Lecture 7: Alzheimer’s Disease 2

Question 1

Alzheimer’s disease

Executive Functions (EF)

Answer 1

• Impairments of EF common in AD
  
  • already in early stage
  • impaired relative to HC on set shifting, flexibility (e.g. WCST), planning (e.g. ToL), inhibition (e.g. Stroop)

Question 2

Executive functions

• Stroop in AD (Bondi et al., 2002)

Answer 2

Stroop in AD (Bondi et al., 2002)

• 51 healthy controls, 59 probable AD
• AD - more errors word reading, color reading, color-word reading trials
• AD - interference score impaired (CW/C)
• No difference mild, moderate AD subgroups (Dementia Rating Scale)
  
  • mild AD already degree psychomotor slowing and inhibitory deficit

Question 3

Executive Functions in Alzheimer Disease: A Systematic Review (Guarino et al., 2019).

Answer 3

• Stroop – most consistently impaired
  
  • Accuracy
  • RTs
  • Interference

AD very mild (MMSE 26) – moderate (MMSE 16)

• WCST – deficits inconsistent
  
  • problem with task difficulty
  • floor effect
• Flanker – no consistent group differences
• Go-NoGo – majority studies no difference

AD: MMSE 18 - 25

Question 4

Language Impairments (AD) early vs later stage:

Answer 4

• Most language related capabilities intact in early stage but impaired in later stage

Question 5

Visuospatial abilities in AD:

Visual Search (Foster et al., 1999):

Mental Rotation (Lineweaver et al., 2005):

Answer 5

• Impairments typically mild in early stage
  
  • severe impairments as disease progresses
  • loss of orientation – lost in familiar surroundings, even their own home
• Visual search: feature (single feature) vs conjunction (two features) search:
  • AD slower than HC, even in feature search
  • impairment more severe in more advanced AD
• Mental rotation
  
  • AD slower to respond (mentally rotate)
  • Accuracy lower in AD patients, greater decline with increasing angles

Question 6

Visuospatial abilities in AD:

Clock drawing (Rouleau et al., 1992):

Answer 6

Clock drawing

• Draw clock from memory, copy clock
• Errors AD mainly conceptual errors, e.g.
  
  • drawing clock without numbers or without hands
  • setting time (10 past 11) incorrectly (Rouleau et al., 1992)
• Clock drawing errors in AD
• Conceptual errors - deficit accessing knowledge
• danger with using it for screening is that often healthy elderly have difficulties with this task (but much larger in AD)

Question 7

Visuospatial abilities

¨Posterior cortical atrophy (PCA) – associated with AD:

Answer 7

Posterior cortical atrophy (PCA) – associated with AD

• Predominantly AD pathology in posterior cortical regions: posterior parietal, occipital
• visual variant AD
• visual functions impaired, e.g. reading, object recognition (visual agnosia)
• relatively preserved memory and language
• Prevalence PCA unknown – 5% in sample 523 AD patients
• Onset PCA earlier than typical amnestic AD, in 50s or 60s

Question 8

Neuropsychological change

Typical pattern memory and EF impairments in early stage AD:

(Weintraub et al., 2012)

Answer 8

Typical pattern memory and EF impairments in early stage AD

• with progression more functions affected
• pattern impairments less distinct from other forms dementia
• early stage dementia seems to impact memory the most compared to other functions like behavioural ones

(Picture: the larger the black bar the more severe the impairment)

Question 9

Severity and profile of cognitive impairments varies with age at diagnosis. AD.

(Salmon & Bondi, 2009)

Answer 9

• Severity and profile of cognitive impairments varies with age at diagnosis.
• someone diagnosed below 70 mostly impaired in memory and EF, those above 80 all functions are imapaired to a similiar degree
• patients are compared relative to healthy individuals of the same age
• Different form AD?

Question 10

Sex differences in AD:

Cognitive impairments.

