Epidemiology of AD
Alois Alzheimer(1907)가 최초 기술
대표적인 원발성퇴행성치매:
치매중 가장 흔한 유형(50%), 혈관성치매와의 혼합형(15%)
발병후 평균 생존 기간: 8년
Prevalence : 1) 60-69세 0.5%, 70-79세 3%, 80-89세 10%
)5년마다 두배로 증가
2) 65-69세 1.5%, 95-99세 44.8%
Incidence : 60세 이상에서 1년에 1%
Risk Factors for AD
(Ritchie 2002)
Confirmed risk factor : age, ApoEε4 allele, vascular pathology, family history of dementia or vascular disorder
Others : 여성, 저학력, alcohol,
출생시 부모 연령40세 이상,
두부외상, 다운증후군, 우울증, homocysteine 증가, folate와 Vit B12 농도저하
Neuropathology of AD Amyloid plaques stained immunohistochemically using an antibody to β/A4 protein.
Jin Sook Cheon, M.D., Ph.D.
Department of Neuropsychiatry, Kosin University College of Medicine, Busan, Korea
‘Flame-shaped’ neurofibrillary tangles in a pyramidal
cell of the temporal cortex. Etiopathogenesis of AD
(Alafuzoff & Soininen 2002)
Genetic, oxidative stress, toxic mechanisms → cascade models
→ neuronal degeneration → AD
Amyloid cascade hypothesis : accumulation of beta-amyloid(Aβ)
Taupathy hypothesis : hyperphosphorylation of
microtubule-associated protein tau
Clinical Signs and Symptoms of AD
Cognitive syndromes
Noncognitvie symptoms : 1) Psychiatric symptoms or syndromes, neuropsychiatric symptoms 2) Behavioral disturbances, behavioral symptoms, behavioral disorder
Cognitive Symptoms of AD
Very mild(CDR 0.5, GDS 2) : subjective memory complaints; no deficits in language, visuospatial, executive function
Mild(CDR 1, GDS 3-4) : recent memory loss, poor recall; mild word finding error;
mild visuospatial, executive dysfunction
Moderate(CDR 2, GDS 5) : nil recall;
frequent word finding error; cannot navigate outside home without companion;
unable to handle money
Severe(CDR 3, GDS 6-7) : nil recall;
sparse meaningful verbal output; severe impairment in other cognitive areas
Behavioral and Psychological Symptoms of Dementia(BPSD)
Disorders of mood : more than 80%
Disorders of thought content : up to 30%
Visual/auditory hallucinations : up to 15%
Other psychiatric symptoms (reduplications, misidentifications) : up to 20%
Behavioral disturbances (aggression, wandering) : 20-25%
Untreated BPSD Contributed to
Premature institutionalization
Increased financial cost
Decreased quality of life for both caregiver and patient
Significant caregiver stress
Stress to nursing staff in residential facilities
Excess disability
DSM-IV Diagnostic Criteria for AD
(American Psychiatric Association 1994)
Multiple cognitive deficits : 1) in memory 2) one or more of language, praxis, gnosis, executive functioning
Causing : 1) significant impairment and decline in social or occupational functioning 2) gradual onset and continuing cognitive decline
Not due to : 1) other CNS or
substance-induced conditions 2) delirium, depression or
schizophrenia
NINCDS-ADRDA Criteria
Definite AD : 1) Clinical criteria for probable AD 2) Histopathology of AD by biopsy or autopsy
Probable AD : 1) Dementia by history and neuropsychological testing 2) Progressive deficits in memory and one other area of cognition 3) No disturbance of consciousness 4) Onset btw ages 40 and 90 5) Absence of systemic or other brain disorder causing dementia
Possible AD : 1) Dementia with variations in onset or course 2) Presence of systemic or other brain disorder 3) Single progressive cognitive deficit
Mini-Mental State Examination
(Folstein et al 1975)
Orientation : Year, season, date, day, month; Where are we?
Registration : Name 3 objects
Attention and Calculation : Serial sevens
Recall : Ask for 3 named objects
Language : Have the patient name pointed pencil & watch; Repeat no, ifs, ands,or buts; 3 stage command;
Have the patient read & obey close your eyes; Write a sentence;
Copy 2 intersected quadrangles
Hasegawa Dementia Scale 개정판(Hasegawa, 1972)
나이는 몇 살입니까?
오늘은 몇 년, 몇 월, 몇 일, 무슨 요일입니까?
우리가 지금 있는 곳은 어디입니까?
지금부터 하는 말을 따라하세요. 나중에 물어보니까
잘 기억하고 계세요. 매화, 개, 자동차
100에서 7을 순서대로 빼보세요.
내가 지금부터 말하는 숫자를 거꾸로 말해 보세요.
6-8-2/ 3-5-9-2
조금 전에 기억했던 단어를 다시 한번 말해주세요.
지금부터 5가지 물건을 보여드린 후 그 물건을 숨길테니까 무엇이 있었는지 말해주세요.
시계, 열쇠, 담배, 펜, 동전
알고있는 야채의 이름을 가능한 많이 말해 보세요.
