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Article ; Online: Changes in Brain Structure and Function in a Multisport Cohort of Retired Female and Male Athletes, Many Years after Suffering a Concussion: Implications for Neuroplasticity and Neurodegenerative Disease Pathogenesis.

Turner, Michael / Belli, Antonio / Castellani, Rudolph J

Journal of Alzheimer's disease reports

2024 Volume 8, Issue 1, Page(s) 501–516

Abstract: Background: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic ... ...

Abstract	Background: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Objective: Compare regional brain volume and connectivity between athletes with a history of concussion and controls. Methods: We evaluated whole-brain volumetric effects with Bayesian regression models and functional connectivity with network-based statistics, in 125 retired athletes (a mean of 11 reported concussions) and 36 matched controls. Results: Brain regions significantly lower in volume in the concussed group included the middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger included the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial postcentral gyrus. Functional connectivity analyses revealed increased edge strength, most marked in motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with concussion. Aligned to meta-analytic neuroimaging data, the observed changes suggest functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language. Conclusions: These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury. Future studies with longitudinal cohorts including autopsy examination are needed to determine whether the latter reflects tissue loss from brain shearing, or the onset of a progressive Alzheimer's disease like proteinopathy.
Language	English
Publishing date	2024-03-19
Publishing country	Netherlands
Document type	Journal Article
ISSN	2542-4823
ISSN (online)	2542-4823
DOI	10.3233/ADR-240021
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Article ; Online: Applying the Consensus Criteria for Traumatic Encephalopathy Syndrome Retrospectively to Case Studies of Boxers from the 20th Century.

Iverson, Grant L / Gardner, Andrew J / Castellani, Rudolph J / Kissinger-Knox, Alicia

Neurotrauma reports

2024 Volume 5, Issue 1, Page(s) 337–347

Abstract: There are no validated diagnostic criteria for traumatic encephalopathy syndrome (TES). During the early and middle 20th century, TES was described as a clinical condition that was experienced by some high-exposure boxers-and it was believed to reflect ... ...

Abstract	There are no validated diagnostic criteria for traumatic encephalopathy syndrome (TES). During the early and middle 20th century, TES was described as a clinical condition that was experienced by some high-exposure boxers-and it was believed to reflect chronic traumatic brain injury. Consensus criteria for the diagnosis of TES were published in 2021. We applied the consensus criteria for TES retrospectively to cases of chronic brain damage in boxers described in articles published in the 20th century that were obtained from narrative and systematic reviews. The sample included 157 boxers identified in 21 articles published between 1929 and 1999. Two authors reviewed each case description and coded the criteria for TES. For the core clinical features, cognitive impairment was noted in 63.1%, and in 28.7% of cases the person's cognitive functioning appeared to be broadly normal. Neurobehavioral dysregulation was present in 25.5%. One third (34.4%) were identified as progressive, 30.6% were not progressive, and the course could not be clearly determined in 35.0%. In total, 29.9% met the TES consensus criteria, 28.0% did not, and 42.0% had insufficient information to make a diagnostic determination. TES, in the 20th century, was described as a neurological condition, not a psychiatric disorder-and this supports the decision of the 2021 consensus group to remove primary and secondary psychiatric diagnoses from being a core diagnostic feature. Future research is needed to determine whether, or the extent to which, cognitive impairment or neurobehavioral dysregulation described as characterizing TES are associated with chronic traumatic encephalopathy neuropathological change.
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Journal Article
ISSN	2689-288X
ISSN (online)	2689-288X
DOI	10.1089/neur.2023.0134
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Article: A narrative review of psychiatric features of traumatic encephalopathy syndrome as conceptualized in the 20th century.

Iverson, Grant L / Kissinger-Knox, Alicia / Huebschmann, Nathan A / Castellani, Rudolph J / Gardner, Andrew J

Frontiers in neurology

2023 Volume 14, Page(s) 1214814

Abstract: Introduction: Some ultra-high exposure boxers from the 20th century suffered from neurological problems characterized by slurred speech, personality changes (e.g., childishness or aggressiveness), and frank gait and coordination problems, with some ... ...

