Brainstem Gliosis Research Articles

Targeted TGF-βR2 Silencing in the Retrotrapezoid Nucleus Mitigates Respiratory Dysfunction and Cognitive Decline in a Mouse Model of Cerebral Amyloid Angiopathy with and without Stroke.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke.Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-βR2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN.CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 silencing in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 silencing similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following silencing.Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

Targeted TGF-βR2 Knockdown in the Retrotrapezoid Nucleus Mitigates Respiratory Dysfunction and Cognitive Decline in a Mouse Model of Cerebral Amyloid Angiopathy with and without Stroke.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke. Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-β2R2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN. CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 knockdown in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 knockdown similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following knockdown. Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

Neuropathology of Pediatric SARS-CoV-2 Infection in the Forensic Setting: Novel Application of Ex Vivo Imaging in Analysis of Brain Microvasculature.

Two years into the COVID-19 pandemic, there are few published accounts of postmortem SARS-CoV-2 pathology in children. We report 8 such cases (4 infants aged 7–36 weeks, 4 children aged 5–15 years). Four underwent ex vivo magnetic resonance neuroimaging, to assist in identification of subtle lesions related to vascular compromise. All infants were found unresponsive (3 in unsafe sleeping conditions); all but 1 had recent rhinitis and/or influenza-like illness (ILI) in the family; 1 had history of sickle cell disease. Ex vivo neuroimaging in 1 case revealed white matter (WM) signal hyperintensity and diffuse exaggeration of perivascular spaces, corresponding microscopically to WM mineralization. Neurohistology in the remaining 3 infants variably encompassed WM gliosis and mineralization; brainstem gliosis; perivascular vacuolization; perivascular lymphocytes and brainstem microglia. One had ectopic hippocampal neurons (with pathogenic variant in DEPDC5). Among the children, 3 had underlying conditions (e.g., obesity, metabolic disease, autism) and all presented with ILI. Three had laboratory testing suggesting multisystem inflammatory syndrome (MIS-C). Two were hospitalized for critical care including mechanical ventilation and extracorporeal membrane oxygenation (ECMO); one (co-infected with adenovirus) developed right carotid stroke ipsilateral to the ECMO cannula and the other required surgery for an ingested foreign body. Autopsy findings included: acute lung injury in 3 (1 with microthrombi); and one each with diabetic ketoacidosis and cardiac hypertrophy; coronary and cerebral arteritis and aortitis, resembling Kawasaki disease; and neuronal storage and enlarged fatty liver. All 4 children had subtle meningoencephalitis, focally involving the brainstem. On ex vivo neuroimaging, 1 had focal pontine susceptibility with corresponding perivascular inflammation/expanded perivascular spaces on histopathology. Results suggest SARS-CoV-2 in infants may present as sudden unexpected infant death, while in older children, signs and symptoms point to severe disease. Underlying conditions may predispose to fatal outcomes. As in adults, the neuropathologic changes may be subtle, with vascular changes such as perivascular vacuolization and gliosis alongside sparse perivascular lymphocytes. Detection of subtle vascular pathology is enhanced by ex vivo neuroimaging. Additional analysis of the peripheral/autonomic nervous system and investigation of co-infection in children with COVID-19 is necessary to understand risk for cardiovascular collapse/sudden death.

Abstract P740: Late Effects of Bilateral Carotid Artery Stenosis in an Aged Mouse Model

Bilateral carotid artery stenosis (BCAS) or global hypoperfusion is an experimental model of vascular dementia known to effect cognition. Chronic global hypoperfusion increases astrogliosis within the cortex and hippocampus, leading to reduced cognition. It is unknown if global hypoperfusion leads to respiratory deficits that could contribute to cognitive decline. We hypothesized that chronic global hypoperfusion in cerebral blood flow will lead to brain stem gliosis, respiratory dysfunction and progressive cognitive impairment. Female C57Bl/6 mice aged 18 months underwent BCAS (n=8) or sham (n=8) surgery to investigate changes in respiration (frequency, tidal volume, apneas), cognition (y-maze-spatial working memory and fear conditioning-contextual working memory), and changes in cortical and brain stem astrogliosis. Results demonstrated BCAS mice had decreased respiratory frequency and apneas (p<0.05), decreased cognition in both spatial and contextual working memory (p<0.05), and increased astrogliosis (p<0.01) within the cortex and brain stem. To determine if increased astrogliosis within the cortex and brain stem contributes to changes in respiration and delayed cognitive deficits, we administered a TGF-β inhibitor (Gw788388 Hydrate) through an osmotic pump 7 days post-BCAS or sham surgery and followed the mice for 56 days post-surgery. Results demonstrated a reduction in periodic apneas (p<0.01), cognitive deficits (p<0.05), and amelioration in gliosis (p<0.01) when comparing BCAS and sham mice. In conclusion, this study demonstrated global hypoperfusion leads to disrupted respiratory function, late cognitive deficits, and increased brain stem gliosis, that can be rescued through administration of TGF-β inhibitor. Respiratory instability may contribute to post-stroke cognitive deficits, and could be a therapeutic target to improve outcomes in patients with vascular dementia.

Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS

Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1G93A allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices.

Neuropathologic Examination in Sudden Unexpected Deaths in Infancy and Childhood: Recommendations for Highest Diagnostic Yield and Cost-Effectiveness in Forensic Settings.

In infants and toddlers (less than four years of age), determination of cause and manner of death often requires a complete autopsy. Few evidence-based guidelines exist regarding optimum nervous system sectioning in this population. Over a six-month interval and using a comprehensive section protocol, we categorized cases having neuropathological findings that were critical (Class A), contributory (Class B), or noncontributory (Class C) to the final cause and manner of death. We further evaluated which sections helped make this determination. Among 53 cases (44 infants, 9 toddlers; 26 girls, 27 boys), Class A neuropathology was noted in nine (16.9%). Seven infants had meningoencephalitis (2/7, 28.6%), craniospinal trauma (3/7, 42.8%), brainstem necrosis suggesting Leigh Disease (1/7, 14.3%), and hydrocephalus in Dandy-Walker malformation (1/7, 14.3%); two toddlers had inflicted craniospinal trauma (2/2, 100%). Class B factors were identified in 11/53 (20.8%), including recent hypoxic-ischemic lesions (2/11, 18.2%), meningitis or dural venous sinus thrombosis in systemic sepsis (2/11, 18.2%), multicystic encephalopathy following peripartum asphyxia (2/11, 18.2%), and microcephaly and delayed myelination (Cri-du-Chat Syndrome) (1/11, 9.09%). Class B also included three toddlers (3/11, 27.2%) with features of hippocampal dysgenesis, two in the setting of febrile seizures. Class C comprised normal brains (3/53, 5.7%), and those with findings of uncertain significance, such as white matter and brainstem gliosis (30/53, 56.6%). The sections most valuable for detection of relevant pathology, and thus recommended for routine sampling, were: 1) bilateral hippocampus; 2) cerebral cortex and leptomeninges; and 3) pons or medulla.

Microglia modulate brainstem serotonergic expression following neonatal sustained hypoxia exposure: implications for sudden infant death syndrome.

Neonatal sustained hypoxia exposure modifies brainstem microglia and serotonin expression. The altered brainstem neurochemistry is associated with impaired ventilatory responses to acute hypoxia and mortality. The deleterious effects of sustained hypoxia exposure can be prevented by an inhibitor of activated microglia. These observations demonstrate a potential cause of the brainstem serotonin abnormalities thought to be involved in sudden infant death syndrome. We showed previously that the end of the second postnatal week (days P11-15) represents a period of development during which the respiratory neural control system exhibits a heightened vulnerability to sustained hypoxia (SH, 11% O2 , 5days) exposure. In the current study, we investigated whether the vulnerability to SH during the same developmental time period is associated with changes in brainstem serotonin (5-HT) expression and whether it can be prevented by the microglia inhibitor minocycline. Using whole-body plethysmography, SH attenuated the acute (5min) hypoxic ventilatory response (HVR) and caused a high incidence of mortality compared to normoxia rats. SH also increased microglia cell numbers and decreased 5-HT immunoreactivity in the nucleus of the solitary tract (nTS) and dorsal motor nucleus of the vagus (DMNV). The attenuated HVR, mortality, and changes in nTS and DMNV immunoreactivity was prevented by minocycline (25mgkg(-1) /2days during SH). These data demonstrate that the 5-HT abnormalities in distinct respiratory neural control regions can be initiated by prolonged hypoxia exposure and may be modulated by microglia activity. These observations share several commonalities with the risk factors thought to underlie the aetiology of sudden infant death syndrome, including: (1) a vulnerable neonate; (2) a critical period of development; (3) evidence of hypoxia; (4) brainstem gliosis (particularly the nTS and DMNV); and (5) 5-HT abnormalities.

