(years)
M =48 male; F = female
Clinical Manifestations
x = Clinical feature was noted as present; blank = clinical feature was not mentioned
Five football players, including our Case 1, had neuropathologically verified CTE at autopsy. All died suddenly in middle age (age at death, range 36–50 years, M = 44.0 years, SD = 5.0) and were younger at the time of death compared to boxers with CTE (boxers age at death, range: 23–91 years, M = 60.0 years, SD = 15.2). The duration of symptomatic illness was also shorter in the football players (range 3–10 years, M = 6.0 years, SD = 2.9) compared to the boxers (range 5–46 years, M = 20.6 years, SD = 12.3). All 5 football players played similar positions: 3 were offensive lineman, one was a defensive lineman and the other was a linebacker. In the football players, the most common symptoms were mood disorder (mainly depression), memory loss, paranoia, and poor insight or judgment (each found in 80%), outbursts of anger or aggression, irritability, and apathy (each found in 60%), confusion, reduced concentration, agitation, or hyperreligiosity (each found in 40%). Furthermore, 4 of the 5 experienced tragic deaths, i.e. 2 from suicide ( 16 , 17 ), 1 during a high-speed police chase ( 40 ), and another from an accidental gunshot while cleaning his gun (Case 1). Case 1 exemplifies these clinical features.
A 45-year-old right-handed Caucasian man died unexpectedly as a result of an accidental gunshot wound to the chest while he was cleaning a gun. He was a retired professional football player who played football in high school, 3 years of college and 10 years in the NFL as a linebacker. According to his wife, he was concussed 3 times during his college football years and at least 8 times during his NFL career; however, only 1 concussion was medically confirmed. He was never formally diagnosed with post-concussive syndrome and never sought medical attention for residual cognitive or behavioral difficulties. There was no history of ever losing consciousness for more than a few seconds and he never required being carried off the field or hospitalization.
At age 40, his family began to notice minor impairments in his short-term memory, attention, concentration, organization, planning, problem solving, judgment, and ability to juggle more than one task at one time. His spatial abilities were mildly impaired and his language was unaffected. He repeatedly asked the same questions over and over, he did not recall why he went to the store unless he had a list, and he would ask to rent a movie that he had already seen. These symptoms gradually increased and became pronounced by the end of his life 5 years later. Using a modification of the Family Version of the Cognitive Difficulties Scale ( 43 , 44 ) he had a moderate amount of cognitive difficulties. On a modified AD8 informant interview for dementia, he received a total score of 4, which indicated “cognitive impairment is likely to be present.” ( 45 ). By contrast, the Functional Activities Questionnaire (FAQ) ( 46 ), an informant-based measure of Instrumental Activities of Daily Living, did not indicate significant functional dependence despite his difficulty assembling tax records, shopping alone, and understanding television (total FAQ = 3). Moreover, he continued to perform his job as a hunting and fishing guide in a satisfactory manner.
Towards the end of his life, he tended to become angry and verbally aggressive over insignificant issues and was more emotionally labile. He also began to consume more alcohol but did not show other signs or symptoms of depression. He had no significant psychiatric history and he had never taken performance-enhancing or illicit drugs. His family history was negative for dementia and psychiatric illness.
Boxing is the most frequent sport associated with CTE and disease duration is the longest in boxers, with case reports of individuals living for 33, 34, 38, 41 and 46 years with smoldering, yet symptomatic disease ( 29 ). Boxers with long-standing CTE are frequently demented (46%) and may be misdiagnosed clinically as AD ( 47 ), as occurred in Cases 2 and 3.
An 80-year-old African-American/American Indian man was first noted to have difficulty remembering things in his mid-twenties. He began boxing when he was 17, quickly rose to professional ranks and fought professionally for 5 years until he retired at age 22. He suffered a mild head injury in his early teenage years while moving farm equipment although he did not lose consciousness or suffer any permanent disability. By his mid-thirties he had brief, occasional episodes of confusion and a tendency to fall. His wife attributed his occasional forgetfulness, falls and confusion to being mildly “punch-drunk.” His symptoms remained more or less stable over the following 4 decades except for an increased tendency to become disoriented when traveling to unfamiliar places. By age 70, he got lost driving on familiar roads; he became increasingly confused and disoriented and did not recognize his daughter. By age 78, he was paranoid, his memory loss had increased, his gait was unsteady, his speech slowed and he fell frequently. He was easily agitated and required multiple hospitalizations for aggressive behaviors. He died at age 80 from complications of septic shock.
He had a period of alcohol abuse as a young adult but was abstinent for the last 40 years of his life. He smoked cigarettes for 20 years. He was employed as a roofer for most of his life and was in excellent physical condition, running miles and doing daily calisthenics. He had no history of depression or anxiety and was generally pleasant and even-tempered. His family history was positive for a paternal grandfather with a history of cognitive decline and a brother with AD. Cerebral computerized axial tomography performed 2 and 3 years before death revealed progressive cerebral and cerebellar atrophy and mild ventricular enlargement.
A 73-year-old Caucasian male began boxing at the age of 11 and fought as an amateur boxer for 9 years and as a professional boxer for 13 years. He fought a total of 48 professional bouts, accumulating 2 world championships before retiring at the age of 33. In his late 50s, he became forgetful with mood swings and restlessness. He changed from his normally happy, easy-going self to become apathetic, socially withdrawn, paranoid, irritable and sometimes violently agitated. Over the next 2 years, he began to confuse close relatives and developed increasing anxiety, aggression and agitation; on occasion, he was verbally abusive towards his wife and tried to strike her. He required neuroleptics for control of his behavior. The following year he had episodes of dizziness, which was suspected to be vertigo and resulted in a hospital admission. Neurological examination found him to be disoriented, inattentive, with very poor immediate and remote memory, and impaired visuospatial skills. Neuropsychological testing showed deficits in all cognitive domains, including executive functioning, attention, language, visuospatial abilities, and profound deficits in learning and memory. CT scan and MRI showed generalized cortical atrophy, enlargement of the cerebral ventricles, cavum septum pellucidum and a right globus pallidus lacune. An EEG, magnetic resonance angiogram and carotid ultrasound were normal. He smoked and drank alcohol occasionally until his early fifties. A first cousin developed dementia in her early 50s and 3 uncles and 1 aunt (of 11 children) were demented.
Over the following 2 years he continued to decline in all cognitive domains. He fell frequently and developed a tremor of his left hand. Repeat neuropsychological testing at age 67 revealed further global deficits, again with prominent impairments in memory. By age 70 he had severe swallowing difficulties, diminished upgaze, masked facies, garbled speech and a slow, shuffling gait. Mini-mental state examination several months prior to death was 7 out of 30. He died at age 73 from complications of pneumonia.
Other sports associated with neuropathologically verified CTE are professional wrestling ( 20 ), and soccer ( 13 ). The first known case of CTE in a professional wrestler involved a 40-year-old Caucasian man who began professional wrestling at age 18 and wrestled for the next 22 years ( 20 ) He was known for his rough, aggressive style and had suffered numerous concussions and a cervical fracture during his career. At age 36 he began to experience problems in his marriage with periods of depression and lapses of memory. During his 40th year he had episodes of violent behavior; he ultimately killed his wife and son and committed suicide. He was believed to have used anabolic steroids and prescription narcotics. His past medical history included a motor vehicle accident at age 6 requiring 3 days of hospitalization for mild traumatic brain injury without known neurological sequelae.
Geddes and colleagues reported finding mild changes of CTE in a 23-year-old amateur soccer player who regularly “headed” the ball while playing and had a history of a single severe head injury ( 13 ). Williams and Tannenberg reported the findings in a 33-year-old achondroplastic dwarf, with a long history of alcohol abuse, who worked for 15 years as a clown in a circus ( 19 ). He had been knocked unconscious “a dozen times” and participated in dwarf-throwing events.
Gross pathology.
In their comprehensive description of the pathology, Corsellis and colleagues summarized the most common gross neuropathological findings, including 1) a reduction in brain weight, 2) enlargement of the lateral and third ventricles, 3) thinning of the corpus callosum, 4) cavum septum pellucidum with fenestrations, 5) scarring and neuronal loss of the cerebellar tonsils ( 29 ). The reduction in brain weight is generally mild (mean 1261 grams, range 950–1833) and associated with atrophy of the frontal lobe (36%), temporal lobe (31%), parietal lobe (22%), and less frequently, occipital lobe (3%) ( Tables 3 – 6 ). With increasing severity of the disease, atrophy of the hippocampus, entorhinal cortex and amygdala may become marked. The lateral ventricles (53%) and III ventricles (29%) are frequently dilated; rarely there is dilation of the IV ventricle (4%). Cavum septum pellucidum is often present (69%), usually with fenestrations (49%). Other common gross features include pallor of the substantia nigra and locus ceruleus, atrophy of the olfactory bulbs, thalamus, mammillary bodies, brainstem and cerebellum, and thinning of the corpus callosum. Many of these gross pathological features were found in our Cases 2 and 3.
