Alzheimer's Disease PDF

Ch 13. Alzheimer's ↓ matter greg Inevious loss) leading to death...

Ch 13. Alzheimer's ↓ matter greg Inevious loss) leading to death 1. Akheimer's bisease -meurodegenerat causing dimentia A Dimentia - progressive cognitive Lecline interfere indep. function severe enough to. caused by It can be multiple diseases · Alzheimer's-most common cause 70% of all aredue I - cases to Alzheimer first and most prominent symptom : memory loss B) Diagnostic tria · Clinical Syndrome vS. - aetiology subtype (Dimeutia) (te cause of the clinical syndrome) just timentia Major Disorder Neurocognitive · = decline in 1 > Significant cognitiveconcerns - or more domains based on : 11 about decline compared to previous level of functioning expressed by patient/relative 2) > 2 SD from the normative mean > - interference with Gaily life > - cognitive impaire : can't be explained by other Liseases + don't occur in deliriume  · Dimentia due to Alzheimer's ist determing clinical syndrome - of Alzheimer zud-determing level of certainty as underlying pathology aetiology subtype = Symptoms > progressiveness visuals - > - cognitive imp (min.. 2) = memory , executive , language > - no evidence of other diseases Level of evidence of certainty - > - progressive cognitive decline evidence from I crebrospinal anal > - neuroimaging Case : 79 female Symptoms ↓ : memory ex · misplacing itees forgets appointment interference with life - need external help Test : MOCA Rey Auditory Verbal Association learning - memoryimpairm. Visual test - learning associat visual Impair Stropp Color executive imp. Word Test t X Trail making Boston naming - language production Test  MRI-global atrophy - bilateral hippocamp atrophy - - white matter abnormal, = Diagnosis : Dimentit due to Alzheimer's - 2. Mild Cognitive Impairment. Al US- Dimentia function people can relatively independ. 1st - Mpreceeding diment a B) Diagnostic Criteria · Modest decline cognitive > - concerns about mild decline compared with previous level of functioning > modest impairment in cognitive - performance (112 SD below) · no severe interet. with independ, life · can't be explained by other disorders 2) NIA-AA criteria - syndrome MCI car be caused Alzheimer's pathology by if there is : > - prominent impair. in Episodic Memory > Alzheimer's - Siomarker reflecting  d) Amnestic MCT - of Alzheimer - prodormal stage Cearly) direcutio MCI the amnestic subtype is - predictor for most consistent progression to Alzheimer's dementia Case : Profile - male G7y -. Symptones - forgetfullness - main issue - minimal interference in life ① history (brother have Alzheime a - No impaire. In other doma in MOCA testing : attentiono test for speed impairme Rey-memory Visual associat below I low very - - Diagnosis Amnestic - aMCI US MCD · primary symptom memory : a primary symptoms recent events other tha ex. remembering inf areas conversations, memory main issue /if only) not ex attention. problem-solving  3. Epidemiologyin NL - 290 , 000 - somil world al Prevalance - higher risk for women (1 : 3) iman 1: 71 B) Lifetime 7 - 10 y Actiology (causes) 4. c) and abnormal Plaques accumulation of - tangles extracellular plaques of amyloid- protein and to intracellular of of proteins for tangles cells leading degeneration nerve Hampyniahe Degeneration of nerve cells = abnormal accumul -. amyloid-p proteins senile plaques ↓ - tan introcellular protein fangles a of protein tan b) Amyloid Cascade Hypothesis= abnormal accumulation of amyloid-p protein ( mutation in APP gene = Amyloid Precursor protein - overprod of amyloid-B eventually developing Akheicer's dimentia  a accumulation triggerspomps of amyloid-p > tan pathology - leading to ↓ leads to neuronal death < loss synapse - Hav pathology = abnormal accumulation of tou protein · plaques presentot -20/30 years before dimentia onset of Presence of anyloid das't B necessarily imply that someone has About Alzheimer's or will develop dimentia. 