Review: Neuropathological features of unexplained sudden unexpected death in infancy: current evidence and controversies

Sudden infant death syndrome (SIDS) is a leading cause of postneonatal infant death in the developed world. The cause of SIDS is unknown but several hypotheses have been proposed, including the 'triple risk hypothesis', which predicts that foetal development of infants who subsequently succumb to SIDS is abnormal, leaving them unable to respond appropriately to stressors. Consistent with this hypothesis, a large number of studies have reported changes in the brain in SIDS. However, on nearly every subject, the reported findings vary widely between studies. Inconsistencies in the definitions of SIDS used and in control group selection are likely to underlie much of this variability. Therefore, in our analysis, we have included only those studies that met simple criteria for both the definition of SIDS and the control group. Of the 153 studies retrieved by our review of the literature, 42 (27%) met these criteria. Foremost among the findings reported by these studies are abnormalities of the brain stem, in particular brain stem gliosis and defects of neurotransmission in the medulla. However, these studies have not identified what could be considered in diagnostic terms a causative structural or biochemical abnormality for use in routine clinical practice. An assessment of changes in the architecture and composition of brain regions and changes in neurotransmission in multiple systems in a single, large cohort of well- and consistently characterized infants dying suddenly of a range of causes is needed before the inter-relation of these different features can be appreciated.

Minocycline prevents the attenuated acute hypoxic ventilatory response and changes in brainstem neurochemistry following neonatal sustained hypoxia exposure (1092.11)

Sustained hypoxia (SH) exposure uniquely during the end of the second postnatal week of life (postnatal (P) age 11‐15) attenuates the acute hypoxic ventilatory response (HVR) in rats. In the current study, we investigated whether the microglia inhibitor minocycline would be protective against the SH‐induced attenuation of the HVR and changes in brainstem neurochemistry. Neonatal rats were exposed to SH (11% O2, 5 days) starting at P11 and received an i.p. injection of minocycline (25mg/kg) or saline midway into the exposure period; plethysmography and measurements of brainstem immunoreactivity for Iba1 and 5‐HT were performed the day after SH ended (P16). SH exposure attenuated the HVR, increased Iba1 and decreased 5‐HT immunoreactivity in the nTS compared normoxia raised rats. Minocycline prevented the SH‐induced attenuated HVR including the changes in nTS Iba1 and 5‐HT immunoreactivity. We speculate that brainstem microglia may be involved in SH‐induced changes in brainstem neurochemistry leading to a 5‐HT‐induced modification of the mechanisms mediating the acute HVR. These data share several similarities to Sudden Infant Death Syndrome victims including evidence of impaired (cardio)‐respiratory control, brainstem gliosis, and serotonergic deficits associated with a vulnerability to an environmental stressor.

Similarities between familial and sporadic autopsy-proven progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a relatively common neurodegenerative tauopathy clinically characterized by parkinsonism, axial rigidity, and supranuclear gaze palsy. Pathologic findings of PSP are neuronal loss, gliosis, and neurofibrillary tangles in basal ganglia, diencephalon, and brainstem; there is increasing recognition of clinicopathologic variants of PSP.(1.)

Autopsy-proven progressive supranuclear palsy presenting as behavioral variant frontotemporal dementia