Gross Pathological Features: Atrophy
0 = feature not present; + = mild; ++ = moderate; +++ = severe; blank = feature was not mentioned
Microscopic Pathological Features: Other
The brain weighed 1,360 grams. There was a mild yellow-brown discoloration in the leptomeninges over the temporal poles. There was mild atrophy of the frontal, parietal and temporal lobes, most pronounced in the temporal pole. The floor of the hypothalamus was thinned and translucent and the mammillary bodies were atrophic. The medial thalamus was atrophic and concave. The frontal, temporal and occipital horns of the lateral and third ventricles were enlarged with a 0.5-cm cavum septum pellucidum. The corpus callosum was thinned in its mid-portion. The anterior hippocampus, amygdala and entorhinal cortex were severely atrophic. By contrast, the posterior hippocampus was only mildly atrophic. The substantia nigra and locus ceruleus were markedly pale.
The brain weighed 1,220 grams. There was moderate atrophy of the frontal, parietal and temporal lobes, most pronounced in the temporal pole. The floor of the hypothalamus was markedly thinned and the mammillary bodies were atrophic. The corpus callosum was thinned, most prominently in its anterior portion. There was a large cavum septum pellucidum (0.8 cm) with fenestrations. The frontal and temporal horns of the lateral ventricles and the third ventricle were moderately enlarged. The entorhinal cortex, hippocampus, and amygdala were markedly atrophic throughout their entire extent. The medial thalamus was atrophic and concave. The perivascular spaces of the temporal and frontal white matter were prominent. A 1.0-cm lacune was present in the internal segment of the right globus pallidus. There was severe pallor of the substantia nigra and locus ceruleus with discoloration and atrophy of the frontopontine fibers in the cerebral peduncle.
Neuronal loss.
A few reports in the literature (cases 3, 4, 10, 12, 14, 29; Table 5 ) described neuronal loss and gliosis in the hippocampus, substantia nigra and cerebral cortex without appreciable neurofibrillary pathology. Neuronal loss and gliosis most commonly accompany neurofibrillary degeneration, however, and are pronounced in the hippocampus, particularly the CA1 and subiculum, the entorhinal cortex and amygdala. If the disease is advanced, neuronal loss is also found in the subcallosal and insular cortex and to a lesser degree in the frontal and temporal cortex. Other areas of neuronal loss and gliosis include the mammillary bodies, medial thalamus, substantia nigra, locus ceruleus and nucleus accumbens. In Cases 2 and 3, the cerebral cortex showed mild neuronal loss in the insular and septal cortices and moderate neuronal loss in the entorhinal cortex, amygdala, medial thalamus, mammillary bodies, substantia nigra pars compacta and pars reticulata and to a lesser extent, locus ceruleus. In Case 2, CA1 of the hippocampus showed moderate loss of neurons, and in Case 3, CA1 and the subiculum of the hippocampus showed severe neuronal loss and gliosis.
Microscopic Pathological Features: Neuronal Loss
Case Number | Frontal Cortex | Parietal Cortex | Temporal Cortex | Occipital Cortex | Hippocampus | Entorhinal Cortex | Amygdala | Cerebellum |
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49 | 0 | 0 | 0 | 0 | + | + | + | |
50 | + | + | + | + | ++ | ++ | ++ | |
51 | ++ | ++ | ++ | ++ | +++ | +++ | +++ |
Neurofibrillary tangles (NFTs), astrocytic tangles, and dot-like and spindle-shaped neuropil neurites (NNs) are common in the dorsolateral frontal, subcallosal, insular, temporal, dorsolateral parietal, and inferior occipital cortices. The tau-immunoreactive neurofibrillary pathology is characteristically irregular in distribution with multifocal patches of dense NFTs in the superficial cortical layers, often in a perivascular arrangement. This superficial distribution of neocortical NFTs was originally described by Hof and colleagues who noted that the NFTs in CTE were preferentially distributed in layer II and the upper third of layer III in neocortical areas and generally more dense than in AD ( 47 ).
Geddes and colleagues drew attention to the perivascular distribution of NFTs in their description of the neuropathological alterations in the brain and frontal lobectomy specimens of 5 young men, ranging in age from 23 to 28 years ( 13 , 37 ). The 5 cases included 2boxers, a soccer player, a person described as “mentally subnormal” with a long history of head banging, and an epileptic patient who frequently hit his head during seizures. Microscopically, all the brains showed argyrophilic, tau-positive neocortical NFTs, strikingly arranged in groups around small intracortical blood vessels, associated with neuropil threads and granular tau-positive neurons. There were also NFTs along the basal surfaces of the brain, usually at the depths of sulci. The hippocampi of the 4 autopsy cases were normal.
In CTE, tau-immunoreactive protoplasmic astrocytes are interspersed throughout the superficial cortical layers appearing as plaque-like accumulations composed of primarily globular neurites. The corpus callosum and subcortical white matter of the cortex show NNs and fibrillar astrocytic tangles. The U-fibers are prominently involved. Subcortical white matter structures such as the extreme and external capsule, anterior and posterior commissures, thalamic fasciculus, and fornix also show NNs and astrocytic tangles.
Dense NFTs, ghost tangles, and astrocytic tangles are found in the olfactory bulbs, hippocampus, entorhinal cortex, and amygdala, often in greater density than is found in AD. Abundant NFTs and astrocytic tangles are also found in the thalamus, hypothalamus, mammillary bodies, nucleus basalis of Meynert, medial geniculate, substantia nigra (pars compacta more than the pars reticulata), locus ceruleus, superior colliculus, periaqueductal gray, medial lemniscus, oculomotor nucleus, trochlear nucleus, ventral tegmental area, dorsal and median raphe, trigeminal motor nucleus, pontine nuclei, hypoglossal nucleus, dorsal motor nucleus of the vagus, inferior olives and reticular formation. The nucleus accumbens is usually moderately affected; the globus pallidus, caudate, and putamen are less involved. In the brainstem and spinal cord, midline white matter tracts show dense astrocytic tangles especially around small capillaries. Fibrillar astrocytic tangles are also common in the subpial and periventricular zones. Neurons in the spinal cord gray matter contain NFTs, and astrocytic tangles are frequent in the ventral gray matter. This unique pattern of tau-immunoreactive pathology was found in all 3 of our cases, with increasing severity from Case 1 to Case 3.
NFTs immunopositive for tau epitopes ( Appendix ) were prominent in the inferior frontal, superior frontal, subcallosal, insular, temporal, and inferior parieto-temporal cortices ( Fig. 1 ). Primary visual cortex showed no NFTs; anterior and posterior cingulate cortex showed only scant NFTs. NFTs occurred in irregular patches, often greatest at the sulcal depths ( Fig. 2 ). Tau-positive fibrillar astrocytes (“astrocytic tangles”) were prominent in foci, especially in subpial regions and around small blood vessels ( Figs. 2 , ,3). 3 ). NFTs were especially numerous in cortical laminae II and III, where a prominent perivascular distribution of neuronal NFTs and fibrillar astrocytic tangles was evident ( Fig. 3 ). Although some neuronal NFTs showed multiple tau-positive perisomatic processes, most neuronal NFTs were morphologically similar to those found in AD. In the cortex there were many tau-positive astrocytes bearing a corona of tau-positive processes. These tau-positive protoplasmic astrocytes were similar in appearance to the astrocytic plaques of corticobasal degeneration except that the perikaryon was often tau-positive ( Fig. 3 ).
( A–D ) Case 1: Whole mount 50-μm coronal sections immunostained for tau with monoclonal antibody AT8 and counterstained with cresyl violet showing irregular, patchy deposition of phosphorylated tau protein in frontal, subcallosal, insular, temporal, and parietal cortices and the medial temporal lobe.
( A–C ) Whole mount 50-μm coronal sections of superior frontal cortex from case 1 ( A ), case 2 ( B ), case 3 ( C ) immunostained for tau with monoclonal antibody CP-13 showing extensive immunoreactivity that is greatest at sulcal depths (asterisks) and is associated with contraction of the cortical ribbon. ( D–F ) Microscopically there are dense tau-immunoreactive neurofibrillary tangles (NFTs) and neuropil neurites throughout the cortex, case 1 ( D ), case 2 ( E ) and case 3 ( F ). There are focal nests of NFTs and astrocytic tangles around small blood vessels ( E , arrow) and plaque-like clusters of tau-immunoreactive astrocytic processes distributed throughout the cortical layers ( F , arrows).
Whole mount 50-μm sections from cases 1 and 2 immunostained with anti-tau monoclonal antibody AT85. ( A ) Case 2. There is a prominent perivascular collection of neurofibrillary tangles (NFTs) and astrocytic tangles evident in the superficial cortical layers with lesser involvement of the deep laminae. Prominent neuropil neurites (NNs) are found in the subcortical U-fibers (arrow), original magnification x150. ( B ) Case 1. There is a preferential distribution of NFTs in layer II and NNs extending into the subcortical white matter even in mildly affected cortex, original magnification x150. ( C ) Case 1. Focal subpial collections of astrocytic tangles and NFTs are characteristic of chronic traumatic encephalopathy (CTE), original magnification x150. ( D ) Case 1. The shape of most NFTs and NNs in CTE is similar to those found in Alzheimer disease, original magnification x150. Some NFTs have multiple perisomatic processes ( E ) and spindle-shaped and dot-like neurites are found in addition to thread-like forms ( E , Case 1, original magnification x350. ( F ) Case 1. Astrocytic tangles are interspersed with NFTs in the cortex (arrows, original magnification x350). ( G ) Case 1. Tau-immunoreactive astrocytes are common in periventricular regions, original magnification x150. ( H, I ) Case 1. Tau-immunoreactive astrocytes take various forms; some appear to be protoplasmic astrocytes with short rounded processes ( H, I , double immunostained section with AT8 (brown) and anti-glial fibrillary acidic protein (red), ( H ) original magnification x350, ( I ) original magnification x945). ( J ) Case 2: Dot-like or spindle-shaped neurites predominate in the white matter although there are also some threadlike forms, original magnification x150.