1 in 3 healthy when have them land still not sure if and they will develop ste) · Treatment the clearing plagues - drugs - · Explanation for inconclusive medication > - intervention happened too late amyloid alone is not > I enough - to develo the disease > multiple = potecophys. role processes play a  c) Vascular hypothesisrole cerebrovascular - disease plays an important in developing Alzheimer's · Risk factors : hypertension presently o - Hood ligh - - Licletes - obesity im bregen ↓ leads do of the arteries stiffening p protein and overproduction of therefore meurodegeneration 6) Amyloid + Vascular · combined hypoth. cerebrovascular amyloid B + damage co-occur effect and way have additive/synergetic. 5 Risk Factors Al Modifiable - it could be changed ex. exercise , Lief , I risk factors leading to 40% of dimentias · lower educat level. · depression ↑ flood · pressure · little physical · bearing loss Liabetes activity · smoking · obesity Small social · · network  B) Non-modifiable old 65y age. - - female genetic predisposition - · Inheritance - travel only in autosomal dominant inherited caused in App by mutation IPS-1 or PS-2 gene) mostly not inlerted · Genetic risk factors > - apolipoprotein E the 4 allel presence of APOE ex · is assoc. with an increased risk of developing Alzheimer while ApoE 2 allel is protect. Clinical Profile 6. + Cognitive  a) Clinical Course - continuum of gradual progressive cognitive decline - starts with subtle followed cognitive changes persistent decline by increasingly functional imp cognitive , , dimentia · most reported cognitive complaint - diff remembering recent events. forgetting appointments - · Stages > - mild cognitive impairment (MCI) I > - mild dementia dementio > - moderate dementia > - severe dementia (6 domains) · CDR-Clinical Dimentia Rating Scale memory - - orientation problem-solving - -social activities - home + hossies - personal care b) Cognitive Profile tests MOCA (determing syndrome) for later stage - - · dementia Lue to Alzheimer's · deficit + decline in Semantic prominent Episodic + - Memory memory language + WM + executive functions + risnoconstructive deficits  ⑦. Stages of CDR CDR al Amnestic MCI (predementia) (0. 5) · Episodic memory - 1st signs (new) - mainly anterograda amnesia impaired ex. learning/retrieving this is due to ↓ memory consolidation caused neuronal loss of hippocampus by · word-finding problem · still independant b) Mild Dementia (CDR1) ↓ functions knowledge · Cognitive ↑ ↓ semantic atrophy in medial temporal lobe language - = orientation related to EM ↑ ex forgetting date - =. planing - life limitations to daily · 2) Moderate dementia (CDR2) Episodic exposed memory · others · Dependent on 2) Severe dementia (CDR3) · Dependent Completely · Loss of speech · Orientation to · Motor functions are affected ex. chewing/ swallowing  8. Brain dange a) Neuroimaging (CT/MRI) - used to rule out another disease signs for of - to ID causes Limentio · Pattern grey - matter volume loss followed starting at medio-temporal frontal lobe Sy more posterior and regions to global atrophy · If Alzheimer is suspected : 1st to check hippocampus Alzheimer'sMAScale-predicting progression o a 00 00 b) EEG-detects abnormal changes el activity Most by measuring.. = dominant : overall of the dominant rhythm slowing doesn't out · Advantage : normal EEG rule Alzheimer's dimentia , but argue gainst other dem. such as Lewy body dementia.  