A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer's disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05821153.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

Tropical spastic paraparesis.

A large number of causative agents can result in spinal cord disorders in the tropics including etiologies similar to those of temperate regions such as trauma, spinal bone and disc lesions, tumors, epidural abscess, and congenital malformations. Yet infectious and nutritional disorders differ in their higher prevalence in tropical regions including Pott's disease; brucellosis; neuroborreliosis; various parasitic diseases such as schistosomiasis, neurocysticercosis, and eosinophilic meningitis. Notably, the retrovirus HTLV-1 is the causeof tropical spastic paraparesis/paraplegia or TSP. Nutritional causes of TSP include vitamin B and folate deficiencies, while endemic clusters of konzo and tropical ataxic myeloneuropathy occur in Africa, along with malnutrition and excessive consumption of cyanide-containing bitter cassava. Other toxic etiologies of TSP include lathyrism and fluorosis. Nutritional forms of myelopathy are associated often with optic and sensory neuropathy, hence the name tropical myeloneuropathies. Acute transverse myelopathy, seen in association with vaccination, infections, and fibrocartilaginous embolism of the nucleus pulposus, can be ubiquitous. Multiple sclerosis and optic myelopathy occur in the tropics but with lesser prevalence than in temperate regions. The advent of modern imaging in the tropics, including computed tomography and magnetic resonance imaging, has allowed better diagnosis and treatment of these conditions that are a frequent cause of death and disability. This chapter provides an overview of TSP emphasizing the most common causes with clues to diagnosis and effective therapy.

What does aducanumab treatment of Alzheimer's disease mean for research on vascular cognitive disorders?

•Controversial registration of aducanumab for Alzheimer's Disease•Aducanumab is the subject of post-licensing observational studies aiming to follow the effects of the drug•Given the high prevalence of cerebrovascular pathology it is important that these studies do not ignore vascular cognitive disorders•The studies may give detailed phenotyping data that may lead to knowledge of targets for treatments of patients with vascular cognitive disorders.

Pleural effusion and respiratory compromise from spontaneous migration of a ventriculoperitoneal shunt catheter in a patient with normal-pressure hydrocephalus.

Background: Ventriculoperitoneal shunt (VPS) insertion is one of the most common neurosurgical procedures done around the world to treat hydrocephalus. The occurrence of spontaneous migration of the peritoneal shunt catheter into the thoracic cavity is a very rare complication; we report here case number 27 of respiratory complications of a VPS in a patient with normal-pressure hydrocephalus (NPH). Case Description: A 76-year-old woman with Alzheimer's disease and anosognosia was diagnosed idiopathic NPH treated surgically with a VPS. Pleural effusion and pulmonary complications occurred 4 weeks after the insertion of the shunt due to the spontaneous migration of the peritoneal catheter of the VPS into the thoracic cavity. The hydrothorax of cerebrospinal fluid was drained and the distal catheter was removed and replaced. The patient made an uneventful recovery. Conclusion: Due to the rarity of this complication, there are no standard corrective procedures. Some of the methods used to diagnose and successfully treat this rare complication of the VPS are presented.

Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies.

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-ß, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.

The pericyte: A critical cell in the pathogenesis of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.

Colgajo naso geniano para reconstrucción de lesiones de cavidad oral: Reporte de Caso / Nasogenian flap for reconstruction of oral cavity lesions a Case report / Retalho nasogeniano para reconstrução de lesões da cavidade oral a Relato de caso

Introducción: La maxilectomía es la intervención quirúrgica recomendada para la exéresis de neoplasias faciales, esta técnica comprende la resección de los maxilares y de estructuras anatómicas adyacentes, y conlleva diferentes grados de alteración funcional. La reconstrucción de defectos medio faciales re-presenta un gran desafío, se utilizan diferentes técnicas desde el uso de prótesis obturadoras, colgajos locales, hasta colgajos libres, con la finalidad de la mayor recuperación de funciones sofisticadas como el habla, la deglución y la ventilación en vía área superior. Reporte de caso: Paciente hombre de 89 años de edad con 4 meses de evolución de masa tumoral decrecimiento progresivo y constante en la mitad del paladar superior y se extiende tomando el maxilar superior derecho. Al examen físico se observa la cavidad con deficiente cuidado de las piezas dentales y una masa tumoral de más de 15 cm de diámetro que deforma la cavidad oral. Evolución: Se realizó tumorectomía y vaciamiento ganglionar con preservación de nervio espinal, hipogloso, lingual, musculo esternocleidomastoideo, vena yugular interna, vena y arteria facial. Se realizó una reconstrucción de neopaladar con colgajo nasogeniano. La patología definitiva recibida en días posteriores reportó un carcinoma escamo celular pobremente diferenciado de estirpe epitelial con borde quirúrgico positivo para el tumor. Dentro del período postoperatorio el paciente presentó una neumonía asociada a los cuidados de la salud, acompañada con déficit neurológico, el cuadro involucionó hasta sepsis de origen pulmonar y fallece 21 días posteriores a la cirugía. Conclusiones: El crecimiento acelerado de una masa del maxilar en este paciente se asoció con la presencia de un carcinoma escamo celular pobremente diferenciado.