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by neuronal loss, gliosis and tau-positive neurofibrillary tangles in basal ganglia, brainstem and cerebellar nuclei. Five presenting clinical syndromes of PSP are well-described: (i) the classic Richardson's syndrome; (ii) asymmetric parkinsonism with tremor; (iii) freezing of gait; (iv) asymmetric limb apraxia, and (v) apraxia of speech. Aim: To determine whether autopsy-proven PSP cases may present with another clinical phenotype. Methods: Medical records of 66 autopsy-proven PSP cases between 1973 and 2010 were reviewed to determine whether all could be classified into one of five well-defined syndromes listed above. Three cases presented with prominent behavioral and personality changes, meeting diagnosis of behavioral variant frontotemporal dementia. MRI midbrain and pons volumes and pons/midbrain ratios were compared to healthy controls and typical PSP cases. Results: All three bvFTD cases developed at least one PSP symptom or sign that emerged up to 5 years after initial presentation. One case was re-diagnosed as PSP 6 years after presentation as bvFTD. Compared to controls, midbrain volume was significantly smaller in both bvFTD (p = .03) and PSP cases (p = .008), without significant difference between PSP and bvFTD cases (.44). However pontine volumes were similar across all three groups. Conclusions: While most autopsy-confirmed PSP cases present with one of the five well-described syndromes, there are cases that may present as bvFTD. In these, at least one cardinal symptom or sign of PSP later emerges, associated with smaller midbrain volume and increased pons/midbrain ratio. Thus underlying PSP pathology should be considered in these cases.

Paraneoplastic Jaw Dystonia and Laryngospasm With Antineuronal Nuclear Autoantibody Type 2 (Anti-Ri)

Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. Retrospective case series with prospective clinical follow-up. Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Symmetric corticobasal degeneration (S-CBD)

Background Corticobasal degeneration (CBD) is a neurodegenerative disease characterized pathologically by neuronal loss, gliosis and tau deposition in neocortex, basal ganglia and brainstem. Typical clinical presentation is known as corticobasal syndrome (CBS) and involves the core features of progressive asymmetric rigidity and apraxia, accompanied by other signs of cortical and extrapyramidal dysfunction. Asymmetry is also emphasized on neuroimaging. Objective To describe a series of cases of CBD with symmetric clinical features and to compare clinical and imaging features of these symmetric CBD cases (S-CBD) to typical cases of CBS with CBD pathology. Methods All cases of pathologically confirmed CBD from the Mayo Clinic Rochester database were identified. Clinical records were reviewed and quantitative volumetric analysis of symmetric atrophy on head MRI using atlas based parcellation was performed. Subjects were classified as S-CBD if no differences had been observed between right- and left-sided cortical or extrapyramidal signs or symptoms. S-CBD cases were compared to 10 randomly selected typical CBS cases. Results Five cases (2 female) met criteria for S-CBD. None had limb dystonia, myoclonus, apraxia or alien limb phenomena. S-CBD cases had significantly less asymmetric atrophy when compared with CBS cases ( p = 0.009); they were also younger at onset (median 61 versus 66 years, p < 0.05) and death (67 versus 73 years, p < 0.05). Family history was present in 40% of S-CBD cases. Conclusions CBD can have a symmetric presentation, clinically and radiologically, in which typical features of CBS, such as limb apraxia, myoclonus, dystonia and alien limb phenomenon, may be absent.

Brainstem mechanisms underlying the sudden infant death syndrome: Evidence from human pathologic studies

The brainstem hypothesis is one of the leading hypotheses concerning the sudden infant death syndrome (SIDS). It states that SIDS, or an important subset of SIDS, is due to abnormal brainstem mechanisms in the control of respiration, chemosensitivity, autonomic regulation, and/or arousal which impairs the infant's response to life-threatening, but often occurring, stressors during sleep (e.g., hypoxia, hypercarbia, asphyxia, hyperthermia) and leads to sudden death in a vulnerable developmental period. In this review, we summarize neuropathologic evidence from SIDS cases that support this hypothesis, beginning with the seminal report of subtle brainstem gliosis three decades ago. We focus upon recent neurochemical studies in our laboratory concerning the neurotransmitter serotonin (5-HT) and its key role in mediating protective responses to homeostatic stressors via medullary circuits. The possible fetal origin of brainstem defects in SIDS is reviewed, including evidence for adverse effects of prenatal exposure to maternal cigarette smoking and alcohol upon the postnatal development of human brainstem 5-HT pathways.