2) PET + FDE - measures reduction crebral metabolic which is in of rate of glucose , neuronal a measure activity Abnormalities in glucose can be detected in early stages of Alzheimer · visualising : amyloid g and ton jenabling en viro detection of Alzheimer's al lumbar cerebro puncture collecting - spinal fluid to determine anyloid po + tan + phosphor ton IP-taul 3 Alzheimer's ↓ concentration of I myloid ↑ tal and p-tau in the slid cerebrospinal Benefits-quick costs 7 than · - lower PET Disadvantage no jef about localization - ·. prominent 9. Atypical various Typical = memory - same causes (plaques impairm t atrophy and ton tangles)but Surin In mexio-temporal lose start in diff - cortical changes. regions diff leading issues to. Cognitive  oizag Occipital a) Posterior Cortical Atrophy (Visual deficits in visuospot funct Lobe -.. visual - agnosit - memory relatively intact occipital labe - targeted : b) Temporal Logopenia2 varieut progressive aphasia lobe - Language ( LuppA) deficit word-finding - diff repeating -. - targeted : left temporal lobe - language compreh. (verbal mominy affected Frontal c) the behov/Dysexecutive variant - -below - changes ex. apathy frontal lases - tagetted : 10. Early Ouset · Age- before 65y. · Neuropsychiatric Symptoms - agitation - anxiety - apathy - hallucination > - Prevalence ↓ ↓ MCI = 13-55 % Dementin = 50 /88 %  cure ↑ no ⑪ Drugs-reduce cognitive delinesterase and below. Symptoms = inhibitor = decrease - the breakdown of actylcholine resulting higher in concentration of acetylcholine > = N communication between nerve cells ex. mine virasti 3 stabilize improve memoryde a attention  16/09/2024 DEMENTIA IN THE DSM-5 MAJOR NEUROCOGNITIVE DISORDER = name of dementio in DSMS Cognitive decline with regard to previous performance level A ⑧ in one or more cognitive domains & Presence of interference in daily activities support needed to perform complex (or instrumental) activities of daily ⑳ living (iADL), such as internet banking, using a smartphone, administration, medication intake, cooking, etc. No delirium present % No other psychiatric disorder present that could explain the cognitive disorders such as depression, schizophrenia 3 EPIDEMIOLOGY DEMENTIA ↑ 12,000 people in the Netherlands with dementia < 65 (cf. 20,000 people with lung cancer) age ! women usually gets older than man (men die sooner 4 2  16/09/2024 EPIDEMIOLOGY DEMENTIA Average health-care costs in the Netherlands (x 1,000 Euros ) Prognosis of increase in number of dementia patients number year men double aging-people get older women line people longer - 5 SUBTYPES DEMENTIA Dementia = syndrome (descriptive), says nothing about underlying disease / pathology Underlying cause/aetiology must therefore be specified: ‘Major neurocognitive disorder due to…’ (DSM-5) Alzheimer’s disease most common cause - Frontotemporal lobe degeneration Lewy body dementia Vascular aetiology Traumatic brain injury Alcohol and drug use most prominent HIV infection Prion disease Parkinson’s disease Huntington’s disease … 6 3  16/09/2024 DEFINITION ALZHEIMER’S DISEASE First patient described in 1911 by Alois Alzheimer “Cortical dementia” 50-60% of all dementias Progressive and degenerative (poor prognosis) Structural and functional abnormalities in the brain Disease (one of the causes of dementia syndrome) dementit is a syndrome Alzheimer is Lisease a ↳ one of the causes for dementit 7 daged PATHOPHYSIOLOGY ALZHEIMER’S DISEASE - medial tempera lose is Atrophy: neuronal cell death ↓ - Senile plaques (protein accumulations) and neurofibrillary tangles -Lisfunction On connection 8 4  16/09/2024 PATHOPHYSIOLOGY ALZHEIMER’S DISEASE Video 1: How Alzheimer's Changes the Brain 9 DIAGNOSIS ALZHEIMER’S DISEASE Clinical diagnosis on basis of exclusion or post-mortum Supporting diagnostic evidence: MRI/SPECT/PET Protein abnormalities in cerebrospinal fluid (CSF or liquor) Neuropsychological assessment Differential diagnosis often difficult: vascular dementia, depression, frontotemporal dementia, etc. 10 5  16/09/2024 MEDIAL TEMPORAL LOBE ATROPHY ALZHEIMER’S DISEASE Coronal view minimal mild moderate hippocampus Chardly severe and hippocampal alls even in early stage , are be seem it hoppocampul atrophy 11 DIAGNOSIS ALZHEIMER’S DISEASE The cognitive profile of Alzheimer's dementia in Korsakoff - also Memory impairment present from the start (with temporal gradient) ↳ new int. is remembered Decline in abstract thinking (intelligence) slower Impaired orientation in time, place, person