Abstract	Introduction: Some ultra-high exposure boxers from the 20th century suffered from neurological problems characterized by slurred speech, personality changes (e.g., childishness or aggressiveness), and frank gait and coordination problems, with some noted to have progressive Parkinsonian-like signs. Varying degrees of cognitive impairment were also described, with some experiencing moderate to severe dementia. The onset of the neurological problems often began while they were young men and still actively fighting. More recently, traumatic encephalopathy syndrome (TES) has been proposed to be present in athletes who have a history of contact (e.g., soccer) and collision sport participation (e.g., American-style football). The characterization of TES has incorporated a much broader description than the neurological problems described in boxers from the 20th century. Some have considered TES to include depression, suicidality, anxiety, and substance abuse. Purpose: We carefully re-examined the published clinical literature of boxing cases from the 20th century to determine whether there is evidence to support conceptualizing psychiatric problems as being diagnostic clinical features of TES. Methods: We reviewed clinical descriptions from 155 current and former boxers described in 21 articles published between 1928 and 1999. Results: More than one third of cases (34.8%) had a psychiatric, neuropsychiatric, or neurobehavioral problem described in their case histories. However, only 6.5% of the cases were described as primarily psychiatric or neuropsychiatric in nature. The percentages documented as having specific psychiatric problems were as follows: depression = 11.0%, suicidality = 0.6%, anxiety = 3.9%, anger control problems = 20.0%, paranoia/suspiciousness = 11.6%, and personality change = 25.2%. Discussion: We conclude that depression, suicidality (i.e., suicidal ideation, intent, or planning), and anxiety were not considered to be clinical features of TES during the 20th century. The present review supports the decision of the consensus group to remove mood and anxiety disorders, and suicidality, from the new 2021 consensus core diagnostic criteria for TES. More research is needed to determine if anger dyscontrol is a core feature of TES with a clear clinicopathological association. The present findings, combined with a recently published large clinicopathological association study, suggest that mood and anxiety disorders are not characteristic of TES and they are not associated with chronic traumatic encephalopathy neuropathologic change.
Language	English
Publishing date	2023-07-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2023.1214814
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Article ; Online: Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

Høilund-Carlsen, Poul F / Alavi, Abass / Castellani, Rudolph J / Neve, Rachael L / Perry, George / Revheim, Mona-Elisabeth / Barrio, Jorge R

International journal of molecular sciences

2024 Volume 25, Issue 7

Abstract: The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, ... ...

Abstract	The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.
MeSH term(s)	United States ; Humans ; Alzheimer Disease/therapy ; Ice Cover ; Amyloidogenic Proteins ; Radioimmunotherapy ; Antibodies, Monoclonal, Humanized
Chemical Substances	donanemab ; Amyloidogenic Proteins ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2024-03-31
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25073892
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Article ; Online: Authors' Reply: Age-Related Tau Aggregates Resemble Chronic Traumatic Encephalopathy Neuropathologic Change.

Iverson, Grant L / Luoto, Teemu M / Castellani, Rudolph J

Journal of neuropathology and experimental neurology

2020 Volume 79, Issue 8, Page(s) 924–928

MeSH term(s)	Chronic Traumatic Encephalopathy ; Humans ; Neurofibrillary Tangles ; Neuropathology
Language	English
Publishing date	2020-07-17
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlaa047.001
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Article ; Online: An unusual blunt force trauma pattern and mechanism to the cranial vault: Investigation of an atypical infant homicide.

Isaac, Carolyn V / Cornelison, Jered B / Devota, Clara J / Shattuck, Brandy L / Castellani, Rudolph J

Journal of forensic sciences

2022 Volume 68, Issue 1, Page(s) 315–326

Abstract: This case report presents an unusual fracture pattern in the cranium of a four-month-old infant indicative of child abuse. Upon postmortem examination, the infant presented with numerous bilateral linear cranial fractures running perpendicular to the ... ...