Neuropil neurites (NNs) and astrocytic tangles were abundant in the frontal and temporal white matter ( Fig. 3 ). NNs were often dot-like and spindle-shaped in addition to threadlike forms similar to those found in AD. The hippocampus, entorhinal, and transentorhinal cortex contained dense NFTs, ghost tangles and NNs, including many ghost tangles in CA1 and subiculum; NFTs were denser in the anterior hippocampus compared to the posterior hippocampus. The amygdala showed dense tau immunoreactivity, including NFTs, astrocytic tangles and NNs ( Fig. 4 ). NFTs were most frequent in the lateral nuclear group of the amygdala.
( A–C ) Whole mount 50-μm-thick coronal sections immunostained for tau (AT8) from case 1 ( A ), case 2 ( B ), case 3 ( C ) (counterstained with cresyl violet) showing extremely dense deposition of tau protein in the amygdala with increasing severity from left to right. ( D–F ) Microscopically, there is a moderate density of NFTs and astrocytic tangles in case 1 ( D ), the density is increased in case 2 ( E ), and extremely marked in case 3 ( F ), original magnification x350.
The nucleus basalis of Meynert, hypothalamic nuclei, septal nuclei, fornix, and lateral mammillary bodies showed dense NFTs and astrocytic tangles. NFTs and astrocytic tangles were also found in the olfactory bulb, thalamus, caudate, and putamen. The globus pallidus and subthalamic nucleus were relatively spared. The lateral substantia nigra pars compacta showed mild neuronal loss, extraneuronal pigment deposition, and moderate numbers of NFTs and NNs. The pars reticulata was unremarkable. The cerebellar peduncle showed mild perivascular hemosiderin deposition. NFTs were numerous in the dorsal and median raphe nuclei. The internal, external and extreme capsules, fornix and mammillothalamic tract showed moderate NNs, although, in general, the white matter was less affected than adjacent gray matter.
There were abundant tau–positive NFTs, glial tangles, and dot-like and spindle-shaped NNs in the superficial layers of cerebral cortex (I–III) ( Fig. 3 ). Cortical tau pathology was most prominent in patchy areas of the superior frontal and temporal lobes, especially the medial temporal lobe, often in a vasocentric pattern. The olfactory bulb, hippocampus, entorhinal cortex and amygdala showed extremely dense NFTs with many ghost tangles ( Figs. 4 – 6 ). Tau-positive glia and NNs were also found in the subcortical white matter and corpus callosum. The olfactory bulb, thalamus, hypothalamus, nucleus basalis, striatum, globus pallidus, substantia nigra, raphe, periventricular gray, locus ceruleus, oculomotor nucleus, red nucleus, pontine base, tegmentum, reticular nuclei, inferior olives, and dentate nucleus showed dense NFTs and glial tangles. Spindle-shaped NNs and tau-positive glia were pronounced in the midline white matter tracts of the brainstem.
Tau-immunoreactive (AT8) NFTs, astrocytic tangles and neuropil neurites are found in many subcortical nuclei including the substantia nigra ( A , case 3, original magnification x350) and nucleus basalis of Meynert ( B , case 3, original magnification x350). NFTs are also abundant in the olfactory bulb ( C , case 2, Bielschowsky silver method, original magnification x150) and thalamus (case 1, original magnification x350, AT8 immunostain counterstained with cresyl violet).
Microscopic examination showed dense accumulations of tau-immunoreactive NFTs, astrocytic tangles, and NNs in irregular patches of the dorsolateral frontal, insular, subcallosal, inferior frontal, superior parietal and posterior temporo-occipital cortices, and most severely in the medial temporal lobe. The hippocampus, entorhinal cortex and amygdala contained extremely dense NFTs with ghost tangles and severe neuronal loss ( Figs. 4 , ,6). 6 ). Tau-positive glia and NNs were also found in the subcortical white matter, particularly in the subcortical U-fibers. The olfactory bulb, thalamus, hypothalamus, nucleus basalis, striatum, globus pallidus, substantia nigra, raphe, periventricular gray, locus ceruleus, oculomotor nucleus, red nucleus, pontine base, pontine tegmentum, hypoglossal nuclei, reticular nuclei, inferior olives, midline tracts of the medulla, and dentate nucleus contained dense NFTs and astrocytic tangles ( Figs. 5 , ,7). 7 ). Subcortical white matter tracts including the anterior and posterior commissure, thalamic fasciculus, external and extreme capsule also showed astrocytic tangles and NNs.
Whole mount 50-μm coronal sections of case 2 ( A ) and case 3 ( B ), immunostained for tau (AT8) and counter-stained with cresyl violet. There is extremely dense deposition of tau protein in the hippocampus and medial temporal lobe structures. There is also prominent tau deposition in the medial thalamus.
Whole mount tau (AT8)-immunostained 50-μm coronal sections of the brainstem from case 3 showing severe involvement of the locus ceruleus, pontine tegmentum, pontine base, midline medulla, and hypoglossal nuclei.
The abnormal tau proteins that are found in the glial and neuronal tangles in CTE are indistinguishable from NFTs in AD and are composed of all 6 brain tau isoforms ( 39 ). Neuropathologically, CTE resembles several other neurodegenerative diseases characterized by accumulations of hyperphosphorylated tau protein in neurons or glial cells, including ALS/PDC of Guam, post-encephalitic parkinsonism, progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) ( 36 , 48 – 50 ). Like ALS/PDC of Guam, neurofibrillary tau pathology in CTE is found in the medial temporal lobe structures, cerebral cortex and spinal cord with only a subset of cases showing evidence of diffuse plaques ( 51 ). Like ALS/PDC and PSP, CTE preferentially involves the superficial cortical layers and involves the accumulation of tau-immunoreactive astrocytes ( 36 ). However, CTE differs from ALS/PDC of Guam and PSP in that the cortical involvement is irregular and patchy, greatest at sulcal depths, and distributed in a prominent perivascular, periventricular and subpial pattern. Furthermore, there is a unique regional involvement of subcortical and brainstem structures in CTE ( Tables 5 , ,6 6 ).
β-Amyloid (Aβ) deposition is an inconstant feature in CTE. Fourteen of the 15 brains originally described by Corsellis ( 29 ) and 6 additional boxers were re-examined by Roberts and colleagues using Aβ immunocytochemistry with formic acid pretreatment; 19 of the 20 cases showed widespread diffuse Aβ deposits ( 18 ). The only case that did not contain diffuse Aβ was that of a 22-year-old boxer who died during a fight. Similarly, Tokuda and colleagues who found abundant diffuse Aβ deposits in 8 cases of CTE and cerebrovascular Aβ deposits in 3 cases ( 52 ). In our series, only Case 2 showed moderate numbers of diffuse Aβ plaques in the frontal, parietal and temporal cortex, and sparse neuritic plaques; there was no vascular amyloid. Of the 51 neuropathologically verified cases of CTE, diffuse plaques were found in 22 (44%), neuritic plaques in 13 (27%), and amyloid angiopathy in 3 (6%). There was also one report of a fatal cerebral hemorrhage from amyloid angiopathy associated with CTE ( 15 ).
Tau-positive fibrillar astrocytic tangles are found in the white matter, but the major abnormality is that of dot-like or spindle-shaped tau-positive neurites. The shape of the tau-immunoreactive neurites is distinct from the predominantly threadlike forms found in AD and suggests an axonal origin. Tokuda and colleagues characterized the neuropil neurites in CTE as shorter and less prominent than the neuropil threads found in AD and not spatially related to senile plaques ( 52 ). Generally, tau abnormalities in the white matter are not as severe as in adjacent gray matter. Other abnormalities found frequently in the cerebral and cerebellar white matter include small arterioles with thickened fibrohyalinized walls with perivascular hemosiderin-laden macrophages, widened perivascular spaces, and white matter rarefaction. In our cases 1 3, mild to moderate myelin and axonal loss was found in the corpus callosum and subcortical white matter of the frontal and temporal lobes and cerebellum with mild perivascular hemosiderin deposition.
Extensive accumulation of α-synuclein has been found in axons following acute traumatic brain injury (TBI) ( 53 ) but α-synuclein immunostaining was not a feature of any of the 51 cases of CTE, including our 3 cases.