Neuronal cell death in the arcuate nucleus of the medulla oblongata in stillbirth

The hypothesis that unexplained stillbirth arises in a similar manner as the sudden infant death syndrome (SIDS) is based in part on shared neuropathologic features between the two entities, including hypoxic-ischemic lesions such as white matter and brainstem gliosis, as well as aplasia or hypoplasia of the arcuate nucleus on the ventral surface of the medulla. The arcuate nucleus is the putative homologue of the respiratory chemosensory region at the ventral medullary surface in animals that is involved in central chemosensitivity. To determine arcuate nucleus pathology in stillbirth, and its co-occurrence with evidence of hypoxia-ischemia, we reviewed brain specimens from the archives of our hospitals from 22 consecutive stillbirths from 22 to 41 gestational weeks. Explained causes of death (n=17) included nuchal cord, acute chorioamnionitis, placental abruption, and fetal glomerulosclerosis; 5 cases were unexplained. In 12 brains, we observed nuclear karyorrhexis and/or pyknosis with cytoplasmic hypereosinophilia in neurons in the arcuate nucleus in both explained (n=8) and unexplained (n=4) cases (54.5% of total cases). Three additional cases had arcuate aplasia (n=1) or hypoplasia (n=2) (13.6% of total cases); one of the latter cases also had neuronal necrosis in the hypoplastic arcuate. The degree of gliosis in the region of the arcuate nucleus was variable across all cases, without statistically significant differences between groups with and without arcuate nucleus necrosis. Other lesions in association with (n=14) and without (n=8) arcuate nucleus abnormalities were diffuse cerebral white matter gliosis, periventricular leukomalacia (PVL), and neuronal necrosis in the hippocampus, basal ganglia, thalamus, basis pontis, and brainstem tegmentum. In 16/20 (80.0%) cases (with or without histologic necrosis of the arcuate), immunostaining with caspase-3 demonstrated positive neurons. Our findings suggest that neuronal pathology in the arcuate nucleus may be both developmental (13.6%) and acquired (54.5%). The association of neuronal necrosis and apoptosis in the arcuate nucleus with systemic entities involving fetal ischemia, and with other brain lesions consistent with ischemia, e.g., cerebral white matter gliosis, suggests that ischemia plays a role in the arcuate nucleus damage as well. Thus, the underpopulation of arcuate neurons detected postnatally in some SIDS infants may be secondary to an acquired insult in mid- or late gestation, and in other cases, a primary developmental lesion in early gestation, or both. The role of arcuate nucleus pathology in the pathogenesis of fetal demise remains to be determined.

Leigh Syndrome: An MR Study of Three Cases

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is the most common childhood mitochondrial encephalopathy, accounting for more than 50% of cases in this age group. Its estimated incidence is 1:40,000 - 1:77,000 liveborn infants a year. LS is a rare progressive multisystem fatal disorder inherited by autosomal recessive, X-linked and maternal transmission. Clinical onset is predominantly in the first two years of life (average: six months); 50% of patients die within a year, even though there are later- and even adult-onset forms with a more protracted evolution. LS is due to a deficit of various respiratory chain and Krebs cycle enzymes resulting in insufficient production of adenosine triphosphate (ATP), in particular cytochrome-c-oxidase (COX), pyruvate carboxylase, pyruvate dehydrogenase complex and complex I of the respiratory chain, which share an autosomal recessive and X-linked mode of transmission. Cases with maternal inheritance (MILS) are due to a mitochondrial DNA (mtDNA) point mutation. LS is clinically heterogeneous in relation to the severity of the metabolic dysfunction and is characterized by muscle involvement and especially CNS disorders, particularly psychomotor retardation, ocular symptoms, hypotonia and pyramidal signs. Death is most commonly due to respiratory failure, status epilepticus and sudden coma. The major neuropathological findings, first described by Leigh in 1951, are symmetrical foci of spongy necrosis associated with vessel proliferation and reactive gliosis in basal nuclei, brainstem and thalamus grey matter. The neuronal metabolic alteration can also affect the white matter, resulting in delayed myelination or hypomyelination. The diagnosis rests on clinical signs, elevated CSF lactate, pyruvate and alanine, and biochemical and neuroradiological data. We describe two patients with LS studied with morphological MR associated with diffusion and spectroscopy techniques to assess the diagnostic potential of standard MR imaging and establish whether the association of functional MR methods can improve its diagnostic accuracy. A case of LS with a post-mortem MR study is also described. Three patients with a diagnosis of LS based on clinical, CSF and laboratory data were studied on a GE SIGNA EXCITE 1.5 T unit using an eight-channel phased-array head coil to acquire standard sequences (SE T1; TSE DP T2; FLAIR) and echo-planar diffusion-weighted sequences (DWI; b= 1000 s/mm2) with calculation of ADC maps. The spectroscopic study used single-voxel (TE/TR ms = 144/1500) and multi-voxel techniques (TE/TR ms = 144/1000) at the level of the basal nuclei. Bilateral and symmetrical involvement of basal nuclei grey matter with T2 hyperintensity was a consistent finding in the morphological MR study. In one patient, associated white matter involvement with T2 hyperintensity in periventricular and retrotrigonal areas reflected delayed myelination or hypomyelination. The deep grey matter changes, sometimes associated with white matter lesions, suggested a diagnosis of subacute necrotizing encephalomyelopathy, in line with the literature. Acute-phase ADC values in affected areas were lower than those of normal grey and white matter and displayed signal hyperintensity on DWI. Reduced ADC values are associated with restricted water diffusivity typical of cytotoxic edema. Spectroscopy showed a high lactate peak, reflecting altered anaerobic glycolysis, and a reduced NAA peak in affected areas, which are however non-specific findings. The most informative study in these patients is standard MR associated with functional techniques, which can confirm the diagnosis obtained with morphological imaging.

