Lecture 5: Mild Cognitive Impairment & Subjective Cognitive Decline

Question 1

Mild Cognitive Impairment & Subjective Cognitive Decline:

• Which is considered part of normal ageing and which is considered part of abnormal ageing?

Answer 1

Mild Cognitive Impairment: part of abnormal cognitive ageing Subjective Cognitive Decline: part of normal ageing

Question 2

Overview of possible cognitive age-related concerns:

Answer 2

Question 3

Subjective Cognitive Decline

SCD (Jessen er al. 2014) :

Answer 3

• Older adults complain about perceived decline in cognitive abilities
• Within normal limits standard neuropsychological or other clinical measures
• No impairments IADL (Instruments Activity of Daily Living)

Criteria for diagnosis (for SCD):

• Decline relative to prior levels (subjective decline)
• Decline not due to psychiatric or other conditions, medicattion, substance use (reversable causes)

(for a long time they were referred to as the “worried well” and it was thought that there is nothing wrong with them)

Question 4

Subjective Cognitive Decline (consequences)

Answer 4

• increased risk developing MCI and AD
  
  • Rates vary: 5 – 50%
  • Meta-analysis (Mitchell et al., 2014):
    
    • adults SCD twice as likely (10.9%) to develop dementia than without SCD over 4 year period
• Higher frequencies AD biomarkers (“SCD plus”)
  
  • Volume loss hippocampus, medial temporal areas
  • Amyloid plaques
  • Evidence mixed
  • in SCD “plus” the “plus” refers to the presence of biomarkers

Question 5

Differential diagnosis (SCD vs MCI or dementia):

Answer 5

• Formal neuropsychological assessment (simple because SCD is - contrary to MCI and dementia - defined as being in the limits of normal ageing by neuropsychological assessments)

Question 6

Differential diagnosis, SCD vs normal ageing:

Answer 6

• Lack objective measures SCD (can’t use neuropsychological tests)
• Differentiation based on self report
  
  • No SCD typical complaint of cogntive domain
  • Concern/worry more sensitive as indicator SCD
    
    • Increased risk conversion dementia
• Other etiologies (e.g. depression, chronic medical conditions)

Question 7

Mild cognitive impairment (MCI):

Answer 7

• decline in cognitive performance greater than expected from person’s age, not sufficient to warrant diagnosis dementia.
  
  • MCI is stage between normal cognition and dementia
• MCI: pathological condition, not part of normal ageing
• MCI: stage between normal cognition and dementia in terms of severity and progression
  
  • however, it does not necessarily lead to dementia, some also return to normal functioning

Question 8

Mild cognitive impairment, Diagnosis.

Original criteria Petersen (1999), Mayo criteria:

Answer 8

Original criteria Petersen (1999), Mayo criteria:

• subjective complaint memory impairment
• objective evidence of memory deficit (disctinction to SCD)
  
  • 1.5. SD below norm on 20 min. delayed recall story A of WMS Logical Memory task
• overall cognitive functions preserved (MMSE >= 24)
• intact activities of daily life (global Clinical Dementia Rating (CDR) scale of 0.5)
• absence of dementia (consensus diagnosis)

These criteria were strict and limited to memory.

Question 9

Mild cognitive impairment, Revised criteria for Diagnosis.

NIA-Alz Association task force for MCI (Albert et al. 2011):

Answer 9

• Concern about change in cognition.
  
  • Change larger than expected from person’s age, education
• Evidence impairment one or more cognitive domains
  
  • no longer memory only
  • 1 - 2 SDs below mean
• Preservation independence in daily functioning
  • or only mild difficulties
• Not demented
  
  • impairments and mild difficulties IADL not severe enough interfere with social or occupational functioning
• MCI as diagnosis (associated with dementia pathology)
  
  • Not description of current functioning
  • MCI is a condition\diagnosis based on functioning but not just a description of the degree of functioning
• Overlap criteria for minor neurocognitive impairment DSM 5.
  
  • DSM also requires that changes not due to delirium or Axis 1 disorders (depression, schizophrenia).

Question 10

Mild cognitive impairment, Revised criteria.

Overlap with other diagnoses or pathologies:

Answer 10

• Overlap criteria for minor neurocognitive impairment DSM 5.
  
  • DSM also requires that changes not due to delirium or Axis 1 disorders (depression, schizophrenia).
• Overlap “cognitive impairment no dementia”(CIND)
  • Label first used in Canadian epidemiological studies
  • CIND – any cognitive disorder (not only memory) from various possible causes, including drug use, alcohol abuse, psychiatric illness, degenerative illness.
  • MCI more specific than CIND

Question 11

Mild cognitive impairment, revised criteria.

