2024
Central Nervous System Effects of Early HIV Infection and Consequences of Antiretroviral Therapy Initiation during Acute HIV
Chan P, Spudich S. Central Nervous System Effects of Early HIV Infection and Consequences of Antiretroviral Therapy Initiation during Acute HIV. Viruses 2024, 16: 1082. PMID: 39066244, PMCID: PMC11281648, DOI: 10.3390/v16071082.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsEarly HIV infectionCentral nervous systemHIV infectionEffects of early HIV infectionIncrease awareness of HIV infectionCentral nervous system opportunistic infectionsImmediate initiation of antiretroviral therapyInitiation of antiretroviral therapyAwareness of HIV infectionCentral nervous system complicationsCentral nervous system involvementAntiretroviral therapy initiationCentral nervous system effectsLong-term neuroprotectionHIV-associated dementiaOvert clinical manifestationsYears of infectionMulti-organ diseaseNucleic acid testingAcute HIVHIV neuroinvasionHIV RNAAntiretroviral therapyOpportunistic infectionsTherapy initiationPrevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy
Wagner T, Tierney C, Huang S, Nichols S, Malee K, Montañez N, Coletti A, Spiegel H, Krotje C, Bone F, Wilkins M, Abuogi L, Purswani M, Bearden A, Wiznia A, Agwu A, Chadwick E, Richman D, Gandhi M, Mehta P, Macatangay B, Spector S, Spudich S, Persaud D, Chahroudi A, Team F. Prevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy. AIDS 2024, 38: 1494-1504. PMID: 38814693, PMCID: PMC11239098, DOI: 10.1097/qad.0000000000003937.Peer-Reviewed Original ResearchCell-free HIV RNAAntiretroviral therapyHIV DNACentral nervous systemDetect HIV DNACerebrospinal fluidHIV RNAPerinatal HIVLong-term virologic suppressionFluid cognition composite scoresSuppressive antiretroviral therapyCerebrospinal fluid cellsHair antiretroviral concentrationsHIV DNA detectionQuantify HIVVirologic suppressionAntiretroviral concentrationsCD4 countCerebrospinal fluid collectionHIV infectionHIV GagPol DNANeurocognitive impairmentCognitive impairmentHIV
2023
Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus
Letendre S, Chen H, McKhann A, Roa J, Vecchio A, Daar E, Berzins B, Hunt P, Marra C, Campbell T, Coombs R, Ma Q, Swaminathan S, Macatangay B, Morse G, Miller T, Rusin D, Greninger A, Ha B, Alston-Smith B, Robertson K, Paul R, Spudich S, Team T. Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus. Clinical Infectious Diseases 2023, 77: 866-874. PMID: 37183889, PMCID: PMC10506779, DOI: 10.1093/cid/ciad265.Peer-Reviewed Original ResearchConceptsAntiretroviral therapyART intensificationNeurocognitive impairmentWeek 48Z-scoreAntiretroviral therapy intensificationPersistent HIV replicationPlacebo-controlled trialPlasma HIV RNASuppressive antiretroviral therapyAge 52 yearsBody mass indexHuman immunodeficiency virusCopies/mLTotal Z-scoreBaseline z-scoresCentral nervous systemDual placeboEfavirenz useTherapy intensificationHIV RNAStudy drugAdverse eventsSymptomatic HIVPrimary outcomeRebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus
Kincer L, Joseph S, Gilleece M, Hauser B, Sizemore S, Zhou S, Di Germanio C, Zetterberg H, Fuchs D, Deeks S, Spudich S, Gisslen M, Price R, Swanstrom R. Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus. Nature Microbiology 2023, 8: 260-271. PMID: 36717718, PMCID: PMC10201410, DOI: 10.1038/s41564-022-01306-6.Peer-Reviewed Original ResearchConceptsCentral nervous systemT cell-tropic virusesInfected T cellsCerebrospinal fluidAntiretroviral therapyHIV-1Rebound virusViral loadT cellsMacrophage-tropic HIV-1CSF viral loadSuppressive antiretroviral therapyHIV-1 reservoirMacrophage-tropic virusesHigh viral loadWhite blood cellsTherapy interruptionLatent reservoirLymphoid systemNervous systemSystemic infectionVirus replicationBlood cellsTransient influxVirusHIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells
Kincer L, Schnell G, Swanstrom R, Miller M, Spudich S, Eron J, Price R, Joseph S. HIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells. Pathogens And Immunity 2023, 7: 131-142. PMID: 36865569, PMCID: PMC9973728, DOI: 10.20411/pai.v7i2.524.Peer-Reviewed Original ResearchBlood-cerebrospinal fluid barrierBlood-brain barrierCentral nervous systemHIV-1Cerebrospinal fluidInfected cellsCSF samplesNervous systemCo-infected participantsHCV viral loadHIV-1 replicationCross-sectional studyMigration of HIVHIV-1 particlesHIV-1 populationsBlood plasmaHCV concentrationAntiviral regimensViral loadHCV entryInflammatory responseFluid barrierHCVVirus entryNormal surveillance
2022
Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection
Killingsworth L, Spudich S. Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection. Seminars In Immunopathology 2022, 44: 709-724. PMID: 35882661, PMCID: PMC10126949, DOI: 10.1007/s00281-022-00953-5.Peer-Reviewed Original ResearchConceptsCentral nervous systemHIV infectionInflammatory responseHIV entryChronic HIV infectionAcute HIV infectionNeuropathogenesis of HIVEarly inflammatory responsePathological inflammatory responsesOngoing neuropathologyAntiretroviral therapyViral suppressionNeurologic healthViral reservoirChronic infectionImmune mechanismsT lymphocytesHIV-1Viral infectionNervous systemInfectionHIVPathological consequencesBrainNeuropathogenesis
2021
Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection
Sharma V, Creegan M, Tokarev A, Hsu D, Slike BM, Sacdalan C, Chan P, Spudich S, Ananworanich J, Eller MA, Krebs SJ, Vasan S, Bolton DL. Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection. PLOS Pathogens 2021, 17: e1010105. PMID: 34874976, PMCID: PMC8683024, DOI: 10.1371/journal.ppat.1010105.Peer-Reviewed Original ResearchConceptsT-cell infectionCentral nervous systemAcute HIV-1HIV-1 replicationCerebrospinal fluidT cellsHIV-1Peripheral bloodViral reservoirCell infectionBroad immune activationCerebrospinal fluid CD4CNS viral reservoirCSF T cellsHIV-1 cureActive viral transcriptionLong-term inflammationViral RNACSF CD4Early neuroinflammationAntiretroviral therapyHuman cerebrospinal fluidAcute infectionImmune activationCNS compartment
2020
Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.
Handoko R, Chan P, Jagodzinski L, Pinyakorn S, Ubolyam S, Phanuphak N, Sacdalan C, Kroon E, Dumrongpisutikul N, Paul R, Valcour V, Ananworanich J, Vasan S, Spudich S. Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection. AIDS 2020, 35: 777-782. PMID: 33306551, PMCID: PMC7969409, DOI: 10.1097/qad.0000000000002786.Peer-Reviewed Original ResearchConceptsAcute HIV-1 infectionHIV-1 RNACentral nervous systemCSF escapeAntiretroviral therapyHIV-1 infectionWeek 96Week 24HIV-1CSF HIV-1 RNAInitiation of ARTLong-term neurological outcomePlasma HIV-1 RNAWeeks of ARTProspective cohort studyPersistence of HIVHIV-1 persistenceLevels of CSFYears of treatmentHIV-1 replicationNeurological outcomeCohort studyVoluntary counselingChronic infectionEarly treatmentCentral Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus
Hellmuth J, Muccini C, Colby DJ, Kroon E, de Souza M, Crowell TA, Chan P, Sacdalan C, Intasan J, Benjapornpong K, Tipsuk S, Puttamaswin S, Chomchey N, Valcour V, Sarnecki M, Tomaka F, Krebs SJ, Slike BM, Jagodzinski LL, Dumrongpisutikul N, Sailasuta N, Samboju V, Michael NL, Robb ML, Vasan S, Ananworanich J, Phanuphak P, Phanuphak N, Paul R, Spudich S. Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus. Clinical Infectious Diseases 2020, 73: e1885-e1892. PMID: 32916708, PMCID: PMC8492357, DOI: 10.1093/cid/ciaa1344.Peer-Reviewed Original ResearchConceptsAnalytic treatment interruptionHuman immunodeficiency virusAntiretroviral therapyCentral nervous systemRemission trialsDiffusion tensor imagingTreatment interruptionMedian timeImmunodeficiency virusCentral nervous system safetyCSF HIV-1 RNAAdverse CNS effectsAcute HIV infectionImmune activation markersPlasma viral loadHIV-1 RNAMedian participant ageCerebrospinal fluid samplingCognitive performanceHIV remission trialsBrain diffusion tensor imagingMagnetic resonance spectroscopyART resumptionCNS safetyMild worseningNeuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019
Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019. JAMA Neurology 2020, 77: 1018-1027. PMID: 32469387, PMCID: PMC7484225, DOI: 10.1001/jamaneurol.2020.2065.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCentral nervous systemCoronavirus disease 2019Nervous systemDisease 2019Respiratory syndromeCOVID-19Severe acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Long-term neurologic sequelaeRespiratory syndrome coronavirus 2Middle East respiratory syndromeSevere acute respiratory syndromeClinical neurological complicationsFurther neuropathological studiesBest treatment algorithmImproved clinical outcomesBlood-brain barrierImpairment of consciousnessSyndrome coronavirus 2Peripheral nervous systemAcute respiratory syndromeHuman coronavirus disease 2019Common neurologic complaintsSARS-CoV-2Neurologic sequelae
2019
Exosomal MicroRNAs Associate With Neuropsychological Performance in Individuals With HIV Infection on Antiretroviral Therapy.
OʼMeara T, Kong Y, Chiarella J, Price RW, Chaudhury R, Liu X, Spudich S, Robertson K, Emu B, Lu L. Exosomal MicroRNAs Associate With Neuropsychological Performance in Individuals With HIV Infection on Antiretroviral Therapy. JAIDS Journal Of Acquired Immune Deficiency Syndromes 2019, 82: 514-522. PMID: 31714431, PMCID: PMC6857839, DOI: 10.1097/qai.0000000000002187.Peer-Reviewed Original ResearchConceptsCombination antiretroviral therapyNeuropsychological performanceAntiretroviral therapyViral suppressionHIV infectionNeurocognitive dysfunctionExo-miRNAsEarly infection groupCentral nervous systemSystemic viral suppressionTyrosine receptor kinaseInfection groupChronic infectionPLWHCross-sectional examinationNervous systemEarly infectionNeuropsychological scoresInfectionConsistent findingNeuropsychological batteryHIVNeurodegeneration pathwaysDysfunctionTherapyHIV persistence in the central nervous system during antiretroviral therapy: evidence and implications.
Spudich S, Clements JE. HIV persistence in the central nervous system during antiretroviral therapy: evidence and implications. AIDS 2019, 33 Suppl 2: s103-s106. PMID: 31789813, DOI: 10.1097/qad.0000000000002439.Peer-Reviewed Original ResearchPotential for early antiretroviral therapy to reduce central nervous system HIV-1 persistence.
Spudich S, Peterson J, Fuchs D, Price RW, Gisslen M. Potential for early antiretroviral therapy to reduce central nervous system HIV-1 persistence. AIDS 2019, 33 Suppl 2: s135-s144. PMID: 31789814, DOI: 10.1097/qad.0000000000002326.Peer-Reviewed Original ResearchConceptsHIV-1 infectionCentral nervous systemEarly antiretroviral therapyAntiretroviral therapyHIV-1 persistenceEarly treatmentInitiation of ARTCentral nervous inflammationEarly-treatment cohortHIV-1 exposureHIV-1 reservoirCourse of infectionClinical neurological diseaseCNS infectionHIV reservoirTreatment cohortsImmune activationCNS compartmentViral controlHIV-1Cerebrospinal fluidClinical reportsNervous systemEarly infectionNeurological diseasesDeep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection
Tovanabutra S, Sirijatuphat R, Pham PT, Bonar L, Harbolick EA, Bose M, Song H, Chang D, Oropeza C, O’Sullivan A, Balinang J, Kroon E, Colby DJ, Sacdalan C, Hellmuth J, Chan P, Prueksakaew P, Pinyakorn S, Jagodzinski LL, Sutthichom D, Pattamaswin S, de Souza M, Gramzinski RA, Kim JH, Michael NL, Robb ML, Phanuphak N, Ananworanich J, Valcour V, Kijak GH, Sanders-Buell E, Spudich S, Core T, Team T. Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection. Cells 2019, 8: 902. PMID: 31443253, PMCID: PMC6721674, DOI: 10.3390/cells8080902.Peer-Reviewed Original ResearchConceptsAcute HIV-1 infectionCentral nervous systemHIV-1 infectionCerebrospinal fluidCNS compartmentalizationHIV-1HIV-1 compartmentalizationHIV-1 exposureHIV-1 neuropathogenesisHIV-1 reservoirSingle-genome sequencingHIV reservoirFounder virusesRemission strategiesNeurological impairmentNervous systemF infectionsViral replicationInfectionPotential long-term implicationsNext-generation sequencingEnvelope geneTissue compartmentsF variantLong-term implicationsVery Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma
Hellmuth J, Slike BM, Sacdalan C, Best J, Kroon E, Phanuphak N, Fletcher JLK, Prueksakaew P, Jagodzinski LL, Valcour V, Robb M, Ananworanich J, Allen IE, Krebs SJ, Spudich S. Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma. The Journal Of Infectious Diseases 2019, 220: 1885-1891. PMID: 30668739, PMCID: PMC6833977, DOI: 10.1093/infdis/jiz030.Peer-Reviewed Original ResearchConceptsAcute HIV infectionAntiretroviral therapyART initiationCerebrospinal fluidWeek 96Week 24HIV infectionImmune activationAHI groupHuman immunodeficiency virus (HIV) infectionEarly ART initiationPlasma CCL2 levelsTrajectory of HIVChronic immune activationImmune activation markersSuppressive antiretroviral therapyImmunodeficiency virus infectionInterleukin-6 levelsMarkers of inflammationPlasma neopterin levelsWeeks of treatmentCentral nervous systemART regimenCCL2 levelsNeopterin levels
2018
Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells
Joseph SB, Kincer LP, Bowman NM, Evans C, Vinikoor MJ, Lippincott CK, Gisslén M, Spudich S, Menezes P, Robertson K, Archin N, Kashuba A, Eron JJ, Price RW, Swanstrom R. Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells. Clinical Infectious Diseases 2018, 69: 1345-1352. PMID: 30561541, PMCID: PMC6938202, DOI: 10.1093/cid/ciy1066.Peer-Reviewed Original ResearchConceptsCentral nervous systemHIV-1 RNA concentrationsAntiretroviral therapySuppressive antiretroviral therapyCerebrospinal fluidCNS reservoirsCSF escapeCSF HIV-1 RNA concentrationsCentral nervous system reservoirYears of ARTHuman immunodeficiency virus type 1 (HIV-1) populationHuman immunodeficiency virus type 1 (HIV-1) RNAStable antiretroviral therapyHIV-1 RNAMacrophages/microgliaInfected T cellsRNA concentrationViral envelope sequencesType 1 populationViral populationsViral suppressionMacrophage-tropicAsymptomatic participantsMultiple time pointsT cellsNormalization of Soluble CD163 Levels After Institution of Antiretroviral Therapy During Acute HIV Infection Tracks with Fewer Neurological Abnormalities
D’Antoni M, Byron MM, Chan P, Sailasuta N, Sacdalan C, Sithinamsuwan P, Tipsuk S, Pinyakorn S, Kroon E, Slike BM, Krebs SJ, Khadka VS, Chalermchai T, Kallianpur KJ, Robb M, Spudich S, Valcour V, Ananworanich J, Ndhlovu LC, Teeratakulpisarn N, Fletcher J, Sacdalan C, Chomchey N, Sutthichom D, Rattanamanee S, Prueksakaew P, Ubolyam S, Eamyoung P, Puttamaswin S, Karnsomlap P, Luekasemsuk T, Intasan J, Benjapornpong K, Ratnaratorn N, O’Connell R, Trichavaroj R, Akapirat S, Phuang-Ngern Y, Sukhumvittaya S, Sajjaweerawan C, Jongrakthaitae S, Saetun P, Tragonlugsana N, Nuntapinit B, Tantibul N, Savadsuk H, Michael N, Trautmann L, Tovanabutra S, Ouellette M, Butterworth O, Crowell T, Turk E, Eller L, Milazzo M, Bandar I, Shiramizu B, Shikuma C. Normalization of Soluble CD163 Levels After Institution of Antiretroviral Therapy During Acute HIV Infection Tracks