotemporal and medial temporal lobe neurodegeneration, and increased likelihood for a cavum septum pellucidum. The literature offers promising neuroimaging biomarker targets of CTE, but it is limited by cross-sectional studies of small samples where the presence of underlying CTE is unknown. Imaging-pathological correlation studies will be important for the development and validation of neuroimaging biomarkers of CTE.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01028-3.Key Words: Chronic traumatic encephalopathy, Biomarkers, Neuroimaging, Atrophy, MRI, Traumatic brain injury, Neurodegenerative disease     

Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer's disease

The microtubule-associated protein tau, a major antigenic component of paired helical filaments, has been demonstrated in neurofibrillary tangles and in neurites of senile plaques. With optimal fixation and histochemical methods, we show the normal axonal location of tau protein in human cerebral cortex and the striking alterations of tau distribution that affect the cortical neuropil in Alzheimer's disease. Normally, cortical tau-immunoreactive fiber bundles form a pattern resembling that seen with myelin stains. The prominence of white matter staining suggests that tau may be especially enriched in projection systems. Alzheimer's disease causes massive axonal disruption and the dislocation of tau protein from its usual axonal domain into neuronal cell bodies, dendrites, and presynaptic regions. The normal pattern of axonal staining in cortex is disrupted and white matter staining is reduced. Prominent abnormal tau-immunoreactive neuropil fibers are densely present even in cortical regions without classical neurofibrillary tangle and senile plaque formation. The striking neuropil abnormalities, revealed by the aberrant localization of tau protein, are likely to contribute to neuronal dysfunction in Alzheimer's disease.     

Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease

BackgroundIn the earliest clinical stages of Alzheimer’s disease (AD) when symptoms are mild, clinical diagnosis can be difficult. AD pathology most likely precedes symptoms. Biomarkers can serve as early diagnostic indicators or as markers of preclinical pathologic change. Candidate biomarkers derived from structural and functional neuroimaging and those measured in cerebrospinal fluid (CSF) and plasma show the greatest promise. Unbiased exploratory approaches, eg, proteomics or cortical thickness analysis, could yield novel biomarkers. The objective of this article was to review recent progress in selected imaging and neurochemical biomarkers for early diagnosis, classification, progression, and prediction of AD.MethodsWe performed a survey of recent research, focusing on core biomarker candidates in AD.ResultsA number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy, hold promise as biomarkers. These neurobiologic measures appear to relate closely to pathophysiologic, neuropathologic, and clinical data, such as hyperphosphorylation of tau, amyloid beta (Aβ) metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. Current advances in the neuroimaging of mediotemporal, neocortical, and subcortical areas of the brain of mild cognitive impairment (MCI) and AD subjects are presented. CSF levels of Aβ42, tau, and hyperphosphorylated tau protein (p-tau) can distinguish subjects with MCI who are likely to progress to AD. They also show preclinical alterations that predict later development of early AD symptoms. Studies on plasma Aβ are not entirely consistent, but recent findings suggest that decreased plasma Aβ42 relative to Aβ40 might increase the risk of AD. Increased production of Aβ in aging is suggested by elevation of BACE1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and p-tau are increased in MCI as well and show predictive value. Other biomarkers might indicate components of a cascade initiated by Aβ, such as oxidative stress or inflammation. These merit further study in MCI and earlier.ConclusionsA number of neuroimaging candidate markers are promising, such as hippocampus and entorhinal cortex volumes, basal forebrain nuclei, cortical thickness, deformation-based and voxel-based morphometry, structural and effective connectivity by using diffusion tensor imaging, tractography, and functional magnetic resonance imaging. CSF Aβ42, BACE1, total tau, and p-tau are substantially altered in MCI and clinical AD. Other interesting novel marker candidates derived from blood are being currently proposed (phase I). Biomarker discovery through proteomic approaches requires further research. Large-scale international controlled multicenter trials (such as the U.S., European, Australian, and Japanese Alzheimer’s Disease Neuroimaging Initiative and the German Dementia Network) are engaged in phase III development of the core feasible imaging and CSF biomarker candidates in AD. Biomarkers are in the process of implementation as primary outcome variables into regulatory guideline documents regarding study design and approval for compounds claiming disease modification.     

Epidemiology of mild traumatic brain injury and neurodegenerative disease

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.     

Tau protein aggregation in the frontal and entorhinal cortices as a function of aging

OBJECTIVES: The abnormal accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementing illness in which frontotemporal lobar degeneration occurs. In this paper we examined the age-dependant deposition of tau protein in the frontal and entorhinal neocortices. METHODS: We examined autopsy records from 1997 to 2002 and selected 87 cases (10 in each decade from 0 to 79 years of age, 7 in 80-89 decade) with no history of dementia or other neurodegenerative diseases, and for which neurodegenerative diseases were excluded neuropathologically. Archival paraffin-embedded frontal and entorhinal cortices were examined by both Gallyas-Braak silver staining and a panel of antibodies recognizing tau protein accumulation. RESULTS: Tau neuronal aggregates were observed in both frontal and entorhinal cortices in the third decade. While the frontal neuronal tau aggregates remained infrequent in the remaining decades, the number and extent ofneuronal tau aggregates in the entorhinal cortex increased such that by the 7th decade the majority of cases showed extensive tau aggregate formation. The most consistent morphological observation was of dense, perikaryal neuronal tau-immunoreactive aggregates, similar to the total tau distribution, firstly presenting in cortical layers II and III and subsequently involving in layers IV-VI. Neuropil threads became maximal in the 9th decade in both frontal and entorhinal cortices. Astrocytic tau accumulation was first observed in both frontal and entorhinal cortices in the 6th decade, predominantly in layer I and subcortical white matter, and increased in number with aging. Extraneuronal tau reactive aggregates and coiled bodies were rarely observed in the entorhinal cortex, and when present, were scattered through layer II to VI. CONCLUSIONS: We have observed an age-dependant pattern of neuronal, extraneuronal and glial tau protein accumulation in the entorhinal cortex in individuals without neurodegenerative diseases. In contrast, tau protein aggregation is infrequently observed in the frontal cortex as a function of aging.