The distribution of the tau abnormalities in CTE suggests distinctive core pathology within the amygdalo-hippocampal-septo-hypothalamic-mesencephalic continuum, i.e. the Papez circuit ( 54 , 55 ). The early involvement of these anatomical regions, sometimes referred to as “emotional” or “visceral” brain, may underlie many of the early behavioral symptoms, including the tendency toward emotional lability, aggression and violent outbursts. The early involvement of the hippocampus, entorhinal cortex and medial thalamus may explain episodic memory disturbance as a frequent presenting symptom ( 56 ). Neurofibrillary degeneration of the frontal cortex and underlying white matter most likely contributes to the dysexecutive symptoms. Although less common and generally less severe, neurofibrillary degeneration in the dorsolateral parietal, posterior temporal, and occipital cortices likely accounts for the visuospatial difficulties. The parkinsonian features found in 42% of cases are likely due to degeneration of the substantia nigra pars compacta. The gait disorder, variously described as staggered, slowed, shuffled, or frankly ataxic, may result from a combination of cortical and subcortical frontal damage, degeneration of cerebellar tracts in the brainstem, direct cerebellar injury, as well as Parkinsonism from substantia nigra pathology. Similarly, speech abnormalities, most often described as slowed and slurred, likely reflect multiregional degeneration. Symptoms of dysarthria, dysphagia, and ocular abnormalities probably result from degeneration of brainstem nuclei, e.g. the hypoglossal and oculomotor nuclei.
Acceleration and deceleration forces are thought to be important events in concussion, particularly rotational acceleration and deceleration ( 57 – 59 ). Sagittal (front-to-back) injuries result in relatively good recovery whereas lateral (side-to-side) injuries produce the most injury, with injury directed related to the severity of the generating force ( 58 ). Conceivably, a concussive impact imparts a fluid wave in the lateral ventricles that produces a shearing force on the septum pellucidum; this may explain the development of an enlarged cavum septum pellucidum and, if severe or repeated, fenestrations.
The patchy, irregular location of the cortical NFTs and astrocytic tangles suggests that the distribution is related to direct mechanical injury from blows to the side or top of the head, given their multifocal dorsolateral frontal and parietal, inferior frontal and occipital, and lateral temporal distribution. The possibility that ischemia may contribute to the development of the tau pathology is suggested by the concentration of tau-immunoreactive pathology at the depths of sulci. Damage to the blood-brain barrier and release of local neurotoxins might explain some of the tendency toward perivascular nests of tau-immunoreactive NFT, tau-positive glia, and NNs ( 13 ). Buee and Hof studied the microvasculature of several cases with dementia pugilistica and found decreased microvascular density and tortuosity with a strong correlation between the laminar distribution of NFTs and pathological microvasculature. Hof and colleagues suggested that the shear forces of repetitive head trauma might lead to vascular damage followed by perivascular NFT and NN formation ( 60 ). Further supporting a possible vascular connection to the pathological changes in CTE, Bouras reported laser microprobe mass analysis of NFTs and nuclei of NFT-free neurons in CTE contained substantially higher amounts of iron and aluminum than NFTs in AD ( 61 ).
Axonal injury.
Acute concussion produces diffuse axonal injury ( 62 ). The “diffuse degeneration of the cerebral white matter” was first described by Strich as the shearing or mechanical tearing of axons at the time of injury ( 63 ). It is now appreciated that axons are not sheared at the time of injury except in the most severe instances of diffuse axonal injury, but instead undergo a series of changes that may result in a secondary axotomy within 24 hours ( 64 ). The axolemma is one of the initial sites of injury; the increased permeability, uncontrolled influx of Ca++, swelling of mitochondria, disruption of microtubules, and alterations in axonal transport that follow produce axonal swelling and secondary axotomy ( 64 – 66 ). Rapid axonal swelling, perisomatic axotomy and Wallerian degeneration may also occur without changes in axolemmal permeability, suggesting that trauma may have diverse effects on axons. McKenzie showed that 80% of patients who died from acute head injury showed immunocytochemical evidence of axonal injury within 2 hours of injury; after 3 hours of injury, axonal bulbs were identified, and as the survival time increased, the amount of axonal damage and axonal bulb formation increased. Axonal injury was found most frequently in the brainstem, followed by the internal capsule, thalamus, corpus callosum and parasagittal white matter ( 67 ). Axonal damage may continue for weeks after the acute TBI ( 68 ).
In individuals undergoing surgical brain tissue resection for acute TBI, tau-immunoreactive dystrophic axons were found in the white matter and diffuse tau immunoreactivity was found in some neuronal cell bodies, dendrites, and glial cells within 2–3 hours post injury ( 67 ). Studies of acute TBI in experimental animal models and postmortem human brain also demonstrate that Aβ deposition, amyloid precursor protein (APP) processing, production and accumulation are increased after injury ( 69 – 78 ). Increased APP production in experimental TBI has also been associated with heightened neuronal loss in the hippocampus ( 73 , 79 ). In acute TBI, diffuse cortical Aβ plaques have been found in 30% to 38% of cases as early as 2 hours after injury ( 73 , 76 , 80 ). In addition, individuals with cortical Aβ plaques showed increased levels of soluble Aβ42 and half were Apolipoprotein E (ApoE) ε4 allele carriers ( 81 ). In acute TBI, Aβ deposition is widely distributed throughout the neocortex without apparent association with the injury sites ( 82 ). The predominant form of Aβ in acute TBI is Aβ 42 whereas the Aβ 40 form predominates in serum and CSF, a situation similar to that in AD ( 83 ). A recent report also showed that interstitial soluble Aβ concentrations in the brain appear to correlate directly with neurological outcome following TBI ( 84 ).
There are multiple reasons for neuronal loss in acute traumatic injury including neuronal death from direct physical damage, necrosis from the immediate release of excitatory transmitters such as glutamate, and diffuse, delayed cell death involving both necrotic and apoptotic death cascades ( 85 , 86 ). Other contributing factors include focal ischemia, breakdown of the blood-brain barrier, inflammation and the release of cytokines. Experimental lateral percussive injury in the rat produces apoptotic and necrotic neuronal death that progresses for up to one year after injury with degeneration of the cortex, hippocampi, thalami and septum, ventriculomegaly, and impaired memory performance ( 62 , 85 , 87 – 89 ). The thalamic degeneration typically follows the cortical degeneration by weeks, suggesting that a secondary process such as deafferentation may play a role in the thalamic neuronal death. Neuronal loss in the hippocampus and thalamus has also been reported following blunt head injury in humans using stereological techniques ( 90 , 91 ). One of the key features of CTE is that the disease continues to progress decades after the activity that produced traumatic injury has stopped. It is most likely that multiple pathological cascades continue to exert their effects throughout the individual’s lifetime once they are triggered by repetitive trauma; the longer the survival after the initial events and the more severe the original injuries, the greater the severity of the neurodegeneration. It is clear that neuronal loss, cerebral atrophy, and ventricular enlargement all increase with longer survival and greater exposure to repetitive trauma.
Presently there are no available biomarkers for the diagnosis of CTE. Although significant decreases in CSF ApoE and Aβ concentrations have been reported that correlated with severity of the injury after TBI, there have been no similar studies in CTE ( 92 ). Nonetheless, advances in neuroimaging offer the promise of detecting subtle changes in axonal integrity in acute TBI and CTE. Standard T1- or T2-weighted structural MR imagining is helpful for quantitating pathology in acute TBI, but diffusion tensor MRI (DTI) is a more sensitive method to assess axonal integrity in vivo ( 93 , 94 ). In chronic moderate to severe TBI, abnormalities on DTI have been reported in the absence of observable lesions on standard structural MRI ( 83 ). More severe white matter abnormalities on DTI have been associated with greater cognitive deficits by neuropsychological testing ( 94 , 95 ) and increases in whole-brain apparent diffusion coefficient and decreases in fractional anisotropy using DTI have been found in boxers compared to controls ( 96 , 97 ).
ApoE genotyping has been reported in 10 cases of CTE, including our most recent cases. Five of the 10 cases of CTE carried at least one ApoE ε4 allele (50%), and 1 was homozygous for ApoE ε4 (our case 1). The percentage of ApoE ε4 carriers in the general population is 15%; this suggests that the inheritance of an ApoE ε4 allele might be a risk factor for the development of CTE.
In acute TBI there is accumulating evidence that the deleterious effects of head trauma are more severe in ApoE ε4-positive individuals ( 98 – 100 ). Acute TBI induces Aβ deposition in 30% of people ( 75 , 76 ) and a significant proportion of these individuals are heterozygous for ApoE ε4 ( 101 , 102 ). ApoE4 transgenic mice suffer greater mortality from TBI than ApoE ε3 mice ( 102 ). Furthermore, transgenic mice that express ApoE ε4 and overexpress APP show greater Aβ deposition after experimental TBI ( 103 ).