Introduction: Maxillectomy is the recommended surgical intervention for the excision of facial neoplasms. This technique includes the resection of the jaws and adjacent anatomical structures, and en-tails different degrees of functional alteration. The reconstruction of mid-facial defects represents a great challenge, different techniques are used from the use of obturator prostheses, local flaps, to free flaps, with the aim of greater recovery of sophisticated functions such as speech, swallowing and ventilation in via upper area. Case report: An 89-year-old male patient with a 4-month evolution of a tumor mass with progressive and constant growth in the middle of the upper palate and extending taking the right upper jaw. Physical examination revealed the cavity withpoor dental care and a tumor mass of more than 15 cm in diameter that deformed the oral cavity. Evolution: A lumpectomy and lymph node dissection were performed with preservation of the spinal, hypoglossal, lingual, sternocleidomastoid muscle, internal jugular vein, vein and facial artery. A neo-palatal reconstruction with a nasolabial flap was performed. The definitive pathology received in later days reported a poorly differentiated squamous cell carcinoma of epithelial lineage with a positive surgical border for the tumor. Within the postoperative period, the patient presented pneumonia associated with health care, accompanied by neurological deficit, the condition regressed to sepsis of pulmonary origin and died 21 days after surgery. Conclusions: The accelerated growth of a maxillary mass in this patient was associated with the pres-ence of a poorly differentiated squamous cell carcinoma.

Introdução: A maxilectomia é a intervenção cirúrgica recomendada para a excisão de neoplasias faciais, esta técnica inclui a ressecção da mandíbula e das estruturas anatômicas adjacentes e acarreta diferentes graus de alteração funcional. A reconstrução dos defeitos médios da face representa um grande desafio, diferentes técnicas são utilizadas desde o uso de próteses obturadoras, retalhos locais, até retalhos livres, com o objetivo de maior recuperação de funções sofisticadas como fala, deglutição e ventilação em via. . Relato do caso: Paciente do sexo masculino, 89 anos, com evolução de 4 meses de massa tumoral progressiva e constante decrescente em meio palato superior e extensão em maxilar superior direito. Ao exame físico, observa-se cavidade com mau atendimento odontológico e massa tumoral de mais de 15 cm de diâmetro que forma a cavidade oral. Evolução: Realizada lumpectomia e dissecção dos linfonodos com preservação da coluna vertebral, hipoglosso, nervo lingual, músculo esternocleidomastóideo, veia jugular interna, veia e artéria facial. Foi realizada reconstrução neo-palatina com retalho nasolabial. A patologia definitiva recebida em dias posteriores relatou um carcinoma de células escamosas pouco diferenciado de linhagem epitelial com uma borda cirúrgica positiva para o tumor. No pós-operatório, o paciente apresentou pneumonia associada aos cuidados de saúde, acompanhada de déficit neurológico, o quadro regrediu para sepse de origem pulmonar e faleceu 21 dias após a cirurgia. Conclusões: O crescimento acelerado de uma massa maxilar neste paciente foi associado à presença de um carcinoma espinocelular pouco diferenciado.

Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort.

BACKGROUND: Alzheimer's disease with a causative genetic mutation (AD-CGM) is an uncommon form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected. OBJECTIVE: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China. METHODS: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. RESULTS: We studied the following gene mutation variants: 12 AßPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AßPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD. CONCLUSION: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset dementia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.

Acute Transverse Myelitis (ATM):Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222).