Progressive Supranuclear Palsy: Pathology and Genetics

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia. Neuropathologically, the subthalamic nucleus and brainstem, especially the midbrain tectum and the superior cerebellar peduncle, show atrophy. The substantia nigra shows loss of pigment corresponding to nigrostriatal dopaminergic degeneration. Microscopic findings include neuronal loss, gliosis and neurofibrillary tangles in basal ganglia, diencephalon and brainstem. Characteristic tau pathology is also found in glia. The major genetic risk factor for sporadic PSP is a common variant in the gene encoding microtubule-associated protein tau (MAPT) and recent studies have suggested that this may result in the altered expression of specific tau protein isoforms. Imaging studies suggest that there may be sensitive and specific means to differentiate PSP from other parkinsonian disorders, but identification of a diagnostic biomarker is still elusive.

Possible Pathomechanisms of Sudden Infant Death Syndrome

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children.

Clinicopathological correlation between brainstem gliosis using GFAP as a marker and sleep apnea in the sudden infant death syndrome

Background: Chronic hypoxia, leading to brainstem gliosis, has been postulated as a factor in the sudden infant death syndrome (SIDS), which is still the main cause of postneonatal infant death. Gliosis detected by immunohistochemistry of glial fibrillary acidic protein (GFAP) is a marker of apoptosis. The correlation between GFAP-positive reactive astrocytes in the brainstem and sleep apnea in SIDS was investigated. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, including 26 cases of SIDS. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected and immunohistochemistry of GFAP carried out. The density of GFAP-positive reactive astrocytes was measured quantitatively. Correlation analyses were carried out between the data on gliosis and the physiological data of sleep apnea. Results: A SIDS-specific negative correlation between the density of gliosis in the dorsal vagus nucleus in the medulla oblongata and the frequency of obstructive apnea ( P=0.022) was found. Conclusions: A significant SIDS-specific correlation with gliosis in the dorsal vagus nucleus and the characteristics of sleep apnea might invite the cardiorespiratory changes in SIDS.

Clinicopathological correlation between brainstem gliosis using GFAP as a marker and sleep apnea in the sudden infant death syndrome

Background: Chronic hypoxia, leading to brainstem gliosis, has been postulated as a factor in the sudden infant death syndrome (SIDS), which is still the main cause of postneonatal infant death. Gliosis detected by immunohistochemistry of glial fibrillary acidic protein (GFAP) is a marker of apoptosis. The correlation between GFAP-positive reactive astrocytes in the brainstem and sleep apnea in SIDS was investigated. Materials and Methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, including 26 cases of SIDS. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected and immunohistochemistry of GFAP carried out. The density of GFAP-positive reactive astrocytes was measured quantitatively. Correlation analyses were carried out between the data on gliosis and the physiological data of sleep apnea. Results: A SIDS-specific negative correlation between the density of gliosis in the dorsal vagus nucleus in the medulla oblongata and the frequency of obstructive apnea ( p=0.022) was found. Conclusions: A significant SIDS-specific correlation with gliosis in the dorsal vagus nucleus and the characteristics of sleep apnea might invite the cardiorespiratory changes in SIDS.