Advances In Clinical Diagnosis - UCI MIND

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Advances in Clinical DiagnosisALZHEIMER’S DISEASE 2019David Sultzer, MDInstitute for Memory Impairments and Neurological DisordersDepartment of Psychiatry and Human Behavior

“Jewels”Alzheimer’sDisease Amyloid Plaques Neurofibrillary Tangles Lewy BodiesToolsImprovingClinical Diagnosis Neuroimaging Fluid Biomarkers Clinical AssessmentsRules Diagnostic Criteria Differential Diagnosis

Early Concepts of DementiaPlato, 350 BCCognitive decline is an inevitable consequence of agingdue to the weakness of the brainCauses of dementiaCicero, 50 BCA consequence of weak will. An active mental life couldprevent or postpone cognitive declineGalen, 200 ADPsychic and cognitive abilities are localized to the brainWillis, 1650Developmental disability separate from acquireddementia; specific etiologies for dementia, includinghead injury, aging, and stroke19th CenturyPsychiatric and neurologic conditions weredistinguishable; cortical atrophy recognized; vascularcalcification prominent; Kraepelin “dementia praecox”;“general paresis” (neurosyphilis) in 10% ;arteriosclerotic brain atrophy is predominant cause ofsenile dementiaSequelae of deliveryHead injuriesMenstrual disordersSevere weather conditionsProgression of age (20%)ManiaSyphilis and mercury abuseDietary excessWine abuseMasturbationUnhappy lovePolitical upheavalsUnfulfilled ambitionsPovertyDomestic problemsEsquirol, 1838Assal 2019

Alzheimer 1906New histological stains – cortex51 yo woman with confusion and psychosis Presenile dementia Prominent plaques and tangles vs Senile dementia: arteriosclerosis Distinction persisted for 50 years1960s: Blessed, Tomlinson, Roth In older adults (mean age 78), cognition and functionduring life associated with cortical neuritic plaquedensity at post-mortem

Clinical Diagnostic CriteriaNINCDS-ADRDA, 1984ProbableAD Dementia, objective testing Two or more cognitive domains Progressive worsening No disturbance of consciousness Onset between age 40 and 90 Absence of other CNS orsystemic etiology Supportive factors Progressive decline incharacteristic domains Impaired ADLs and “patternsof behavior” Family history CT: atrophy May be depression, psychosis,emotional outbursts No focal neuro signs, seizures,or gait change earlyPossible ADVariations in the onset,presentation, or clinicalcourseAnother systemic or CNSdisorder that may bedriving the dementiaDefinite ADClinical criteria forProbable ADHistopathologicevidenceSingle cognitivedeficitMcKhann 1984

AD Clinical DiagnosisPubMed Citations, By 02001-20102011 -Pub Med; Sept 24, 2019

Key AdvancesImproving Clinical Diagnosis1. Longitudinal studies of symptoms and biologyMild Cognitive Impairment2. Neuropathology and relationship with clinical symptoms3. In vivo biomarkers for AD proteins4. Refined clinical diagnostic criteria5. What isn’t Alzheimer’s disease6. Role of distinct cognitive and non-cognitive symptoms

Alzheimer’s Pathology Isn’t AloneComorbid Pathology in 1153 PatientsWith AD Neuropathology0Percent of Cases10203040AD Alone33AD Vascular Dz16AD Amyloid AngiopathyAD Other213795043% of cases with AD pathology had at least 3different pathologies Clinicians aren’t always seeing AD pathology21AD Lewy BodiesAD Hipp Sclerosis Mixed cases are very common in the brainMore than one-third of those with “pure AD” atautopsy were thought to have a non-AD diagnosisduring life Clinicians often see “AD” when otherpathologies are present 80% of those with a clinical diagnosis of AD havemixed pathologies (70%) or no AD pathology ( 10%)Mayo Clinic Brain Bank 2007-2016; DeTure 2019

Biomarkers for Alzheimer’s DiseaseMaximumGenetics, EpigeneticsInflammatory ResponseBiomarkerAbnormalityVascular Factors, HypertensionAge, EducationAnxiety, DepressionCognitive and Physical ActivityMinimumTimeØ AD biomarker changes occur at least 15 years before memory is compromised.3Jack 2013

PET Imaging - Amyloid and TauØ Amyloid Imaging – Clinical Amyloid Persistent or progressive unexplained MCIPossible AD: atypical course or mixedetiologiesEarly-onset progressive dementiaAssuming:o Dementia expert involvedo Cognitive deficit presento Expected to increase dx certainty orchange managementAn Outcome Study:N 11,409 with MCI or dementia60% with change in med rx or safety/planning25% with dx change from AD to non-ADTauHealthyControlPreclinical AD Prodromal ADAsymptomaticMCIADDementiaJohnson 2013Rabinovici 2019

Cholinergic Receptor Binding in AD and MCINRS Agitation/Disinhibition FactorScoreAnterior Cingulate, Left16Anterior Cingulate, Right141210Lower binding in MCI and AD Medial thalamus Medial temporal cortex (hipp, amyg, parahipp) Anterior cingulate InsulaØ In healthy older adults, cholinergic, binding isstrongly inversely correlated with ageSultzer 20178642rs -.500345678Nicotinic Receptor Binding (VT/fp)9Richter 2018, BrainØ Clinical and cortical activation (fMRI) response to AChEItreatment in MCI depends on local acetylcholinesteraseenzyme activity (MP4A-PET imaging)

