Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Abstract Background and Scope of Review Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aβ-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aβ-PET, and tau-PET in addition to comprehensive clinical examinations before death. Review Conclusions Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual’s head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer’s disease).

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The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature

Seminars in Neurology ◽

10.1055/s-0040-1713632 ◽

2020 ◽

Vol 40 (04) ◽

pp. 359-369

Author(s):

Ann C. McKee

Keyword(s):

White Matter ◽

Head Trauma ◽

Chronic Traumatic Encephalopathy ◽

The Elderly ◽

Brain Regions ◽

American Football ◽

Cumulative Exposure ◽

Football Players ◽

Tau Pathology ◽

The Status

AbstractChronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head trauma, including concussion and asymptomatic subconcussive impacts. CTE was first recognized in boxers almost a century ago and has been identified more recently in contact sports athletes, military veterans exposed to blast, and victims of domestic violence. Like most neurodegenerative diseases, CTE is diagnosed conclusively by a neuropathological examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs), neurites, and, sometimes, astrocytes, surrounding small blood vessels in a patchy distribution at the sulcal depths of the cerebral cortex. In 2015, using the McKee proposed criteria for the neuropathological diagnosis of CTE, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic lesion and published the preliminary NINDS (National Institute of Neurological Disorders and Stroke) criteria for CTE. Since that time, the NINDS criteria for CTE have been implemented and validated in multiple international publications. Using the NINDS criteria, the largest clinicopathological series of CTE to date was reported that included 177 former American football players, including 110 (99%) of 111 former National Football League players, 48 (91%) of 53 former college football players, and 3 (21%) of 14 former high school players. Studies have also shown a significant association between cumulative exposure to repetitive head trauma, as judged by the length of American football playing career, and risk for and severity of CTE. There is also a significant relationship of the length of football playing career with p-tau pathology, inflammation, white matter rarefaction, and age at death in CTE. While p-tau pathology, inflammation, white matter rarefaction, and arteriolosclerosis contribute to dementia in CTE, whether they also influence the behavioral and mood symptoms in CTE has yet to be determined. There have been several instances of aging-related tau astrogliopathy (ARTAG), a common astrocytic pathology in the elderly, misdiagnosed as CTE in the recent literature, provoking claims that CTE pathology is present in people not known to have experienced repetitive head trauma. Although ARTAG is often found in CTE, the pathognomonic lesion of CTE is a neuronal lesion consisting of NFTs and neurites, with or without p-tau immunoreactive astrocytes. Some authors consider β-amyloid (Aβ) to be a primary feature of CTE, yet the data indicate that CTE is a primary tauopathy, with Aβ deposition a function of age and inheritance of the ApoEe4 allele. Some authors also question the progressive nature of CTE pathology, although there is clear evidence in most individuals that p-tau pathology increases in density and affects more brain regions with survival. This review is intended to outline the status of the evidence-based literature regarding CTE neuropathology and to address the misrepresentations and confusions that have arisen in recent reviews and a letter of correspondence.

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In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1409952112 ◽

2015 ◽

Vol 112 (16) ◽

pp. E2039-E2047 ◽

Cited By ~ 111

Author(s):

Jorge R. Barrio ◽

Gary W. Small ◽

Koon-Pong Wong ◽

Sung-Cheng Huang ◽

Jie Liu ◽

...

Keyword(s):

Pet Imaging ◽

Medial Temporal Lobe ◽

Chronic Traumatic Encephalopathy ◽

Amyloid Β ◽

American Football ◽

Subcortical Structures ◽

Imaging Results ◽

History Of ◽

In Vivo Characterization

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer’s dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

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Cerebrospinal fluid dynamics disorders

Neurology ◽

10.1212/wnl.0000000000008616 ◽

2019 ◽

Vol 93 (24) ◽

pp. e2237-e2246 ◽

Cited By ~ 3

Author(s):

Jonathan Graff-Radford ◽

Jeffrey L. Gunter ◽

David T. Jones ◽

Scott A. Przybelski ◽

Christopher G. Schwarz ◽

...