Answer 10

Sex differences in AD:

• AD more prevalent in women
• Cognitive impairments more severe in women with AD
  • Laws et al. (2018) review 298 articles:
  • Women with AD < men with AD
    
    • episodic memory, semantic memory, verbal abilities, visual spatial functions
    • Effect sizes small (d= 0.2)

Question 11

Sex differences in AD

• AD more prevalent in women, possible causes:

Answer 11

Genetic – APOE4 (Mielke et al., 2014)

• Single APOE 4 allele: women 4X higher risk AD, men little increased risk
• Autopsy study: plaques and tangles most prevalent in female APOE 4 carriers

Hormones – changes in oestrogen levels

• Hormonal replacement therapy (HRT) in mid life can reduce risk AD ( although evidence not consistent)
  
  • HRT after menopause can increase risk AD

Cognitive reserve

• Persons with more CR greater capacity to cope with brain pathology
• Education and occupation important factors CR

Question 12

Early cognitive predictors AD

Answer 12

• Episodic memory disturbances years before diagnosis:
  
  • Delayed recall CVLT performance in healthy older adults predictor of subsequent progression to AD (Bondi et al, 1999)
• Memory performance poorer in persons converting to AD 3 years later
  
  • learning score CVLT ( California Verbal Learning Test) distinguished normal group (controls), MCI (questionable) and converters (MCI converted to probable AD (Albert et al., 2001)
• poorer episodic memory than persons who remained cognitively healthy 6 years before diagnosis (Bäckman et al., 2001)

Question 13

Early cognitive predictors AD

• Mild impairments episodic memory as early predictor AD

Answer 13

Mild impairments episodic memory as early predictor AD

• aMCI more likely to convert to AD than naMCI
• aMCI referred to as “MCI due to AD” (memory impairment + biomarkers)

Question 14

How do memory impairments compare with preclinical biomarkers for AD? (Jedynak et al., 2012)

Hypothetical model of changes in biomarkers for AD (Jack et al., 2010)

Answer 14

(Jedynak et al., 2012)

• Used (Jack et al., 2010) Model but added memory
• Delayed free recall Rey Auditory Verbal Learning Test (RAVLT30): earliest predictor AD. Preceded hippocampal volume, amyloid beta and tau.

Question 15

Early cognitive predictors AD

• Stable memory impairments may worsen shortly before symptoms AD:
• Lange et al. (2002)

Answer 15

Stable memory impairments may worsen shortly before symptoms AD

Lange et al. (2002):

• participants completed at least two annual evaluations.
• NC participants classified as nondemented at both evaluations.
• AD diagnosed with possible or probable AD at both evaluations.
• Preclinical AD diagnosed with possible/probable AD at last evaluation AND normal/MCI in preceding evaluation

Performance preclinical AD group on CVLT at 2, 1 and 0 years before diagnosis. Little difference APOE 4 positive or negative (Lange et al., 2002).

• it seems like decline is most steep in those shortly before being diagnosed.
• Little difference APOE 4 positive or negative (Lange et al., 2002).

Question 16

Early cognitive predictors AD.

Episodic memory

EF

Semantic Knowledge

(Mickes et al , 2007)

Answer 16

• Converters: older adults who were cognitively normal 1 and 2 years prior to diagnosis probable AD (in year n)
• Sharp drop memory years before diagnosis.

Question 17

Early cognitive predictors AD

• Decline in episodic memory related to progress of neuropathology?

Answer 17

Rapid decline shortly before clinical stage:

• point where compensation increasing neuropathology no longer possible

Question 18

Neuropsychological differences in preclinical AD (Han et al., 2017)

• Meta-analysis, 71 studies
• Cognitively healthy participants
• Biomarkers amyloid-positive (Presence of Alzheimer pathology) or amyloid negative
  
  • PET or CSF

Answer 18

• Amyloid positive groups < amyloid negative groups on cognitive measures (they performed poorer) including:
  
  • Global cognitive function
  • Memory
  • Language
  • Visuospatial ability
  • Speed of processing
  • Executive functioning
• Amyloid positive groups > amyloid negative groups on measures premorbid functioning (WTAR: The Wechsler Test of Adult Reading, NART: National Adult Reading Test)
  
  • so they were better than those without the pathology before the disease emerged
• Detectable cognitive differences occur early in course AD
  
  • Not only memory or EF affected

Question 19

Associated clinical features AD.