with Fewer Neurological Abnormalities. The Journal Of Infectious Diseases 2018, 218: 1453-1463. PMID: 29868826, PMCID: PMC6151077, DOI: 10.1093/infdis/jiy337.Peer-Reviewed Original ResearchConceptsAcute HIV infectionFiebig stage IIIStage I/IISoluble CD163 levelsHIV infectionCentral nervous systemStage IIICD163 levelsCerebrospinal fluidUninfected controlsChronic human immunodeficiency virus (HIV) infectionCombination antiretroviral therapy (cART) initiationHuman immunodeficiency virus (HIV) infectionInitiation of cARTAntiretroviral therapy initiationImmunodeficiency virus infectionEnzyme-linked immunosorbentCART initiationMyeloid activationAntiretroviral therapyChronic HIVCNS involvementSCD163 levelsTherapy initiationActivation markersCentral Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques
Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, Vasan S. Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques. Journal Of Virology 2018, 92: 10.1128/jvi.00222-18. PMID: 29563297, PMCID: PMC5952152, DOI: 10.1128/jvi.00222-18.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, MyelomonocyticBrainCD4 Lymphocyte CountCD4-Positive T-LymphocytesCells, CulturedDisease Models, AnimalHIV-1HumansMacaca mulattaMacrophagesMeningesMicrogliaMonocytesParenchymal TissueReceptors, Cell SurfaceRNA, ViralSimian Acquired Immunodeficiency SyndromeSimian immunodeficiency virusViral LoadConceptsSimian-human immunodeficiency virusSimian immunodeficiency virusCD68/CD163Immunodeficiency virus infectionCentral nervous systemBrain parenchymaHIV envelopeImmunodeficiency virusVirus infectionEarly human immunodeficiency virus (HIV) infectionSimian-human immunodeficiency virus (SHIV) infectionCentral nervous system inflammationHuman immunodeficiency virus (HIV) infectionCentral nervous system involvementPathogenic simian immunodeficiency virusRhesus macaquesT-cell-mediated processEarly clinical courseSHIV-infected animalsNervous system inflammationT-cell countsCell-mediated inflammationNervous system involvementEnd-stage diseaseHIV cure strategiesAnti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir?
Burbelo PD, Price RW, Hagberg L, Hatano H, Spudich S, Deeks SG, Gisslén M. Anti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir? The Journal Of Infectious Diseases 2018, 217: 1024-1032. PMID: 29401308, PMCID: PMC5939835, DOI: 10.1093/infdis/jix662.Peer-Reviewed Original ResearchConceptsCentral nervous systemHuman immunodeficiency virusAntiretroviral therapyLong-term treatmentCerebrospinal fluidHIV antibodiesCSF antibodiesEarly infectionBlood antibodyChronic infectionVirus antibodiesCentral nervous system reservoirAnti-human immunodeficiency virus antibodiesHuman immunodeficiency virus (HIV) antibodyEarly ART initiationMarkers of persistenceEffective antiretroviral therapySuppressive antiretroviral therapyPre-exposure prophylaxisART initiationHIV persistenceCNS infectionHIV reservoirImmunodeficiency virusBerlin patient
2017
HIV-Associated Neurocognitive Disorders
Letendre S, Iudicello J, Ances B, Marcotte T, Spudich S, Cohen M. HIV-Associated Neurocognitive Disorders. 2017, 175-203. DOI: 10.1093/med/9780199392742.003.0016.Peer-Reviewed Original ResearchHIV-associated neurocognitive disordersHuman immunodeficiency virusDifferential diagnosis of cognitive impairmentNeurocognitive disordersDifferential diagnosisDiagnosis of cognitive impairmentHuman immunodeficiency virus patientsCognitive impairmentInitiation of ARTLoss of dendritesCentral nervous systemSubstance use disordersInfected gliaImmunodeficiency virusMedication toxicityInjured neuronsMetabolic syndromeTissue macrophagesTreatment recommendationsInfluence neurocognitive performanceQuality of lifeNeurocognitive performanceVascular diseaseNervous systemMultimorbid conditions