Clearly, the easiest way to decrease the incidence of CTE is to decrease the number of concussions or mild traumatic brain injuries. In athletes this is accomplished by limiting exposure to trauma, for example, by penalizing intentional hits to the head (as is happening in football and hockey) and adhering to strict “return to play” guidelines. Proper care and management of mild traumatic brain injury in general and particularly in sports will also reduce CTE. No reliable or specific measures of neurological dysfunction after concussion currently exist, and most recommendations are centered on the resolution of acute symptoms such as headache, confusion, sensitivity to light, etc. ( 104 ). Asymptomatic individuals have been shown, however, to have persistent decreases in P300 amplitudes in response to an auditory stimulus at least 5 weeks after a concussion, thereby casting doubt on the validity of the absence of symptoms as a guidepost ( 105 , 106 ). Neuropsychological tests have also helped provide estimates of the appropriate time for athletes to return to practice and play. Studies using event-related potentials, transcranial magnetic stimulation, balance testing, multitask effects on gait stability, PET, and DTI MRI have all shown abnormalities in concussed athletes or nonathletes with TBI lasting for 2 to 4 weeks ( 105 , 107 – 109 ). These studies indicate that safe return to play guidelines might require at least 4 to 6 weeks to facilitate more complete recovery and to protect from reinjury, as a second concussion occurs much more frequently in the immediate period after a concussion ( 106 , 110 ). In addition, experimental evidence in animals suggests that there is expansion of brain injury and inhibition of functional recovery if the animal is subjected to overactivity within the first week ( 111 ).
CTE is a progressive neurodegeneration clinically associated with memory disturbances, behavioral and personality change, Parkinsonism, and speech and gait abnormalities. Pathologically, CTE is characterized by cerebral and medial temporal lobe atrophy, ventriculomegaly, enlarged cavum septum pellucidum, and extensive tau-immunoreactive pathology throughout the neocortex, medial temporal lobe, diencephalon, brainstem, and spinal cord. There is overwhelming evidence that the condition is the result of repeated sublethal brain trauma that often occurs well before the development of clinical manifestations. Repetitive closed head injury occurs in a wide variety of contact sports as well as a result of accidents or in the setting of military service. Pathologically, CTE shares some features of AD, notably tau-immunoreactive NFTs, NNs and, in approximately 40% of cases, diffuse senile plaques. Furthermore, the Aβ and NFTs found in CTE are immunocytochemically identical to those found in AD, suggesting a possible common pathogenesis. Multiple epidemiological studies have shown that head injury is a risk factor for AD and there have been several case reports citing an association between a single head injury and the development of subsequent AD ( 112 , 113 ). Just as acquired vascular injury may interact additively or synergistically with AD, traumatic injury may interact additively with AD to produce a mixed pathology with greater clinical impact or synergistically by promoting pathological cascades that result in either AD or CTE. In athletes, by instituting and following proper guidelines for return to play after a concussion or mild traumatic brain injury, it is possible that the frequency of sports-related CTE could be dramatically reduced or perhaps, entirely prevented.
Gross Pathological Features: Other
Case Number | II Ventricle Enlarged | III Ventricle Enlarged | IV Ventricle Enlarged | Cavum Septum | Fenestrations | SN Pallor | LC Pallor |
---|---|---|---|---|---|---|---|
1 | + | + | |||||
2 | + | + | |||||
3 | |||||||
4 | +++ | ||||||
5 | + | + | |||||
6 | + | ||||||
7 | + | ||||||
8 | + | +++ | |||||
9 | + | + | + | ||||
10 | + | + | + | ||||
11 | + | + | + | ||||
12 | + | + | |||||
13 | + | + | + | ||||
14 | + | + | |||||
15 | ++ | ++ | +++ | + | ++ | ||
16 | +++ | +++ | +++ | +++ | + | ++ | |
17 | ++ | ++ | ++ | + | +++ | ||
18 | ++ | ++ | + | + | +++ | ||
19 | ++ | ++ | + | +++ | + | + | |
20 | ++ | ++ | ++ | + | +++ | ||
21 | ++ | ++ | ++ | + | |||
22 | ++ | ++ | + | ++ | + | ||
23 | ++ | ++ | + | +++ | |||
24 | +++ | +++ | +++ | + | |||
25 | ++ | +++ | + | ||||
26 | + | + | |||||
27 | ++ | ++ | ++ | + | |||
28 | ++ | ++ | ++ | ||||
29 | + | + | |||||
30 | +++ | + | |||||
31 | +++ | ||||||
32 | + | + | |||||
33 | |||||||
34 | +++ | +++ | + | ||||
35 | + | ||||||
36 | 0 | 0 | 0 | ||||
37 | 0 | 0 | 0 | ||||
38 | 0 | 0 | 0 | ||||
39 | |||||||
40 | 0 | 0 | 0 | ||||
41 | + | ++ | ++ | ||||
42 | + | ||||||
43 | + | ||||||
44 | |||||||
45 | + | ||||||
46 | |||||||
47 | |||||||
48 | ++ | + | + | ||||
49 | + | 0 | 0 | ||||
50 | + | + | + | + | +++ | +++ | |
51 | ++ | ++ | ++ | + | +++ | +++ |
Supported by the Boston University Alzheimer’s Disease Center NIA P30 AG13846, supplement 0572063345-5 and the Department of Veterans’ Affairs.
The authors wish to thank Rafael Romero, MD, for his review of the clinical features of case 3.
The following anatomic regions were evaluated microscopically in paraffin sections in Cases 1 to 3: olfactory bulb, midbrain at level of red nucleus, right motor cortex, right inferior parietal cortex (Brodmann Area [BA] 39, 40), right anterior cingulate (BA 24), right superior frontal (BA 8, 9), left Inferior frontal cortex (BA 10, 11, 12), left lateral frontal (BA 45, 46), caudate, putamen, and accumbens (CAP), anterior temporal (BA 38), superior temporal (BA 20, 21, 22), middle temporal cortex, inferior temporal cortex, amygdala, entorhinal cortex (BA 28), globus pallidus, insula, substantia innominata, right hippocampal formation at the level of the lateral geniculate, hippocampus, thalamus with mamillary body, thalamus, posterior cingulate (BA 23, 31), calcarine cortex (BA 17,18), superior parietal cortex (BA 7B), cerebellar vermis, cerebellum with dentate nucleus, parastriate cortex (BA 19) pons, medulla and spinal cord.
The sections were stained with Luxol fast blue and hematoxylin and eosin, Bielschowsky silver impregnation and by immunohistochemistry with antibodies to phosphoserine 202 and phosphothreonine 205 of PHF-tau (mouse monoclonal AT8, Pierce Endogen, Rockford IL, 1:2,000), α-synuclein (rabbit polyclonal, Chemicon, Temecula, CA, 1:15,000), β-amyloid (mouse monoclonal, Dako North America Inc, Carpinteria, CA, 1:2,000) (following formic acid pretreatment), and Aβ 42 (rabbit polyclonal, Invitrogen (Biosource), Carpinteria, CA, 1:2,000). In addition, multiple large coronal fragments were cut at 50 μm on a sledge microtome and stained as free-floating sections using a mouse monoclonal antibody directed against phosphoserine 202 of tau (CP-13, courtesy of Peter Davies, 1:200); this is considered to be the initial site of tau phosphorylation in NFT formation ( 114 – 118 ). Other monoclonal antibodies used for immunostaining were AT8, phosphoserine 396 and phosphoserine 404 of hyperphosphorylated tau(PHF-1, courtesy of Peter Davies, 1:1000) ( 114 – 118 ), glial fibrillary acidic protein (GFAP) (Chemicon, 1:2,000), and HLA-DR-Class II major histocompatibility complex (LN3, Zymed, San Francisco, CA, 1:2,000); some of these sections were counterstained with cresyl violet.
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Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit–risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future.
Vaccines have a key public health role in protecting populations against infectious diseases, including neurological diseases caused by infections.
Serious neurological complications of vaccination are extremely rare, but when they do occur they have the potential to jeopardize vaccination programmes.
Live attenuated vaccines, such as the yellow fever and poliomyelitis vaccines, carry a very small risk of neurotropic infections; vaccine-specific and recipient-specific factors can predispose to these complications.
Very rare neurological complications of vaccination include neuroimmunological conditions such as Guillain–Barré syndrome, acute disseminated encephalomyelitis and narcolepsy, and neurovascular conditions such as cerebral venous sinus thrombosis and stroke.
Apart from live vaccines in immunosuppressed individuals and the yellow fever vaccine in people with myasthenia gravis, vaccination is typically safe in individuals with neurological disease, with strongly positive benefit–risk profiles.
Recent advances in data linkage have allowed monitoring of the neurological safety profile of vaccines as they are rolled out, almost in real time, and have enabled these risks to be weighed against the risks of infection in unvaccinated individuals.
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World Health Organization. Child mortality and causes of death. WHO , https://www.who.int/gho/child_health/mortality/mortality_under_five_text/en/ (2020).
Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21 , 83–100 (2021).
Article CAS PubMed Google Scholar
Cao-Lormeau, V. M. et al. Guillain–Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case–control study. Lancet 387 , 1531–1539 (2016).
Article PubMed PubMed Central Google Scholar
Patone, M. et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat. Med. 27 , 2144–2153 (2021).
Article CAS PubMed PubMed Central Google Scholar
& Barwick Eidex, R. Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination. Lancet 364 , 936 (2004).
Article PubMed Google Scholar
Nath, A. Neurologic complications with vaccines: what we know, what we don’t, and what we should do. Neurology 101 , 621–626 (2023).
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383 , 2603–2615 (2020).
Perry, R. J. et al. Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study. Lancet 398 , 1147–1156 (2021).