Other cortical disorders: aphasia, agnosia, apraxia, executive dysfunction Progressive course Video 2: Memory clinic - psychology test - URE 12 6  16/09/2024 COGNITIVE SCREENING Testing MONTREAL COGNITIVE ASSESSMENT (MOCA) - memory Maximum score = 30 More sensitive than MMSE Especially when the cognitive problems are mild (pre-dementia phase, other disorders) Work group: practice on each other first before you test the actual participant Memory Impairment Score (MIS) Free recall Cued recall Recognition (maximum score = 15) www.mocatest.org 13 COGNITIVE SCREENING MONTREAL COGNITIVE ASSESSMENT (MOCA) Draw a clock (ten past eleven) (3 points) neglect Episode New- combination test ↳ about new memories-hippocampus showed · that image 14 copy - what drawing then 7 - remember you  16/09/2024 COGNITIVE COURSE OVER TIME ALZHEIMER’S DISEASE In principle, all cognitive domains can be impaired 1st memory Course of impairments: Progressive episodic memory decline, especially anterograde amnesia Impaired orientation in time and space Followed by: Deficits in abstract reasoning (intellectual functioning) Executive dysfunction Reduced insight ex E put in order the. Later phases: books I'm Line Language disorders (production, comprehension) Increasing retrograde amnesia with temporal gradient Apraxia Visuospatial deficits Social cognitive deficits Behavioural problems (disinhibition, apathy) Final phase: Mutism, mental retardation 15 PROFILE OF MEMORY IMPAIRMENT ALZHEIMER’S DISEASE  Impairments in episodic memory tasks  Specifically in the encoding of contextual information  Poor delayed recall  Rapid forgetting  Semantic memory in early stages (relatively!) intact general knowledge  However: semantic priming impaired later in the course - (in subcortical dementia, motoric priming is impaired)  Eventually all functions are affected  Working memory  relatively intact on span tasks (phonological loop and visuospatial sketchpad)  impaired on associative (‘binding’) and executive aspects (dual tasks) of WM -  Meta-memory in early stages intact; later severely impaired -  Implicit knowledge often intact -  Skills unimpaired (already learned) but apraxia can be present ↳  Implicit learning intact, but ‘structured learning” required subcortical 16 and because Alzheimer's is cortical disease , subcortical functions 8 are infact  16/09/2024 PATHOPHYSIOLOGY CHOLINERGIC HYPOTHESIS to breakdown r stops the acetylcholine treatment with acetylcholinesterase inhibitors (such as rivastigmine: Exelon® and galantamine: Reminyl ®) does not cure the disease (treats just the symptoms) and may have considerable side effects 17 PATHOPHYSIOLOGY: NEW ANTI-ALZHEIMER DRUGS ADUCANUMAB Zwic week injected in crebrospinal fland FDA approved EMA not approved: “Biogen originally filed an application in 2020 with the agency that recommends whether new drugs should be approved in Europe. Near the end of 2021, the European Medicines Agency concluded there was not enough evidence to allow Biogen's drug, called Aduhelm, on the market.” 18 9  16/09/2024 PATHOPHYSIOLOGY ALZHEIMER’S DISEASE Three hypotheses: A - cholinergic hypothesis [obsolete: it is a consequence] Acetylcholine ↓ - amyloid cascade hypothesis (under debate) is due to the disease - vascular hypothesis: mixed pathology 19 COGNITIVE COURSE OVER TIME ALZHEIMER’S DISEASE In principle, all cognitive domains can be impaired Course of impairments: Progressive episodic memory decline, especially anterograde amnesia Impaired orientation in time and space Followed by: Deficits in abstract reasoning (intellectual functioning) Executive dysfunction Reduced insight Later phases: Language disorders (production, comprehension) Increasing retrograde amnesia with temporal gradient Apraxia Visuospatial deficits ( PCA: posterior variant of Alzheimer's dementia) Social cognitive deficits Behavioural problems (disinhibition, apathy) Final phase: Mutism, mental retardation 20 10  16/09/2024 ↳ the disease can short