• Behavioural disturbances or neuropsychiatric symptoms (NPS).

Answer 19

• Over course of disease, large majority (80%) persons with AD experience behavioural disturbances (Lyketsos et al., 2002)
• Behavioural disturbances greater burden family and caregivers than cognitive impairments

Question 20

Associated clinical features of AD

• Prevalence behavioural disturbances (Lyketsos et al., 2002)
  
  • N = 258 persons diagnosed with AD
  • Neuropsychiatric Inventory (NPI) completed by informant
• Review and meta-analysis (Zhao et al., 2016)
  
  • 48 studies
  • > 10.000 persons with AD
  • 12 NPS of NPI

Answer 20

• Most common: apathy, agitation, depression, sleep disturbances and irritability
  
  • 50% persons with MCI behavioural disturbances over the course of condition
• Graph: (Zhao et al., 2016)
  
  • apathy, depression, aggression most common
    • Prevalence apathy – affected by education level and severity cognitive impairments
    • Prevalence depression - affected by age
    • Prevalence aggression - affected by age and duration of disease
  • Least common euphoria
  • Wide variety in prevalence

Question 21

Interventions in AD

• general

Answer 21

• No existing intervention can cure AD or stop its progression
• At best interventions can slow down rate of decline

Question 22

Pharmacological interventions in AD

• For cognitive symptoms (symptomatic)

Answer 22

• For cognitive symptoms (symptomatic)
  
  • Acetylcholinesterase inhibitors – to increase ACh levels
    
    • Donepezil, rivastigmine, galantamine
  • Glutamate antagonist – to reduce activity glutamate neurotransmitter
    
    • Memantine
  • Positive effects on cognition and daily functioning
  • Limited time (months to several years)
  • Reviews effects acetylcholinesterase inhibitors and glutamate antagonist (DiSanto et al., 2013; Tan et al., 2014)
    • Effects ACHEIs not influenced by AD severity
    • Memantime more effective in more severe AD
    • some patients can’t take any of these due to severe side-effects

Question 23

Pharmacological interventions in AD.

• For behavioural symptoms

Answer 23

• Depression – antidepressives, mood stabilizing medication
• Anxiety – antidepressives, benzodiazepines (risk adverse effects)
• Agitated behaviour – antipsychotics (severe side-effects, not recommended for routine use)

Question 24

Interventions

• Nonpharmacological interventions

Answer 24

• Cognitive training
  
  • Review Bahar-Fuchs et al. (2013): no benefit over control condition
  • CT stand alone – general cognition, small effect in people with dementia (Hill et al., 2017 review)
    
    • Effective studies more stimulating variations: Wii, VR
  • often cognitive ability only increases in the task that was trained and not generally
• Cognitive rehabilitation
  • aim to improve daily functioning via compensation
  • Positive effects on memory, sense of competence, QoL (Clare et al., 2010)
  • Individualized intervention, compensatory aids and strategies.
• Cognitive stimulation
  
  • aim is to engage in poritive experience (singing, playing etc.)
  • Positive effect on cognition and wellbeing/QoL
  • No effect daily functioning or behaviour (Woods et al., 2012, review)
• Computer-based interventions - CT, CR, CS, cognitive recreation (Garcia-Casal et al., 2017, review)
  
  • Modest effects cognition, depression and anxiety
  • No effect on daily functioning

Question 25

Interventions for AD.

Nonpharmacological interventions:

• Interventions for caregivers

Answer 25

• Important management behavioural symptoms:
  
  • improve caregivers’ knowledge of AD
  • identify, modify factors cause/exacerbate behavioural symptoms
• Improve CG wellbeing
  
  • PWD can live at home longer
• CG present intervention
  
  • Cost-effectiveness

Question 26

Interventions

¨Nonpharmacological interventions

• effects overall:

Answer 26

• Effects cognition or behaviour usually small
• Most effective in earlier stages AD
• Multi-component intervention more effective