Godlee, F., Smith, J. & Marcovitch, H. Wakefield’s article linking MMR vaccine and autism was fraudulent. BMJ 342 , c7452 (2011).
Waugh, C. J., Willocks, L. J., Templeton, K. & Stevenson, J. Recurrent outbreaks of mumps in Lothian and the impact of waning immunity. Epidemiol. Infect. 148 , e131 (2020).
Baker, J. P. The pertussis vaccine controversy in Great Britain, 1974–1986. Vaccine 21 , 4003–4010 (2003).
Larson, H. J., Gakidou, E. & Murray, C. J. L. The vaccine-hesitant moment. N. Engl. J. Med. 387 , 58–65 (2022).
Knipe, D. M., Levy, O., Fitzgerald, K. A. & Muhlberger, E. Ensuring vaccine safety. Science 370 , 1274–1275 (2020).
Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396 , 467–478 (2020).
Ramasamy, M. N. et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 396 , 1979–1993 (2021).
Jackson, L. A. et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N. Engl. J. Med. 383 , 1920–1931 (2020).
Voysey, M. et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397 , 99–111 (2021).
Scully, M. et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N. Engl. J. Med. 384 , 2202–2211 (2021).
Candore, G. et al. Comparison of statistical signal detection methods within and across spontaneous reporting databases. Drug. Saf. 38 , 577–587 (2015).
Lazarus, R. et al. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial. Lancet 398 , 2277–2287 (2021).
Verani, J. R. et al. Case–control vaccine effectiveness studies: preparation, design, and enrollment of cases and controls. Vaccine 35 , 3295–3302 (2017).
Farrington, P. The self-controlled case series method and covid-19. BMJ 377 , o625 (2022).
Minor, P. D. Live attenuated vaccines: historical successes and current challenges. Virology 479– 480 , 379–392 (2015).
Norrby, E. Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine. J. Exp. Med. 204 , 2779–2784 (2007).
Baicus, A. History of polio vaccination. World J. Virol. 1 , 108–114 (2012).
Mangtani, P. et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin. Infect. Dis. 58 , 470–480 (2014).
Poyhonen, L., Bustamante, J., Casanova, J. L., Jouanguy, E. & Zhang, Q. Life-threatening infections due to live-attenuated vaccines: early manifestations of inborn errors of immunity. J. Clin. Immunol. 39 , 376–390 (2019).
Reno, E. et al. Prevention of yellow fever in travellers: an update. Lancet Infect. Dis. 20 , e129–e137 (2020).
Garske, T. et al. Yellow Fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med. 11 , e1001638 (2014).
Gianchecchi, E., Cianchi, V., Torelli, A. & Montomoli, E. Yellow fever: origin, epidemiology, preventive strategies and future prospects. Vaccines 10 , 372 (2022).
Staples, J. E., Gershman, M., Fischer, M. & Centers for Disease Control and Prevention. Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm. Rep. 59 , 1–27 (2010).
PubMed Google Scholar
de Abreu, A. J. L., Cavalcante, J. R., de Araujo Lagos, L. W., Caetano, R. & Braga, J. U. A systematic review and a meta-analysis of the yellow fever vaccine in the elderly population. Vaccines 10 , 711 (2022).
Kitchener, S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever vaccine, ARILVAX®. Vaccine 22 , 2103–2105 (2004).
McMahon, A. W. et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 25 , 1727–1734 (2007).
Cohen, M. et al. Case report: yellow fever vaccine-associated neurotropic disease and associated MRI, EEG, and CSF findings. Front. Neurol. 12 , 779014 (2021).
Kengsakul, K., Sathirapongsasuti, K. & Punyagupta, S. Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection. J. Med. Assoc. Thai. 85 , 131–134 (2002).
Ribeiro, A. F. et al. Neurologic disease after yellow fever vaccination, Sao Paulo, Brazil, 2017–2018. Emerg. Infect. Dis. 27 , 1577–1587 (2021).
Guedes, B. F. et al. Potential autoimmune encephalitis following yellow fever vaccination: a report of three cases. J. Neuroimmunol. 355 , 577548 (2021).
Frierson, J. G. The yellow fever vaccine: a history. Yale J. Biol. Med. 83 , 77–85 (2010).
PubMed PubMed Central Google Scholar
DeSilva, M. et al. Notes from the field: fatal yellow fever vaccine-associated viscerotropic disease — Oregon, September 2014. MMWR Morb. Mortal. Wkly Rep. 64 , 279–281 (2015).
Wolfe, G. I., Kaminski, H. J. & Cutter, G. R. Randomized trial of thymectomy in myasthenia gravis. N. Engl. J. Med. 375 , 2006–2007 (2016).
Bastard, P. et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. 218 , e20202486 (2021).
History of Polio. Global Eradication Polio Initiative. https://polioeradication.org/polio-today/history-of-polio/ (2019).
Cooper, L. V. et al. Risk factors for the spread of vaccine-derived type 2 polioviruses after global withdrawal of trivalent oral poliovirus vaccine and the effects of outbreak responses with monovalent vaccine: a retrospective analysis of surveillance data for 51 countries in Africa. Lancet Infect. Dis. 22 , 284–294 (2022).
Hill, M., Bandyopadhyay, A. S. & Pollard, A. J. Emergence of vaccine-derived poliovirus in high-income settings in the absence of oral polio vaccine use. Lancet 400 , 713–715 (2022).
Macklin, G. R. et al. Enabling accelerated vaccine roll-out for Public Health Emergencies of International Concern (PHEICs): novel oral polio vaccine type 2 (nOPV2) experience. Vaccine 41 , A122–A127 (2023).
Platt, L. R., Estivariz, C. F. & Sutter, R. W. Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden. J. Infect. Dis. 210 , S380–S389 (2014).
Shaghaghi, M. et al. Combined immunodeficiency presenting with vaccine-associated paralytic poliomyelitis: a case report and narrative review of literature. Immunol. Invest. 43 , 292–298 (2014).
Jafari, H. et al. Polio eradication. Efficacy of inactivated poliovirus vaccine in India. Science 345 , 922–925 (2014).
Yeh, M. T. et al. Engineering the live-attenuated polio vaccine to prevent reversion to virulence. Cell Host Microbe 27 , 736–751.e8 (2020).
Zaman, K. et al. Evaluation of the safety, immunogenicity, and faecal shedding of novel oral polio vaccine type 2 in healthy newborn infants in Bangladesh: a randomised, controlled, phase 2 clinical trial. Lancet 401 , 131–139 (2023).
Wahid, R. et al. Assessment of genetic changes and neurovirulence of shed Sabin and novel type 2 oral polio vaccine viruses. npj Vaccines 6 , 94 (2021).
Hubschen, J. M., Gouandjika-Vasilache, I. & Dina, J. Measles. Lancet 399 , 678–690 (2022).
Bellini, W. J. et al. Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized. J. Infect. Dis. 192 , 1686–1693 (2005).
Ferren, M., Horvat, B. & Mathieu, C. Measles encephalitis: towards new therapeutics. Viruses 11 , 1017 (2019).
Costales, C. et al. Vaccine-associated measles encephalitis in immunocompromised child, California, USA. Emerg. Infect. Dis. 28 , 906–908 (2022).
Moens, L. et al. A novel kindred with inherited STAT2 deficiency and severe viral illness. J. Allergy Clin. Immunol. 139 , 1995–1997.e9 (2017).
van den Berg, B. et al. Guillain–Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat. Rev. Neurol. 10 , 469–482 (2014).
Leonhard, S. E. et al. An international perspective on preceding infections in Guillain–Barré syndrome: the IGOS-1000 cohort. Neurology 99 , e1299–e1313 (2022).
Pritchard, J. & Hughes, R. A. Guillain–Barré syndrome. Lancet 363 , 2186–2188 (2004).
Drenthen, J. et al. Guillain–Barré syndrome subtypes related to Campylobacter infection. J. Neurol. Neurosurg. Psychiatry 82 , 300–305 (2011).
Hurwitz, E. S., Schonberger, L. B., Nelson, D. B. & Holman, R. C. Guillain–Barré syndrome and the 1978–1979 influenza vaccine. N. Engl. J. Med. 304 , 1557–1561 (1981).
Kurland, L. T., Wiederholt, W. C., Kirkpatrick, J. W., Potter, H. G. & Armstrong, P. Swine influenza vaccine and Guillain–Barré syndrome. Epidemic or artifact? Arch. Neurol. 42 , 1089–1090 (1985).
Martin Arias, L. H., Sanz, R., Sainz, M., Treceno, C. & Carvajal, A. Guillain–Barré syndrome and influenza vaccines: a meta-analysis. Vaccine 33 , 3773–3778 (2015).
Boender, T. S., Bartmeyer, B., Coole, L., Wichmann, O. & Harder, T. Risk of Guillain–Barré syndrome after vaccination against human papillomavirus: a systematic review and meta-analysis, 1 January 2000 to 4 April 2020. Eur. Surveill. 27 , 2001619 (2022).
Article CAS Google Scholar
Goud, R. et al. Risk of Guillain–Barré syndrome following recombinant zoster vaccine in Medicare beneficiaries. JAMA Intern. Med. 181 , 1623–1630 (2021).