Keyword(s):

Pet Imaging ◽

Learning Algorithm ◽

Standard Uptake Value ◽

Structural Mri ◽

Population Based ◽

Cognitive Status ◽

Amyloid Pet ◽

Domain Specific ◽

Tau Pet ◽

Age And Sex

ObjectiveTo determine the frequency of high-convexity tight sulci (HCTS) in a population-based sample and whether the presence of HCTS and related features influenced participants' cognitive status and classification within the new Alzheimer-biomarker framework.MethodsWe analyzed 684 participants ≥50 years of age who were enrolled in the prospective population-based Mayo Clinic Study of Aging and underwent structural MRI, amyloid PET imaging, and tau PET imaging. A fully automated machine-learning algorithm that had been developed previously in house was used to detect neuroimaging features of HCTS. On the basis of PET and MRI measures, participants were classified as having normal (A−) or abnormal (A+) amyloid, normal (T−) or abnormal (T+) tau, and normal (N−) or abnormal (N+) neurodegeneration. The neuropsychological battery assessed domain-specific and global cognitive scores. Gait speed also was assessed. Analyses were adjusted for age and sex.ResultsOf 684 participants, 45 (6.6%) were classified with HCTS according to the automated algorithm. Patients with HCTS were older than patients without HCTS (mean [SD] 78.0 [8.3] vs 71.9 [10.8] years; p < 0.001). More were cognitively impaired after age and sex adjustment (27% vs 9%; p = 0.005). Amyloid PET status was similar with and without HCTS, but tau PET standard uptake value ratio (SUVR) was lower for those with HCTS after age and sex adjustment (p < 0.001). Despite a lower tau SUVR, patients with HCTS had lower Alzheimer disease (AD) signature cortical thickness. With the amyloid-tau-neurodegeneration framework, HCTS was overrepresented in the T−(N)+ group, regardless of amyloid status.ConclusionThe HCTS pattern represents a definable subgroup of non-AD pathophysiology (i.e., T−[N]+) that is associated with cognitive impairment. HCTS may confound clinical and biomarker interpretation in AD clinical trials.

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Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?

Frontiers in Neurology ◽

10.3389/fneur.2018.00483 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Leonie Beyer ◽

Johanna Meyer-Wilmes ◽

Sonja Schönecker ◽

Jonas Schnabel ◽

Eva Brendel ◽

...

Keyword(s):

Progressive Supranuclear Palsy ◽

Pet Imaging ◽

Fdg Pet ◽

Corticobasal Degeneration ◽

Clinical Routine ◽

Tau Pet ◽

Tau Pet Imaging

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Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-04788-w ◽

2020 ◽

Vol 47 (12) ◽

pp. 2911-2922 ◽

Cited By ~ 4

Author(s):

Leonie Beyer ◽

Alexander Nitschmann ◽

Henryk Barthel ◽

Thilo van Eimeren ◽

Marcus Unterrainer ◽

...

Keyword(s):

Parkinson’S Disease ◽

Pet Imaging ◽

Fdg Pet ◽

Early Phase ◽

Correlation Coefficients ◽

Neuronal Injury ◽

Phase Images ◽

Tau Pet ◽

Global Mean ◽

Tau Pet Imaging

Abstract Purpose Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). Methods Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0–60 min p.i.) and static [18F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. Results Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. Conclusion Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

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Tau-negative amnestic dementia masquerading as Alzheimer disease dementia

Neurology ◽

10.1212/wnl.0000000000005124 ◽

2018 ◽

Vol 90 (11) ◽

pp. e940-e946 ◽

Cited By ~ 12

Author(s):

Hugo Botha ◽

William G. Mantyh ◽

Jonathan Graff-Radford ◽

Mary M. Machulda ◽

Scott A. Przybelski ◽

...

Keyword(s):

Alzheimer Disease ◽

Pet Imaging ◽

Standardized Uptake Value ◽

Structural Mri ◽

Hippocampal Volume ◽

Neuropsychological Battery ◽

Molecular Biomarker ◽

Disease Modifying Therapy ◽

Primary Driver ◽

Tau Pet

ObjectiveTo describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.MethodsEight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.ResultsAll participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33).ConclusionsThe participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.

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Perfusion-Phase 18 F-PI-2620 Tau-PET Imaging as a Surrogate Marker of Neuronal Injury

10.1055/s-0040-1708352 ◽

2020 ◽

Author(s):

L Beyer ◽

A Nitschmann ◽

H Barthel ◽

T van Eimeren ◽

M Unterrainer ◽

...

Keyword(s):

Pet Imaging ◽

Surrogate Marker ◽

Neuronal Injury ◽

Tau Pet ◽

Tau Pet Imaging

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Crossed Cerebellar Diaschisis in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205015666180913102615 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1267-1275 ◽

Cited By ~ 1

Author(s):

F.E. Reesink ◽

D. Vállez García ◽

C.A. Sánchez-Catasús ◽

D.E. Peretti ◽

A.T. Willemsen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Left Hemisphere ◽

Pet Imaging ◽

Fdg Pet ◽

Pathophysiological Mechanism ◽

Crossed Cerebellar Diaschisis ◽

Amyloid Accumulation ◽

Cerebellar Diaschisis ◽

18F Fdg

Background: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer’s disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. Methods: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. Results: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. Conclusion: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

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