The 7 Minute Screen
(Solomon et al 1998)
Orientation for time
Memory
Visuospatial and visuoconstruction
Verbal fluency
Global Deterioration Scale
(Reisberg et al 1982)
Stage 1(No cognitive decline) : Normal
Stage 2(Very mild cognitive decline) : Forgetfulness
Stage 3(Mild cognitive decline) : Early confusional
Stage 4(Moderate cognitive decline) : Late confusional
Stage 5(Moderately severe decline) : Early dementia
Stage 6(Severe cognitive decline) : Middle dementia
Stage 7(Very severe cognitive decline) : Late dementia
Clinical Dementia Rating
(Hughes et al 1982)
CDR 0(Healthy) : no memory loss
CDR 0.5(Questionable dementia) : mild consistent forget, partial recollection, fully oriented, fully capable of self care
CDR 1(Mild dementia) : more marked recent memory loss, geographic disorientation, social judgment maintained, mild impairment at home
CDR 2(Moderate dementia) : only highly learned material retained, disoriented to time and place, no pretense of independence outside home
CDR 3(Severe dementia) : only memory fragments remain, orientation to person only, no judgments
MRI Findings in AD
Medial temporal lobe atrophy
(Masdeu & Aronson 1985; Le May et al 1986)
Measurement of superior temporal and anterior cingulate sulci, entorhinal cortex volume
(Killiany et al 2000)
Longitudinal study of hippocampal atrophy(Jack et al 2003)
Medial temporal region is the first affected in MCI, progression into posterior cingulate gyrus and temporo-parietal association cortex
(Rusinek et al 2003; Thompson et al 2003)
Interuncal Distance
Cheon JS, Cho WY, Jeon GS, Song HR, Oh BH. J Kor Geriatr Psychiat 2004;8:121-126.
Healthy Elderly (N=20) : 24.35±2.91 mm
MCI(N=30) : 25.60±2.66 mm
AD(N=34) : *26.52±3.37 mm
*p<0.05 between AD & healthy elderly (one-way ANOVA with Scheffe/Tukey)
White Matter Lesions
Cheon JS, Jeon GS, Cho WY, Song HR, Oh BH. 2006;unpublished data.
Healthy Elderly (N=20) : *PVH 3= 5.0%, DWMH 3=10.0%
MCI(N=30) : *PVH 3=16.7%, DWMH 3=23.3%
AD(N=34) : *PVH 3=38.2%, DWMH 3=35.3%
*p<0.05 between groups on PVH (Pearson Qui-square test)
Major Depression(N=32) : PVH 3=15.6%, DWMH 3=15.6%
(Cheon 1999)
Biological Markers
No universally accepted biological marker for AD.
Five markers have promise for improving diagnostic accuracy of AD : CSF tau, CSF Aβ42, APP isoforms in platelets, neural thread protein, p97.
To monitor treatment directed against plasma and CSF Aβ level.
To predict future risk of developing AD : plasma Aβ has some promise
Disclosing the Diagnosis
Breaking the diagnosis of dementia needs to be done with tact and sensitivity and in an unhurried manner
Maguire et al(1996) : the issue of disclosure needs to be dealt with on a patient by patient basis
Family Members’ View on Telling AD Diagnosis to Patients
Maquire et al. BMJ 1996;313:529-530.
Cheon JS, Kim IS, Oh BH, Cho W.
J Kor Geriatr Psychiat 2005;9:112-121.
Subjects : Korea(N=73) vs USA(N=100)
Yes : Korea 58.9% vs USA 17.0%
No : Korea 41.1% vs USA 83.0%
Core Principles of the
National Service Framework for Dementia Care
(UK Department of Health 2001)
The need to treat individuals with dignity
The need to have a holistic approach to care
The need to coordinate care between health and social services
The importance of staff training for those caring for older people
살고 있는 곳에서 치료하자
지역 사회에서 치료
z치매 클리닉: 약물 치료
z노인 주간치료시설: 보호 및 재활
z방문 간호: 중고도 치매 혹은 신체 질 환 간호
z가정 도우미: 간병 부담 경감
입원 치료 및 시설 수용
z전체 비용의70 ~ 80%가 입원 및 수 용 비용
z고도 치매 환자에 국한
지역사회에서의 치료는 전세계적 추세
Cholinesterase Inhibitors
Donepezil (Aricept®) : reversible inhibitor of acetylcholinesterase;
halflife 70-80 hrs; 5-10mg/day, single dose; drug interaction(yes)
Rivastigmine (Exelon®) : selective pseudoirreversible inhibitor of acetylcholinesterase and butyrylcholinesterase; halflife 1-2 hrs; 6-12mg/day, two divided doses; drug interaction(low)
Galantamine (Reminyl®) : reversible inhibitor of acetylcholinesterase, negligible butyrylcholinesterase, nicotinic agonist; halflife 6 hrs;
16-24mg/day, two divided doses;
drug interaction(possible)
Common Side Effects of Cholinesterase Inhibitors
Nausea
Vomiting
Diarrhea
Abdominal pain
Anorexia
Insomnia
Cholinesterase Inhibitors 의 보험인정기준
• 적응증 : 경도-중등도 AD(AD with CVD), VD(Donepezil)