Melgar, M. et al. Use of respiratory syncytial virus vaccines in older adults: recommendations of the Advisory Committee on Immunization Practices — United States, 2023. Am. J. Transpl. 23 , 1631–1640 (2023).
Article Google Scholar
Keh, R. Y. S. et al. COVID-19 vaccination and Guillain–Barré syndrome: analyses using the National Immunoglobulin Database. Brain 146 , 739–748 (2023).
Anjum, Z. et al. Guillain–Barré syndrome after mRNA-1273 (Moderna) COVID-19 vaccination: a case report. Clin. Case Rep. 10 , e05733 (2022).
Abara, W. E. et al. Reports of Guillain–Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw. Open 6 , e2253845 (2023).
McNeil, M. M. et al. Adverse events following adenovirus type 4 and type 7 vaccine, live, oral in the Vaccine Adverse Event Reporting System (VAERS), United States, October 2011–July 2018. Vaccine 37 , 6760–6767 (2019).
Jacobs, B. C. et al. The spectrum of antecedent infections in Guillain–Barré syndrome: a case–control study. Neurology 51 , 1110–1115 (1998).
Allen, C. M. et al. Guillain–Barré syndrome variant occurring after SARS-CoV-2 vaccination. Ann. Neurol. 90 , 315–318 (2021).
Maramattom, B. V. et al. Guillain–Barré syndrome following ChAdOx1-S/nCoV-19 vaccine. Ann. Neurol. 90 , 312–314 (2021).
Shoamanesh, A. & Traboulsee, A. Acute disseminated encephalomyelitis following influenza vaccination. Vaccine 29 , 8182–8185 (2011).
Baxter, R. et al. Acute demyelinating events following vaccines: a case-centered analysis. Clin. Infect. Dis. 63 , 1456–1462 (2016).
Constantinescu, C. S., Farooqi, N., O’Brien, K. & Gran, B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharmacol. 164 , 1079–1106 (2011).
Plesner, A. M., Arlien-Soborg, P. & Herning, M. Neurological complications and Japanese encephalitis vaccination. Lancet 348 , 202–203 (1996).
Ohtaki, E., Matsuishi, T., Hirano, Y. & Maekawa, K. Acute disseminated encephalomyelitis after treatment with Japanese B encephalitis vaccine (Nakayama-Yoken and Beijing strains). J. Neurol. Neurosurg. Psychiatry 59 , 316–317 (1995).
Francis, A., Palace, J. & Fugger, L. MOG antibody-associated disease after vaccination with ChAdOx1 nCoV-19. Lancet Neurol. 21 , 217–218 (2022).
Francis, A. G. et al. Acute inflammatory diseases of the central nervous system after SARS-CoV-2 vaccination. Neurol. Neuroimmunol. Neuroinflamm. 10 , e200063 (2023).
Rinaldi, V., Bellucci, G., Romano, A., Bozzao, A. & Salvetti, M. ADEM after ChAdOx1 nCoV-19 vaccine: a case report. Mult. Scler. 28 , 1151–1154 (2022).
Copland, E. Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England. Nat. Commun. 15 , 3822 (2024).
Miller, E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346 , f794 (2013).
Kornum, B. R. et al. Narcolepsy. Nat. Rev. Dis. Prim. 3 , 16100 (2017).
Nohynek, H. et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7 , e33536 (2012).
Ahmed, S. S. et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl. Med. 7 , 294ra105 (2015).
Hallberg, P. et al. Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. eBioMedicine 40 , 595–604 (2019).
Bomfim, I. L. et al. The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene–environment interaction. Genes Immun. 18 , 75–81 (2017).
Hippisley-Cox, J. et al. Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. BMJ 374 , n1931 (2021).
Malas, M. B. et al. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis. eClinicalMedicine 29 , 100639 (2020).
Schultz, N. H. et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N. Engl. J. Med. 384 , 2124–2130 (2021).
Kelton, J. G., Arnold, D. M. & Nazy, I. Lessons from vaccine-induced immune thrombotic thrombocytopenia. Nat. Rev. Immunol. 21 , 753–755 (2021).
Kanack, A. J. et al. Monoclonal and oligoclonal anti-platelet factor 4 antibodies mediate VITT. Blood 140 , 73–77 (2022).
Pavord, S. et al. Vaccine induced immune thrombocytopenia and thrombosis: summary of NICE guidance. BMJ 375 , n2195 (2021).
Kanack, A. J. et al. Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies. Am. J. Hematol. 97 , 519–526 (2022).
Marks, P. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. FDA https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine (2021).
Vaxzevria (previously COVID-19 Vaccine AstraZeneca). European Medicines Agency https://www.ema.europa.eu/en/medicines/human/EPAR/vaxzevria-previously-covid-19-vaccine-astrazeneca (2024).
Sahin, U., Kariko, K. & Tureci, O. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13 , 759–780 (2014).
Martinon, F. et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 23 , 1719–1722 (1993).
Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20 , 817–838 (2021).
Patone, M. et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat. Med. 28 , 410–422 (2022).
Patone, M. et al. Risk of myocarditis after sequential doses of COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Circulation 146 , 743–754 (2022).
Ihle-Hansen, H. et al. Stroke after SARS-CoV-2 mRNA vaccine: a nationwide registry study. Stroke 54 , e190–e193 (2023).
Stefanou, M. I. et al. Acute arterial ischemic stroke following COVID-19 vaccination: a systematic review and meta-analysis. Neurology 99 , e1465–e1474 (2022).
Lu, Y. et al. Stroke risk after COVID-19 bivalent vaccination among US older adults. JAMA 331 , 938–950 (2024).
Rakusa, M. et al. COVID-19 vaccination hesitancy among people with chronic neurological disorders: a position paper. Eur. J. Neurol. 29 , 2163–2172 (2022).
Farez, M. F. & Correale, J. Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Arch. Neurol. 68 , 1267–1271 (2011).
Huttner, A. et al. Risk of MS relapse after yellow fever vaccination: a self-controlled case series. Neurol. Neuroimmunol. Neuroinflamm. 7 , e726 (2020).
Papeix, C. et al. Multiple sclerosis: is there a risk of worsening after yellow fever vaccination? Mult. Scler. 27 , 2280–2283 (2021).
Labani, A. et al. Incidence of multiple sclerosis relapses and pseudo-relapses following COVID-19 vaccination. Mult. Scler. Relat. Disord. 77 , 104865 (2023).
Langer-Gould, A. et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol. 71 , 1506–1513 (2014).
Frahm, N. et al. SARS-CoV-2 vaccination in patients with multiple sclerosis in Germany and the United Kingdom: gender-specific results from a longitudinal observational study. Lancet Reg. Health Eur. 22 , 100502 (2022).
Willison, A. G. et al. SARS-CoV-2 vaccination and neuroimmunological disease: a review. JAMA Neurol. 81 , 179–186 (2024).
Wu, X., Wang, L., Shen, L. & Tang, K. Response of COVID-19 vaccination in multiple sclerosis patients following disease-modifying therapies: a meta-analysis. eBioMedicine 81 , 104102 (2022).
Winkelmann, A., Loebermann, M., Barnett, M., Hartung, H. P. & Zettl, U. K. Vaccination and immunotherapies in neuroimmunological diseases. Nat. Rev. Neurol. 18 , 289–306 (2022).
Baxter, R. et al. Recurrent Guillain–Barré syndrome following vaccination. Clin. Infect. Dis. 54 , 800–804 (2012).
Baars, A. E. et al. SARS-CoV-2 vaccination safety in Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. Neurology 100 , e182–e191 (2023).
Grohskopf, L. A. et al. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices — United States, 2022–23 Influenza Season. MMWR Recomm. Rep. 71 , 1–28 (2022).
Zinman, L. et al. Safety of influenza vaccination in patients with myasthenia gravis: a population-based study. Muscle Nerve 40 , 947–951 (2009).
Sansone, G. & Bonifati, D. M. Vaccines and myasthenia gravis: a comprehensive review and retrospective study of SARS-CoV-2 vaccination in a large cohort of myasthenic patients. J. Neurol. 269 , 3965–3981 (2022).
Pang, E. W., Lawn, N. D., Chan, J., Lee, J. & Dunne, J. W. COVID-19 vaccination-related exacerbation of seizures in persons with epilepsy. Epilepsy Behav. 138 , 109024 (2023).
Clayton, L. M. et al. The impact of SARS-CoV-2 vaccination in Dravet syndrome: a UK survey. Epilepsy Behav. 124 , 108258 (2021).
von Wrede, R., Pukropski, J., Moskau-Hartmann, S., Surges, R. & Baumgartner, T. COVID-19 vaccination in patients with epilepsy: first experiences in a German tertiary epilepsy center. Epilepsy Behav. 122 , 108160 (2021).
Edwards, K. M. & Griffin, M. R. Postmarketing vaccine safety assessments: important work in progress. JAMA 331 , 915–917 (2024).
Herati, R. S. & Wherry, E. J. What is the predictive value of animal models for vaccine efficacy in humans? Consideration of strategies to improve the value of animal models. Cold Spring Harb. Perspect. Biol. 10 , a031583 (2018).