Abstract	This case report presents an unusual fracture pattern in the cranium of a four-month-old infant indicative of child abuse. Upon postmortem examination, the infant presented with numerous bilateral linear cranial fractures running perpendicular to the sagittal suture with depressed and curvilinear fractures apparent on the supra-auricular surfaces of the cranium. Histological evidence indicates multiple traumatic events to the cranium. In addition, the stair-step pattern of a parietal fracture may represent multiple contiguous fractures from repeated loading of the head at different times with variation of the focal points of compressive force. Additionally, the left humerus, left radius, and left ulna have healing metaphyseal fractures, and the left ulna also has an antemortem diaphyseal fracture which resulted in the distal metaphysis being rotated 45 degrees medially. Integration of autopsy, anthropological, and neuropathological reports for this case suggest multiple inflicted injury episodes with a repeated atypical mechanism(s) to the cranial vault of the infant. During investigative interviews, the caretaker admitted to squeezing the infant's head and neck on multiple occasions to quiet the child. This reported abusive mechanism is consistent with the pattern of symmetric cranial fractures and soft tissue injuries indicating asphyxiation. This case report provides forensic investigators with a potential trauma mechanism to explore in cases when a similar pattern of cranial trauma is observed and highlights the need for greater research on fracture propagation and fracture healing in the infant cranium.
MeSH term(s)	Child ; Humans ; Infant ; Skull Fractures/pathology ; Homicide ; Child Abuse/diagnosis ; Forensic Medicine/methods ; Wounds, Nonpenetrating/pathology ; Fractures, Multiple ; Skull/pathology
Language	English
Publishing date	2022-11-04
Publishing country	United States
Document type	Case Reports
ZDB-ID	219216-0
ISSN	1556-4029 ; 0022-1198
ISSN (online)	1556-4029
ISSN	0022-1198
DOI	10.1111/1556-4029.15168
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Article: FDG-PET versus Amyloid-PET Imaging for Diagnosis and Response Evaluation in Alzheimer's Disease: Benefits and Pitfalls.

Høilund-Carlsen, Poul F / Revheim, Mona-Elisabeth / Costa, Tommaso / Kepp, Kasper P / Castellani, Rudolph J / Perry, George / Alavi, Abass / Barrio, Jorge R

Diagnostics (Basel, Switzerland)

2023 Volume 13, Issue 13

Abstract: In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed ...

Abstract	In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed by amyloid-PET and, in the case of lecanemab, also a presumption of limited clinical efficacy. Approval of the antibody donanemab is awaiting further data. However, published trial data indicate few, small and uncertain clinical benefits, below what is considered "clinically meaningful" and similar to the effect of conventional medication. Furthermore, a therapy-related decrease in the amyloid-PET signal may also reflect increased cell damage rather than simply "amyloid removal". This interpretation is more consistent with increased rates of amyloid-related imaging abnormalities and brain volume loss in treated patients, relative to placebo. We also challenge the current diagnostic criteria for AD based on amyloid-PET imaging biomarkers and recommend that future anti-AD therapy trials apply: (1) diagnosis of AD based on the co-occurrence of cognitive decline and decreased cerebral metabolism assessed by FDA-approved FDG-PET, (2) therapy efficacy determined by favorable effect on cognitive ability, cerebral metabolism by FDG-PET, and brain volumes by MRI, and (3) neuropathologic examination of all deaths occurring in these trials.
Language	English
Publishing date	2023-07-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13132254
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Article ; Online: Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report.

Castellani, Rudolph J / Shanes, Elisheva D / McCord, Matthew / Reish, Nicholas J / Flanagan, Margaret E / Mesulam, M-Marsel / Jamshidi, Pouya

Journal of Alzheimer's disease : JAD

2023 Volume 93, Issue 2, Page(s) 803–813

Abstract: Host responses to anti-amyloid-β (Aβ) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not ... ...

Abstract	Host responses to anti-amyloid-β (Aβ) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aβ clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aβ drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aβ were present throughout the cerebral cortex. Phagocytosis of parenchymal Aβ plaques was noted. Changes suggestive of Aβ and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aβ treatment stimulated a host response to Aβ, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aβ phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.
MeSH term(s)	Female ; Humans ; Aged ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/therapy ; Tissue Plasminogen Activator ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/diagnostic imaging ; Cerebral Amyloid Angiopathy/therapy ; Cerebral Amyloid Angiopathy/etiology ; Brain/pathology ; Immunotherapy/adverse effects
Chemical Substances	Tissue Plasminogen Activator (EC 3.4.21.68) ; Amyloid beta-Peptides
Language	English
Publishing date	2023-04-26
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-221305
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Article ; Online: Pseudo-Central Pontine Myelinolysis.