Various causes for cognitive impairment:

Answer 11

• Some causes may be reversible
• Persons diagnosed with MCI can revert to normal function
  
  • depending on what the cause is MCI might be reversible to normal functioning or not

Question 12

Mild cognitive impairment.

Petersen (2004): 4 main etiologies for MCI:

Answer 12

1. Degenerative (e.g. AD)
2. Vascular (e.g. cerebrovascular disease)
3. Psychiatric (e.g. depression)
4. Traumatic (e.g. head injury)

Other causes are possible (e.g. drug effects, thyroid dysfunction, B12 deficiency).

• 1 & 2: MCI possibly pre-stage of dementia
• but if due to 3. or 4. (psychiatric or traumatic reasons) it is well ossible that a person returns to normal functioning after the cause is treated/healed.

Question 13

Types of MCI

Answer 13

• Depending on cognitive domains affected
  
  • amnestic MCI (aMCI) – memory impaired, other domains spared
  • nonamnestic MCI (naMCI) – memory spared, other domains impaired (e.g. executive function, language),
• Single domain or multiple domains (distinction)
  
  • One (SD - single domain) or more than one cognitive domain/function (MD - multiple domain) impaired.

Question 14

Cognitive impairments in MCI

Example study about Memory

(Rabin et al., 2009)

Answer 14

MCI group, impaired on range of verbal and visual memory tests – aMCI

• notice that on all different memory tasks the MCI group performs worse than healthy controls

Question 15

Cognitive impairments in MCI

Example study of memory and other cognitive functions.

(Grundman et al., 2004)

Answer 15

MCI group impaired on memory, EF, speed and language tests

• multiple functions can be impaired

Question 16

Cognitive impairments in MCI

Example study: single or multiple domains

(Brandt et al., 2009)

Answer 16

• some of subgroups are only impaired on a single domain (e.g. memory)
• others don’t have imapirments of memory but on different other domains (EF, etc.)

Question 17

Prevalence of MCI

Answer 17

• Uncertainty prevalence MCI
• Wide variation between studies (3% - 54%)
  
  • partly due to diagnostic methods used and populations sampled

Question 18

Reasons for different estimates of the prevalence of MCI:

Answer 18

1. populations sampled:
   * Prevalence higher in clinical samples (persons with memory or other cognitive complaints) than in population samples
2. different diagnostic criteria used

• Criteria to define impairments more strict – lower prevalence
• Criteria to define impairments less strict – higher prevalence

3. different diagnostic methods used

• More cognitive domains assessed, more sensitive tests:
  
  • more likely to find cognitive impairments due to chance (higher prevalence MCI)

Question 19

Prevalence of MCI

Large population studies in US and other countries:

Answer 19

• MCI prevalence elderly persons (70 and older) without dementia: 16% (Petersen et al., 2010), 18.8% (Lopez et al. 2003), 16.3% (Michaud et al., 2017)
• Prevalence found in these large studies were fairly similar
• Similar prevalence rates in Sweden, Germany, Canada
  
  • MCI prevalence estimated 9 - 20% of elderly population (Smith & Bondi, 2013)
  • Higher in clinical samples

Question 20

Prevalence of MCI regarding age and gender

From: Petersen et al (2010)

Answer 20

• increases with age
• higher in men

Question 21

Prevalence of MCI regarding education:

From: Petersen et al (2010)

Answer 21

• lower prevalence with more years of education
• true among men and women

Question 22

Prevalence of MCI regarding amnestic vs non-amnestic MCI and Single vs. multiple domain categories:

From: Petersen et al (2010)

Answer 22

• MCI with memory impairments most prevalent
• Prevalence amnestic MCI higher than non-amnestic MCI (SD and MD).
• least prevalent is the non-amnestic, multi-domain MCI

Question 23

Brain changes in MCI

• Structural - volume

Jack et al. (2000)

Answer 23

• Volume hippocampus in MCI (amnestic MCI) < healthy older adults > AD
• 2 – 4 year follow-up: more reduction volume hippocampus MCI than healthy older adults
  
  • less reduction than in AD (but NS)
• 2 – 4 year follow-up: less reduction volume hippocampus in MCI who maintained baseline cognitive performance (MMSE, Dementia Ratings Scale) than decliners

So, rate of reduction in volume was higher in MCI group compared to control but lower compared to AD group.