Gonsalvez, D. G. et al. A simple approach to induce experimental autoimmune neuritis in C57BL/6 mice for functional and neuropathological assessments. J. Vis. Exp. 129 , 56455 (2017).
Google Scholar
Libbey, J. E. & Fujinami, R. S. Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 29 , 3356–3362 (2011).
Vuorela, A. et al. Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1. Nat. Commun. 12 , 2283 (2021).
Top, K. A. et al. Advancing the science of vaccine safety during the coronavirus disease 2019 (COVID-19) pandemic and beyond: launching an international network of special immunization services. Clin. Infect. Dis. 75 , S11–S17 (2022).
Collection: Immunisation Against Infectious Disease. GOV.UK. https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book (2024).
Wei, J. et al. Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom. Nat. Microbiol. 6 , 1140–1149 (2021).
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D.P.J.H. is supported by a Wellcome Trust Senior Research Fellowship (215621/Z/19/Z) and the Medical Research Foundation, and his research is supported by the UK Dementia Research Institute (Medical Research Council). L.H. is supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre, UK. L.T. is supported by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections (NIHR200907) at the University of Liverpool, UK in partnership with the UK Health Security Agency (UK HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. L.T. is based at the University of Liverpool. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or the UK HSA.
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Lahiru Handunnetthi
Oxford Vaccine Group, University of Oxford, Oxford, UK
Maheshi N. Ramasamy
Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
Lance Turtle
UK Dementia Research Institute, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
David P. J. Hunt
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L.T. has received consulting fees from the UK Medicines and Healthcare products Regulatory Agency (MHRA); consulting fees from AstraZeneca and Synairgen, paid to the University of Liverpool, UK; speakers’ fees from Eisai; and support for conference attendance from AstraZeneca. L.T. was a member of the MHRA yellow fever vaccine safety expert working group. D.P.J.H. is a Commissioner for the UK Government Commission for Human Medicines. L.H. and M.N.R. declare no competing interests.
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Handunnetthi, L., Ramasamy, M.N., Turtle, L. et al. Identifying and reducing risks of neurological complications associated with vaccination. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-01000-7
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Correlation of silent brain infarcts and leukoaraiosis in middle-aged ischemic stroke patients: a retrospective study.
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Background: Cerebrovascular diseases of the brain are usually defined by transient ischemic attacks and strokes. However, they can also cause brain injuries without neurological events. Silent brain infarcts (SBI) and leukoaraiosis are symptoms of both vascular and neurological abnormalities. This study aims to investigate the association between SBI, leukoaraiosis, and middle-aged patients with ischemic stroke. Methods: A single-centre retrospective study of 50 middle-aged, ischemic stroke patients were studied from November 2022 and May 2023. The patients were divided into two groups based on the presence or absence of leukoaraiosis. History taking, physical examination, brain CT scan, and MRI were all part of the diagnostic process. Metabolic syndrome (MetS ) was also assessed through various factors. The statistical analysis included descriptive statistics, logistic regression analysis, and chi-square test. Results: Out of the cohort comprising 50 patients, characterized by a mean age of 52.26 years (SD 5.29), 32 were male, constituting 64% of the sample. Among these patients, 26 individuals exhibited leukoaraiosis, with 17 of them (65.4%) also presenting with SBI. Moreover, within this cohort, 22 patients were diagnosed with MetS, representing 84.6% of those affected. The Multivariate logistic regression analysis showed a strong and independent association between Leukoaraiosis and SBI. Individuals with Leukoaraiosis were nearly five times more likely to have SBI compared to those without Leukoaraiosis. Conclusions: The study highlights leukoaraiosis as a significant risk factor for SBI, alongside MetS. Advanced imaging techniques have facilitated their detection, revealing a higher prevalence among stroke patients, particularly associated with age and hypertension. Further research is needed to fully understand their complex relationship and develop better management strategies for cerebrovascular diseases, ultimately improving patient outcomes.
Keywords: cerebrovascular disease, ischemic stroke, Leukoaraiosis, Silent brain infarcts, silent lacunar infarcts, metabolic syndrome
Received: 09 May 2024; Accepted: 08 Aug 2024.
Copyright: © 2024 Abdulsalam, Shaheen, Shaheen, Alabdallat, Ramadan, Meshref, Mansour, Abed, Fayed, Zaki, El-Adawy, Flouty and Hamed. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Nour Shaheen, Alexandria University, Alexandria, Egypt
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Conflicts of interest, skin nerve phosphorylated α-synuclein in the elderly. authors’ response.
Vincenzo Donadio, Rocco Liguori, Skin nerve phosphorylated α-synuclein in the elderly. Authors’ response, Journal of Neuropathology & Experimental Neurology , 2024;, nlae089, https://doi.org/10.1093/jnen/nlae089
To the Editor:
We carefully read the letter of Dr Kawada 1 related to our paper reporting the prevalence of phosphorylated α-synuclein (p-α-syn) in skin nerves in very old healthy subjects, old subjects with small fiber neuropathy and 490 healthy cases from the scientific literature for a total of 531 subjects. 2 In our paper, we disclosed that only 4 healthy subjects were reported to be positive for p-α-syn (1%). As underlined by Dr Kawada, a similar rate of p-α-syn positivity was recently reported (3.3%) in a study analyzing a large cohort of healthy subjects ( n = 120). 3 A very low positivity rate found in controls confirms that the search of the skin p-α-syn could be a highly specific tool to identify patients with an underlying synucleinopathy in vivo.
Dr Kawada also reported the possibility of finding accumulations of p-α-syn in peripheral macrophages of the skin as an alternative biomarker for PD, 4 although this finding has not been confirmed in other studies. However, Dr Kawada’s main criticism is related to the fact that skin biopsy is a time-consuming, expensive and invasive technique. Accordingly, he suggested to look for p-α-syn accumulations with alternative techniques that, however, are not mentioned or suggested in the letter.
We agree with the Dr Kawada that a less invasive technique for detecting p-α-syn would be preferable to skin biopsy but at the moment we are not aware that the evaluation offered by a skin biopsy can be obtained with another technique. Indeed, we must emphasize that the skin biopsy presents few and negligible side effects. 3 , 5–7 In fact, a direct comparison of skin biopsy with the other sample that can be used to evaluate misfolded α-syn, namely the CSF, underlined how skin biopsy presents lower and less important side effects than lumbar puncture. 8
In addition, skin biopsy is not an expensive technique because the cost of primary and secondary antibodies to obtain p-α-syn staining is in the range of a few tens of euros in a single patient with the technique that we have described. 5 , 7 In addition, the main instrumentation that must be used (cryostat and fluorescence microscope) is usually part of a neuropathology laboratory.
Furthermore, it is not a time-consuming method considering that staining the p-α-syn is achieved in 2 days, although we agree that it is a complex technique that requires adequate and prolonged training. However, skin biopsy presents the advantage of improving the in vivo diagnostic accuracy of synucleinopathies as demonstrated in all variants of synucleinopathies, including multiple system atrophy. 3 , 8–10
No funding was received.
The authors have no conflict of interest to declare.
Kawada T. Letter to the Editor: skin biopsy detection of phosphorylated α-synuclein to identify patients with synucleinopathies . J Neuropathol Exp Neurol . 2024 ; 83 .
Google Scholar
Donadio V , Fadda L , Incensi A , et al. Skin nerve phosphorylated α-synuclein in the elderly . J Neuropathol Exp Neurol . 2024 ; 83 : 245 - 250 .
Gibbons CH , Levine T , Adler C , et al. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies . JAMA . 2024 ; 331 : 1298 - 1306 .
Oizumi H , Yamasaki K , Suzuki H , et al. Phosphorylated alpha-synuclein in Iba1-positive macrophages in the skin of patients with Parkinson’s disease . Ann Clin Transl Neurol . 2022 ; 9 : 1136 - 1146 .
Donadio V , Incensi A , Cortelli P , et al. Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure . Neurology . 2013 ; 80 : 725 - 732 .
Melli G , Vacchi E , Biemmi V , et al. Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease . Ann Clin Transl Neurol . 2018 ; 5 : 1394 - 1407 .
Donadio V , Wang Z , Incensi A , et al. In vivo diagnosis of synucleinopathies: a comparative study of skin biopsy and RT-QuIC . Neurology . 2021 ; 96 : e2513 - e2524 .
Donadio V , Incensi A , Del Sorbo F , et al. Skin nerve phosphorylated α-synuclein deposits in Parkinson’s disease with orthostatic hypotension . J Neuropathol Exp Neurol . 2018 ; 77 : 942 - 949 .
Liguori R , Donadio V , Wang Z , et al. A comparative blind study between skin biopsy and seed amplification assay to disclose pathological α-synuclein in RBD . NPJ Parkinsons Dis . 2023 ; 9 : 34 .
Donadio V , Incensi A , Rizzo G , et al. Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy . Brain . 2023 ; 146 : 1065 - 1074 .
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To the Editor: We carefully read the letter of Dr Kawada 1 related to our paper reporting the prevalence of phosphorylated α-synuclein (p-α-syn) in skin nerves in very old healthy subjects, old subjects with small fiber neuropathy and 490 healthy cases from the scientific literature for a total of 531 subjects. 2 In our paper, we disclosed that only 4 healthy subjects were reported to be ...