Fluid BiomarkersCerebrospinal Fluid Low β-amyloid 42 may precede amyloid seenon PET imaging Variable lab assays Elevated P-tau and tau levels Synaptic markers: neurograninBlood Plasma Small proportion of brain proteins in plasma High concentration of usual blood proteins β-amyloid 42, tau Neurofilament light protein

More Comprehensive Diagnostic CriteriaNormal CognitionNIA-AA Criteria 2011IWG Criteria 2010, 2014-xx Preclinical ADStage 1: Amyloid Stage 2: Amyloid and injury (Tau, FDG-PET, hippor med parietal atrophy)Asymptomatic at risk for AD(CSF amyloid tau, PET amyloid)Presymptomatic AD,if genetic carrierSubtle Cognitive Decline Preclinical AD, Stage 3Not distinguished from normalMild Cognitive Deficit,Preserved ADLs-MCI (one or more domains: memory, executive,language, visuospatial, attention)MCI MCI due to ADHi likelihood: Amyloid Injury Intermed likelihood: Amyloid or injury ; other n/aUninformative: either ; other -Prodromal Alzheimer’s diseaseMemory /- other domainOtherwise: Atypical AD-Probable AD dementiaAt least two domains: memory, reasoning,visuospatial, language, personality/behaviorPossible AD dementia – atypical course or mixedetiology“Dementia” Probable or possible AD dementia- With AD pathologyAlzheimer’s diseaseMemory /- other domainOtherwise: Atypical ADSignificant Cognitive Deficit,With Functional Impairment4ADBiomarker

“Alzheimer’s Disease”“When I use a word,” Humpty Dumpty said, in rather a scornful tone,“it means just what I choose it to mean – neither more nor less.”Humpty Dumpty, Through the Looking Glass (Lewis Carroll 1872)

ATN Research CriteriaAlzheimer’scontinuumA: CSF or PET imaging amyloidT: CSF p-tau, tau imagingN: MRI volume, FDG-PET, CSF total tauSuspected non-Alzheimerdisease pathophysiology(SNAP)Jack 2018

What Isn’t Alzheimer’s DiseaseNormalAgingAlzheimer’s Disease More refined clinicalphenomenology and clinicaldiagnostic criteriaFrontoTemporalDementia:- BehavioralVariant- PPAInternationalConsensusCriteria ntia With LewyBodiesDLB Consortium20175

Profiles of Cognitive and Noncognitive Symptoms Amnestic memory deficitØ vs. retrieval deficit with cue benefits Neuropsychiatric symptoms over the courseof clinical ADØ Fundamental expression of the degenerative process Depression is a risk factor for AD Apathy and anxiety can be early symptoms,before memory impairmentØ Shared biology?Sultzer 20146

Anxiety Drives Amyloid Toxicity Prospective cohort, 333 healthy older adults Amyloid imaging Measures: Anxiety/depression, Neuropsych Anxiety moderated the effect of amyloid burdenLarger effect in those with clinically meaningful symptoms No effect of depressionLow scores Mechanism? Intervention opportunity?Pietrzak 2015

Mild Behavioral ImpairmentoChanges in behavior or personality, age 50oDecreased motivationo Affective dysregulationo Impulse dyscontrolo Social inappropriatenesso Abnormal perception or thoughtoooSocial or occupational consequencesNot attributable to a psychiatric disorderNo dementia; MCI can be concurrentNPS-PIAAlzheimer’s Association, 2015www.MBItest.org

So How Do These AdvancesImprove Diagnosis and Benefit Care?

Challenges To Detection and Accurate Diagnosis “Progressive cognitive difficulties are normal with age” Limited confidence among some primary careproviders Few specialty memory clinics Assessment time and cost Therapeutic nihilism Denial, stigma, Public Health reports

Clinical Diagnosis - Basics 2019 Screening in high-risk people and those withcognitive complaints or early symptoms Clinical history: specific symptoms, onset, course Medication review, substance misuse Neuro exam Focal deficit Tremor, rigidity, gait Labs Chem, CBC, LFTs B12, TSH, (Vitamin D) If indicated: syphilis serology, HIV Neuroimaging MRI CT, if MRI challenges Psychiatric symptoms Apathy Depression Anxiety Cognitive assessment MMSE , MOCA , others Memory/Learning and Executive skills Neuropsychological testing in some cases Function and social assessmentØ Added value – MRI findings Hippocampal volumePattern of regional atrophySmall-vessel cerebrovascular diseaseProgression of atrophy over time

Diagnostic AdvancesSpecific Circumstances FDG-PET DAT to exclude DLB Amyloid PETo If objective impairment, AD is apossible dx, but dx is uncertainafter comprehensive assessmento Knowledge of amyloid statuswould change dx or managemento Persistent unexplained MCI, orearly onset of progressivedementia CSF biomarkersooooEarly onset or atypical dementiaPersistent, progressive, unexplained MCIConsider reliability, ratios, and cutoffsNon-AD: prion, infectious, other rapidly progressive Plasma biomarkerso Limited clinical value currently Genetic testingo Presenilin 1, 2, APP - Familial ADo GRN, C9orf72 - Familial FTD

Summary and The FutureImproved Clinical DiagnosisNext Steps Longitudinal symptoms and biology;MCINeuropathology heterogeneityBiomarkersRefined diagnostic criteriaWhat isn’t Alzheimer’s diseaseNeuropsychiatric symptoms Embrace heterogeneity while refining distinctclinical syndromes Practical assessment in the community Biomarker advances Plasma – e.g., NF-L or synaptic proteins Clinical outcomes Early or preclinical diagnosis Individualized risk score Optimal candidates for specific interventions