Question 24

Mild cognitive impairment

Structural brain changes - volume

• Chang et al (2010) – classification HC or MCI based on performance Rey Auditory Verbal Learning Test – learning and retention scores
• MCI subgroups low on learning (LL HR ≈ acquisition) or retention (HL LR ≈ delayed recall) of both (LL LR)

Answer 24

• More volume reduction in all MCI groups compared to HC
  
  • Volume reduction mainly in temporal and frontal areas (like in normal ageing)
  • Extent volume reduction larger in MCI subgroup impaired in both learning and retention (LL LR) than other subgroups

Question 25

Mild cognitive impairment Areas of volume loss (cortical thinning) of MCI groups relative to HC group: (Chang et al., 2010)

Answer 25

* most volume loss in temporal and frontal areas

Question 26

Structural brain changes Chang et al. (2010): **Conversion rate to AD** over 2 years:

Answer 26

* Conversion rate to AD over 2 years: * **higher in MCI groups** than HC groups * **highest in most impaired group** – LL LR (low on learning & low on retention) So, MCI is a **risk factor** for developing AD

Question 27

Mild cognitive impairment **Functional** brain changes:

Answer 27

* Less activation medial temporal lobe during memory task in MCI than healthy older adults * same area were the hippocmpus lies and where AD patients have particularly high atrophy * No difference activation MCI or AD (Machulda et al., 2003)

Question 28

¨Mild cognitive impairment **Functional** brain changes (more activation) (Dickerson et al., 2004)

Answer 28

* More activation hippocampal formation and parahippocampal gyrus - better memory performance in MCI (Dickerson et al., 2004) * Follow-up 2.5 years: 14 persons with MCI declined on CDR (general cognition), 18 remained at baseline level * so, those that performed better in memory had more activation * Decliners (those of MCI that showed decline in overall cognitive function) – more activation parahippocampal gyrus than stable persons during memory task * No group difference performance memory task * Increased activation despite same level of memory performance. What could this mean? * maybe it is a form of compensation

Question 29

Neuropathology in MCI is heterogeneous. **Pathology** often associated with different forms of dementia. Pathology of **MCI**? Neuropathology refers to **biomarkers** associated with a given diagnosis/disease. Usually found postmortem.

Answer 29

Pathology associated with different forms of dementia: * AD – plaques and neurofibrillary tangles * vascular dementia – infarcts * dementia with Lewy bodies – Lewy bodies * Mixed pathology Substantial proportion persons with MCI: no detectable neuropathology. * MCI not necessarily early stage of dementia

Question 30

Neuropathology in MCI. From: Schneider et al., 2009

Answer 30

Neuropathology in MCI * 400 postmortem examinations * around 25% had no detectable abnormalities associated with forms of dementia

Question 31

From: Schneider et al., 2009. 134 MCI diagnosis * Postmortem 73 persons with AD pathology:

Answer 31

* 44 (59%) diagnosis amnestic MCI * 29 (49%) diagnosis nonamnestic MCI

Question 32

Conversion to dementia * MCI is risk factor for dementia * Conversion rate:

Answer 32

* **Conversion rates:** wide range of rates reported: 3% - 63% (Smith & Bondi, 2013), even 80% conversion rate over 6-year follow-up (Rog & Find, 2013) * **Alzheimer Nederland**: around 44% of persons with MCI will progress to dementia within 5 years (unclear where number comes from) * **Duration follow-up** important for conversion rate: longer follow-up, higher conversion rate * standardized Annual Conversion Rate (ACR) - % of population that progress to dementia per year (to tackle the difficulty that probability of developing dementia increases with age) * Still, wide range ACRs reported: 1% - 20% (Smith & Bondi, 2013, Table 4.2)

Question 33

Conversion to dementia * Variation conversion rates result of methodological differences (Smith & Bondi, 2013):

Answer 33

* Populations from which sample was drawn * Nature of complaints * Number and type of cognitive domains assessed * How dementia was ruled out

Question 34

Range in conversion rate can result from : * Population from which sample is drawn

Answer 34

* from general older population: * more likely MCI cases come from normal population, lower conversion rate * 16% of normal population will score below 1 SD from mean on a cognitive test * from group with clinical concerns (e.g. recruited at memory clinics) * more likely MCI cases come from “predementia” population, higher conversion rate

Question 35

Range in conversion rate can result from : * Nature of complaints

Answer 35

* spontaneous complaints (e.g. memory functioning), more likely clinical/”predementia” population, higher conversion rate * these are subjective complaints * memory functioning established through tests/questionnaires, more likely normal population, lower conversion rate

Question 36

Range in conversion rate can result from : * Number and type of cognitive domains assessed (Loewenstein et al., 2009)

Answer 36

* More domains, more cognitive impairments identified * MD (Multiple-Domain) increased risk factor for conversion * 1 test diagnosis aMCI - 56% improved, 19% declined 3-year period * if diagnosis is made with 2 tests - none improved, 50% declined

Question 37

Range in conversion rate can result from : * How dementia was ruled out:

