RESUMEN
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Vasos Linfáticos/inmunología , Meninges/inmunología , Microglía/inmunología , Envejecimiento/efectos de los fármacos , Envejecimiento/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Nonhemorrhagic neurological deficits are underrecognized symptoms of intracranial dural arteriovenous fistulas (dAVFs) having cortical venous drainage. These symptoms are the consequence of cortical venous hypertension and portend a clinical course with increased risk of neurological morbidity and mortality. One rarely documented and easily misinterpreted type of nonhemorrhagic neurological deficit is progressive dementia, which can result from venous hypertension in the cortex or in bilateral thalami. The latter, which is due to dAVF drainage into the deep venous system, is the less common of these 2 dementia syndromes. Herein, the authors report 4 cases of dAVF with venous drainage into the vein of Galen causing bithalamic edema and rapidly progressive dementia. Two patients were treated successfully with endovascular embolization, and the other 2 patients were treated successfully with endovascular embolization followed by surgery. The radiographic abnormalities and presenting symptoms rapidly resolved after dAVF obliteration in all 4 cases. Detailed descriptions of these 4 cases are presented along with a critical review of 15 previously reported cases. In our analysis of these 19 published cases, the following were emphasized: 1) the clinical and radiographic differences between dAVF-induced thalamic versus cortical dementia syndromes; 2) the differential diagnosis and necessary radiographic workup for patients presenting with a rapidly progressive thalamic dementia syndrome; 3) the frequency at which delays in diagnosis occurred and potentially dangerous and avoidable diagnostic procedures were used; and 4) the rapidity and completeness of symptom resolution following dAVF treatment.