Rumschlag, Matthew / Prahlow, Joseph A / Castellani, Rudolph J / Fisher-Hubbard, Amanda O

The American journal of forensic medicine and pathology

2021 Volume 43, Issue 2, Page(s) 195–198

Abstract: Abstract: Central pontine myelinolysis is most commonly associated with rapid correction of hyponatremia and has historically been associated with alcoholism. In this case report, 2 deaths with gross findings of central pontine lesions led to the ... ...

Abstract	Abstract: Central pontine myelinolysis is most commonly associated with rapid correction of hyponatremia and has historically been associated with alcoholism. In this case report, 2 deaths with gross findings of central pontine lesions led to the possibility that CPM may have been a potential mechanism of death. Subsequent analysis revealed that these lesions were incidental findings. This case report discusses the importance of appropriate microscopic and immunohistochemical analysis of suspected CPM cases.
MeSH term(s)	Alcoholism/complications ; Alcoholism/pathology ; Humans ; Hyponatremia/complications ; Hyponatremia/pathology ; Magnetic Resonance Imaging/adverse effects ; Myelinolysis, Central Pontine/complications ; Myelinolysis, Central Pontine/pathology ; Pons/pathology
Language	English
Publishing date	2021-12-14
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	604537-6
ISSN	1533-404X ; 0195-7910
ISSN (online)	1533-404X
ISSN	0195-7910
DOI	10.1097/PAF.0000000000000731
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Article: Examining for Cavum Septum Pellucidum and Ventricular Enlargement in Retired Elite-Level Rugby League Players.

Stanwell, Peter / Iverson, Grant L / Van Patten, Ryan / Castellani, Rudolph J / McCrory, Paul / Gardner, Andrew J

Frontiers in neurology

2022 Volume 13, Page(s) 817709

Abstract: Objective: A cavum septum pellucidum (CSP) has been reported as a visible brain anomaly in normal individuals as well in some former combat and collision sport athletes. The appearance of CSP with fenestrations and ventricular enlargement are considered ...

Abstract	Objective: A cavum septum pellucidum (CSP) has been reported as a visible brain anomaly in normal individuals as well in some former combat and collision sport athletes. The appearance of CSP with fenestrations and ventricular enlargement are considered associated features of the neuropathological diagnosis of chronic traumatic encephalopathy. The current study examined CSP anatomic features and lateral ventricle size in retired elite rugby league players and controls. Methods: Forty-one retired rugby league players and 41 healthy community controls, similar in age and education, underwent structural MRI scans. CSP grade, CSP length, corpus callosum septal length, and Evans' ratio (for lateral ventricle size) were rated by two of the current study authors. All participants also self-reported concussion exposure histories, depressive symptoms, daytime sleepiness, and impulsivity. They completed a neuropsychological test battery assessing premorbid intellectual functioning, attention, processing speed, language, visuospatial skills, memory, and aspects of executive functioning. Results: The two raters had high agreement for CSP grade (Cohen's κ = 0.80), CSP length [intraclass correlation (ICC) = 0.99], corpus callosum septal length (ICC = 0.73), the CSP/septal ratio (ICC = 0.99), and the Evans' ratio (ICC = 0.75). Twenty-five retired players (61.0%) had an abnormal CSP compared to 17 controls [41.5%; Conclusion: This study revealed a difference in the size of the CSP between retired professional rugby league players and controls. There was no significant difference in the size of the ventricles between the two groups. There were no significant differences between those with vs. without an abnormal CSP on age of first exposure to rugby league, years of exposure to repetitive neurotrauma, number of lifetime concussions, depression, impulsivity, perceived cognitive decline, or on any neuropsychological test.
Language	English
Publishing date	2022-04-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2022.817709
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