Introduction: Although acute transverse myelitis (ATM) is a rare neurological condition (1.34-4.6 cases per million/year) COVID-19-associated ATM cases have occurred during the pandemic. Case-finding methods: We report a patient from Panama with SARS-CoV-2 infection complicated by ATM and present a comprehensive clinical review of 43 patients with COVID-19-associated ATM from 21 countries published from March 2020 to January 2021. In addition, 3 cases of ATM were reported as serious adverse events during the clinical trials of the COVID-19 vaccine ChAdOx1 nCoV-19 (AZD1222). Results: All patients had typical features of ATM with acute onset of paralysis, sensory level and sphincter deficits due to spinal cord lesions demonstrated by imaging. There were 23 males (53%) and 20 females (47%) ranging from ages 21- to 73- years-old (mean age, 49 years), with two peaks at 29 and 58 years, excluding 3 pediatric cases. The main clinical manifestations were quadriplegia (58%) and paraplegia (42%). MRI reports were available in 40 patients; localized ATM lesions affected ≤3 cord segments (12 cases, 30%) at cervical (5 cases) and thoracic cord levels (7 cases); 28 cases (70%) had longitudinally-extensive ATM (LEATM) involving ≥4 spinal cord segments (cervicothoracic in 18 cases and thoracolumbar-sacral in 10 patients). Acute disseminated encephalomyelitis (ADEM) occurred in 8 patients, mainly women (67%) ranging from 27- to 64-years-old. Three ATM patients also had blindness from myeloneuritis optica (MNO) and two more also had acute motor axonal neuropathy (AMAN). Conclusions: We found ATM to be an unexpectedly frequent neurological complication of COVID-19. Most cases (68%) had a latency of 10 days to 6 weeks that may indicate post-infectious neurological complications mediated by the host's response to the virus. In 32% a brief latency (15 hours to 5 days) suggested a direct neurotropic effect of SARS-CoV-2. The occurrence of 3 reported ATM adverse effects among 11,636 participants in the AZD1222 vaccine trials is extremely high considering a worldwide incidence of 0.5/million COVID-19-associated ATM cases found in this report. The pathogenesis of ATM remains unknown, but it is conceivable that SARS-CoV-2 antigens -perhaps also present in the AZD1222 COVID-19 vaccine or its chimpanzee adenovirus adjuvant- may induce immune mechanisms leading to the myelitis.

Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries.

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral attachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hypoperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis, encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World Federation of Neurology we invite national and regional neurological associations to create local databases to report cases with neurological manifestations observed during the on-going pandemic. International neuroepidemiological collaboration may help define the natural history of this worldwide problem.

Multimodal 18F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network.

Although abnormally folded tau protein has been found to self-propagate from neuron to connected neuron, similar propagation through human brain networks has not been fully documented. We studied tau propagation in the left hemispheric syntactic network, which comprises an anterior frontal node and a posterior temporal node connected by the white matter of the left arcuate fasciculus. This network is affected in the nonfluent variant of primary progressive aphasia, a neurodegenerative disorder with tau accumulation. Methods: Eight patients with the nonfluent variant of primary progressive aphasia (age, 67.0 ± 7.4 y; 4 women) and 8 healthy controls (age, 69.6 ± 7.0 y; 4 women) were scanned with 18F-AV-1451 tau PET to determine tau deposition in the brain and with MRI to determine the fractional anisotropy of the arcuate fasciculus. Normal syntactic network characteristics were confirmed with structural MRI diffusion imaging in our healthy controls and with blood oxygenation level-dependent functional imaging in 35 healthy participants from the Alzheimer Disease Neuroimaging Initiative database. Results: Language scores in patients indicated dysfunction of the anterior node. 18F-AV-1451 deposition was greatest in the 2 nodes of the syntactic network. The left arcuate fasciculus had decreased fractional anisotropy, particularly near the anterior node. Normal MRI structural connectivity from an area similar to the one containing tau in the anterior frontal node projected to an area similar to the one containing tau in the patients in the posterior temporal node. Conclusion: Tau accumulation likely started in the more affected anterior node and, at the disease stage at which we studied these patients, appeared as well in the brain region (in the temporal lobe) spatially separate from but most connected with it. The arcuate fasciculus, connecting both of them, was most severely affected anteriorly, as would correspond to a loss of axons from the anterior node. These findings are suggestive of tau propagation from node to connected node in a natural human brain network and support the idea that neurons that wire together die together.

Helicobacter pylori, Vascular Risk Factors and Cognition in U.S. Older Adults.

Previous studies suggested that Helicobacter pylori infection could be a risk factor for stroke, dementia, and Alzheimer's disease (AD). The authors examined data from participants, 60 years old and older in the Third National Health and Nutrition Examination Survey (NHANES-III) to assess the relation between Helicobacter pylori infection and results of the Mini-Mental State Examination (n = 1860) using logistic regression analysis controlling for age, gender, race/ethnicity, education, poverty and history of medically diagnosed diabetes. Moreover, we examined performance on the digit-symbol substitution test (DSST) of 1031 participants in the 1999-2000 NHANES according to their H. pylori infection status controlling for potential confounders using multiple linear regression analyses. In 1988-1991, older adults infected with CagA strains of H. pylori had a 50% borderline statistically significant increased level of cognitive impairment, as measured by low Mini-Mental State Examination (MMSE) scores (age-education adjusted prevalence ratio: 1.5; 95% confidence interval: 1.0, 2.0). In 1999-2000, older US adults infected with H. pylori scored 2.6 fewer points in the DSST than those uninfected (mean adjusted difference: -2.6; 95% confidence interval -5.1, -0.1). The authors concluded that H. pylori infection might be a risk factor for cognitive decline in the elderly. They also found that low cobalamin and elevated homocysteine were associated with cognitive impairment.