from POSTERIOR CORTICAL ATROPHY ALZHEIMER’S DISEASE I not only in medioturou) Atypical form of Alzheimer's dementia Atrophy is occipitoparietal in particular Characterised by visuospatial disorders: Agnosia Hemispatial neglect Spatial cognition More common in younger patients 21 ALZHEIMER’S DISEASE AND BRAIN AGEING – E.g. the Vumc 100+ study 22 11  16/09/2024 PRE-DEMENTIA STAGE MILD COGNITIVE IMPAIRMENT (MCI) normal ageing + forgetfulness MCI (mild cognitive impairment): pre-dementia stage of cognitive decline Memory (or other domain) impairment (established on neuropsychological tests) Cognitive complaints (subjective) No significant limitations in daily life functioning (= no dementia!) About 25-50% of MCI patients develop dementia in the next 2-5 years (often dementia due to Alzheimer’s disease) Research focuses on predictors of conversion to dementia and early treatment to delay onset of dementia (or even stop the disease) they still function independently! 23 MCI IN THE DSM-5 MILD NEUROCOGNITIVE DISORDER Cognitive decline with regard to previous performance level in one or more cognitive domains No interference with daily activities no dementia No delirium No other psychiatric disorder present that could explain the cognitive disorders such as depression, schizophrenia ‘Mild NCD due to...’ Alzheimer’s disease Parkinson’s disease Vascular dementia … 24 12  16/09/2024 NORMAL AGEING – MCI – DEMENTIA CONTINUUM ALZHEIMER’S DISEASE No disorder precedingDementia MCI No cognitive Impairments in one Impairments in impairments or more domains, multiple domains (= normal ageing) no functional with functional impairment impairment Dementia due to MCI due to Alzheimer’s disease (McKhann et al., Alzheimer’s & Alzheimer’s Dementia 2011;7:263-9) disease (Marilyn et al., Alzheimer’s & Dementia 2011;7:270-9) Continuum of cognitive (dys)function (Petersen, 2004; Winblad et al., 2004) 25 BRAIN CHANGES COGNITIVE AGEING 26 13  16/09/2024 BRAIN CHANGES COGNITIVE AGEING Are these changes in the brain also related to cognitive decline? From: Eikelboom, W.S., Bertens, D. & Kessels, R.P.C. (2020). Cognitive rehabilitation in normal aging and individuals with subjective cognitive decline. In J. DeLuca, N. Chiaravalloti & E. Weber (Eds.), Cognitive Rehabilitation: Examining the Evidence from Brain to Behavior. Springer. - 27 METHODOLOGICAL CHALLENGES COGNITIVE AGEING Cross-sectional research Longitudinal research Less decline than previously assumed, but decline does set in with advancing age Factors : Sackground Inchos altural Nyberg et al., TICS 2012 28 14  16/09/2024 EXECUTIVE FUNCTION THEORY COGNITIVE AGEING In young adults less brain activation needed, only in one hemisphere In older adults, more activation needed, also more bilateral To maintain the same behavioural performance Hemispheric Asymmetry Reduction in OLDer adults (HAROLD; Cabeza, 2002) 29 COMPENSATORY MECHANISMS SCAOFFOLDING THEORY OF COGNITIVE AGING (STAC) using brain your (Reuter-Lorenz & Park, 2014) 30 15  16/09/2024 COMPENSATORY MECHANISMS COGNITIVE RESERVE Cognitive reserve (CR) is a concept coined by Stern (2009) Protective against effects of brain pathology (compensatory mechanism) Higher cognitive reserve – slower cognitive decline CR ~ “cognitive scaffolding” : education, social activity, cognitively demanding lifestyle education people witen higher dementin lato than develop peoplewith lowerechonare - as they can compensate for the cognitive impairments Anita Van Loenhoud, AAIC 2017 31 ALZHEIMER’S DISEASE, DEMENTIA AND MCI LEARNING OBJECTIVES Understand the difference between Alzheimer’s disease and Alzheimer’s dementia Understand the concept ‘mild cognitive impairment’ (MCI) Have knowledge on the epidemiology, etiology and neuropathology of Alzheimer’s disease Understand the cognitive profile and its course of Alzheimer’s dementia Have knowledge about the cognitive assessment of MCI and Alzheimer’s dementia Relate cognitive ageing to brain changes 32 16