Answer 37

* How establish daily functioning is spared? * Self report, informants’ questionnaires may miss changes in ADL or IADL * MMSE of 24 may fail to identify persons with dementia. * not applicable for people with high education levels; for the 24 would mean already impairment * Fail to identify persons with dementia – underestimate conversion rate

Question 38

MCI to Dementia. **Range** in **conversion rates**; Meta-Analysis: ## Footnote (Mitchell & Shiri-Feshki, 2009)

Answer 38

* Meta-analysis 41 conversion studies (Mitchell & Shiri-Feshki, 2009) * Overall ACR 6.7% progression to dementia (any type) * Specialist settings 9.6% (clinics etc.) * Community studies: 4.9% * Majority of persons with MCI did not progress to dementia * Cumulative progression 30-40% over up to 5 years * MCI not necessary or sufficient for dementia

Question 39

Conversion to dementia (MCI to Dementia). Return to normal: Alexopolous et al. (2006) Pandya et al. (2016)

Answer 39

Majority of persons with MCI do not progress to dementia * Return to normal or remain stable * Alexopolous et al. (2006), 41% of persons with MCI remained stable over 3.5 years and 17% returned to normal functioning * Pandya et al. (2016): review reversion rate 20-50% returned to normal cognition

Question 40

Conversion to dementia Difference conversion rate aMCI and naMCI: Gauthier et al. (2006). consensus from 2005 expert conference on MCI.

Answer 40

* persons with aMCI more likely to convert to AD than persons with naMCI * MCI affecting multiple domains more likely to convert to dementia * Especially if memory was one of domains affected (Loewenstein (2013) in: Handbook Neuropsychology of Aging and Dementia) * MD aMCI more likely to progress to dementia than SD aMCI (Michaud et al., 2017) * Persons with naMCI higher risk for other forms dementia (Lewy bodies, frontotemporal dementia) than for AD

Question 41

Difference between amnestic MCI and non-amnestic MCI in frequency of AD, Lewy body and vascular pathology .

Answer 41

134 MCI diagnosis Little difference between amnestic MCI and non-amnestic MCI in frequency of AD, Lewy body and vascular pathology . From: Schneider et al., 2009

Question 42

¨Neuropsychological profile who likely to revert? (MCI to normal)

Answer 42

* Persons with naMCI more likely to revert to normal performance (Handbook Neuropsychology of Aging and Dementia, 2013) * SD MCI, younger age, more complex mental activity, men, married persons - more likely to revert to normal cognition (Pandya et al., 2016)

Question 43

Assessment of MCI * Differential diagnosis:

Answer 43

* symptoms of MCI can be caused by various disorders * not necessarily dementia/some causes may be reversible * identify etiology of cognitive impairment

Question 44

Assessment of MCI * Procedure:

Answer 44

* ¨Medical assessment * rule out reversible medical causes cognitive impairment * Clinical interview: * course of decline/emergence of cognitive symptoms * neurodegenerative disease usually slow course * life event linked with emergence * Subjective cognitive complaint is one of diagnostic criteria (from person or informant), so not necessarily from the patient himself. * Perception of decline * late stages MCI, early dementia – person underestimates deficit * early stage MCI, SCD – person readily reports * Neuropsychological tests * ideally repeated assessments * broad range of measures * at least two measures 1 SD below norm * avoid false negatives in premorbid high-functioning persons (well educated people) * ¨Functional independence/impairments * critical for diagnosis * subtle changes, less obvious due to compensation * Lindbergh et al. (2016) review: * more functional disability in MCI than healthy persons * multidomain MCI worse IADL * nonamnsestic MCI worse IADL * highest ES with informant report of functioning * functional decline result of cognition, not physical or other causes

Question 45

Interventions (MCI) * Pharmacological:

Answer 45

* AD medication (e.g. actylcholinesterase inhibitions) little effect in MCI * little effect slowing down progression to AD * little effect cognition * MCI heterogeneous * cognitive measures (MMSE, ADAS-Cog) insensitive * management risk factors, e.g. cardiovascular disease

Question 46

Interventions (MCI) * Non-pharmacological:

Answer 46

* Cognitive training: tasks to improve cognitive test performance * Hill et al. (2017) – computerized cognitive training in MCI * Overall positive effects - attention, WM, verbal learning * Effect on conversion rate unclear * effects often not generalisable to cognitive functioning (only improvement in what specifically was trained) * overall generally small * Cognitive rehabilitation (compensation, enhance everyday functioning) * Huckans et al. (2013) review RCTs. * Range of interventions (exercise, diet, cognitive stimulation, psychoeducation, multimodal) * Overall positive effects (“encouraging”) on cognitive measures * Chandler et al (2016) review effect daily functioning * Overall small positive effect (including mood, ADL * Multimodal (physical activity + cognitive intervention) beneficial