• MMSE 10~26(Donepezil & Rivastigmine), 10~24(Galantamine)
• CDR 1~2 or GDS 3~5
• 보험약가
Aricept® 3891원/5mg, 4546원/10mg Reminyl® 1320원/4mg,1979원/8mg Exelon® 1928원/3mg,1936원/6mg
Memantine(Ebixa®)
기전: NMDA receptor antagonist
적응증: 중등도-고도 AD
보험인정기준: MMSE 20점 이하, CDR 2-3, GDS 5-6
보험약가: 1정(10mg) 1,578원
용법: 1주 아침 5mg; 2주 5mg BID;
3주 아침 10mg, 저녁 5mg;
4주 10mg BID
General Management Approaches for BPSDs
Behavioral Management : 1) Reassessment of behavior 2) Changing behaviors by influencing the carer 3) Changing the environment
Pharmacological Management
Institutional Care
Drugs Commonly Used to Treat BPSD in AD
(Wright & Cummings 1996)
Agitation &
Aggression : Carbamazepine Divalproex Trazodone Buspirone, Lorazepam Propranolol Haloperidol, Risperidone Olanzapine, Quetiapine
Psychosis : Haloperidol Risperidone Olanzapine Quetiapine
Anxiety : Lorazepam, Oxazepam, Propranolol, Buspirone
Depression SSRI : Citalopram, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine TCA : Desipramine, Nortriptyline Others : Venlafaxine
Insomnia : Trazodone Zolpidem Temazepam
Cholinesterase Inhibitors
Donepezil : Improvement in delusions, agitation, anxiety, disinhibition, irritability in 86 AD;
28% worsening(Mega et al 1999)
Rivastigmine : In 58% of 173 AD, clinically relevant improvement in aberrant motor behavior, agitation, anxiety, delusions, hallucinations, irritability, nighttime behavior
(Cummings et al 2000)
Galantamine : improvement in NPI for anxiety and apathy item ; aberrant motor behavior worsened
(Erkinjuntti et al 2002)
Memantine
A beneficial effect on behavioral symptoms in moderate to severe dementia, with the most pronounced effect on agitation or aggression(Gauthier et al 2005)
Combination Therapy
Coadministration of ChE inhibitors and antipsychotic drugs may provide a synergistic benefit for the severe BPSD : 1) Rivastigmine + risperidone (Weiser et al 2002)
2) Donepezil + risperidone (Magnuson et al 1998)
3) Donepezil + bromperidol (Ueki et al 2001)
A Case of AD with Cognitive Symptoms and Hypersexuality
80 yr-old male, supermarket, elementary school
MMSE 20/30, Hachinski Ischemic Score 2, CDR 1, GDS 4, IADL 23
Diagnosis : Alzheimer’s Dementia
Became irritable on increased libido, rubbing genitals 2 yrs after onset of dementia symptoms
Treatment : donepezil 5mg, cimetidine 400mg, clonazepam 0.5mg, moclobemide 150mg
MRI showing multiple patch high signal
in parietal with cerebral atrophy Milestones in Progression
of AD(Gauthier 2000)
Conversion from mild cognitive impairment to dementia
Loss of instrumental activities of daily living
Emergence of neuropsychiatric symptoms
Nursing-home replacement
Loss of self-care ADLs
Death
Rapid Decline
(Knopman 2002)
Early extrapyramidal signs
Early psychosis
Severe aphasia
Concomitant vascular disease
Early myoclonus
Non-AD dementias
Greater age
Unmarried men
Caregiver psychological morbidity
Quality of Life in Patients with AD
Cheon JS, Cho W, Oh BH.
J Kor Geriatr Psychiat 2005;9:63-69.
54 Patients with AD
KQOL-AD was higher in AD(p<0.005)
Significant predictors influencing on KQOL-AD : age, cognitive function, severity of dementia, ADL, depression, homocysteine
Support for Carers
Caregiver burden : the physical, psychological or emotional, social and financial problems that can be experienced by family members caring for impaired older adults(George & Gwyther 1986)
Measurement of caregiver burden : Overall distress and strain;
Financial concerns; Isolation and lack of family support; Physical and/or emotional health; Self esteem and self worth; Emotional stress(hostility, grief, guilt, resentment)
Caregiver Burden for Patients with AD
Cheon JS, Jo SG, Song HR, Oh BH.
J Kor Geriatr Psychiat 2003;7:154-162.
31 Caregivers with age 45.5±12.6 yrs
SCB scores were higher in in caregivers for AD(p<0.001)
Factors significantly related to SCB : primary stressor(RMBPC) secondary stressors(depression, anxiety)
Conclusions
AD is the most frequent cause of dementia.
Early detection is most crucial.
Initially, cognitive symptoms and BPSDs can be treated by cholinesterase inhibitors and NMDA antagonist.
QOL and burden of patient and caregiver should be considered.
