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Neuropsychology of Ageing > Lecture 6: Alzheimer’s Disease 1 > Flashcards

Lecture 6: Alzheimer’s Disease 1 Flashcards

1
Q

¨Alzheimer’s disease:

  • AD most common form of dementia
A
  • more common than other main forms put together:
    • vascular dementia, dementia with Lewy bodies, frontotemporal dementia
  • NL: 70% persons with dementia
  • “Alzheimer’s” often used as equivalent for “dementia”
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2
Q

First described in 1906 by Alois Alzheimer:

A

First patient Auguste Deter. Admitted to mental hospital at age 51 - severe memory impairments (presenile dementia - early onset dementia).

  • Alzheimer described amyloid plaques and neurofibrillary tangles in Deter’s brain.
  • term “Alzheimer’s disease” used for first time in 1910 by Kraepelin.
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3
Q

Current definition (of AD):

A
  • Alzheimer’s disease - degenerative brain disorder characterized by progressive intellectual and behavioural deterioration
  • Dementia of Alzheimer Type (DAT) – symptoms associated with Alzheimer’s disease
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4
Q

Clinical features

  • Key difference with MCI:
A

Key difference with MCI

  • cognitive impairments severe enough to interfere with daily functioning, difficulties with IADL or ADL.
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5
Q

Key features for Dementia’s.

DSM V criteria for major neurocognitive disorders:

A
  1. Significant cognitive decline from previous level of performance based on report patient or informant AND clear objective deficits (>2 SD below appropriate norm population)
  2. Cognitive deficits sufficient to interfere with independence
  3. Cognitive deficits do not exclusively occur in context of delirium
  4. Cognitive deficits can not be attributed to Axis 1 disorder (e.g. depression or schizophrenia)
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6
Q

Criteria for diagnosis AD (McKhann et al. 2011):

A
  • Insidious onset: symptoms develop gradually over months - years
  • Worsening of cognition from report or observation
  • Cognitive impairment in one of two categories:
    • Amnestic presentation: most common: main impairment in memory.
    • Nonamnestic or atypical presentation: main impairments in language (e.g. word finding difficulties) or executive functioning or visuospatial function
    • In both categories: disorders in other cognitive functions should also be present
  • These criteria are additional to the ones for dementia/ neurocognitive disorders
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7
Q

Alzheimer’s disease

  • Uncertainty of diagnosis
A

Definite diagnosis AD only post-mortem:

  • Pathologically proven AD
    • Meets clinical and cognitive criteria probably AD during life
    • AD pathology present in brain
  • Until that time, diagnosis with different degrees of certainty:
    • probable, possible
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8
Q

Probably AD dementia (more certainty):

(Most patients have this diagnosis while they are still alive)

A
  • meets the criteria for AD (McKhann et al. 2011)
  • no evidence for alternative explanations symptoms
    • in particular: no significant cerebrovascular disease.
  • certainty diagnosis enhanced by presence of 3 further sources:
    • documented decline: by informants or testing

OR

* presence of biomarkers

OR

* presence of genetic mutations that enhance AD risk
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9
Q

Possible AD dementia (less certainty):

A
  • atypical course. Meets clinical and cognitive criteria, but no evidence/ uncertainty of progressive decline

OR

  • biomarkers obtained and negative

OR

  • mixed presentation: clinical and cognitive features of AD, AND evidence of e.g. cerebrovascular disease or features of dementia with Lewy bodies
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10
Q

No AD dementia (diagnosis):

A
  • Criteria for diagnosis AD are not met

OR

  • sufficient evidence for alternative explanation
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11
Q

Etiology/ Neuropathology

Characteristic neuropathology AD:

A
  1. senile plaques
    • Plaques between nerve cells
  2. neurofibrillary tangles
    • Tangles within nerve cells
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12
Q

Etiology/ Neuropathology of AD

Neuritic plaques:

A
  • Neuritic plaques (senile, dendritic, amyloid plaques):
    • deteriorating neuronal material surrounding a sticky protein, amyloid beta (beta amyloid, Abeta, Aβ)
  • Aβ formed when protein (amyloid precursor protein) folds incorrectly.
  • Aβ accumulates in the brain and forms plaques
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13
Q

Etiology/ Neuropathology

Neurofibrillary tangles:

A
  • Neurofibrillary tangles: twisted protein fibres within nerve cells.
  • fibres consist of protein, tau, that normally occurs in neurons (in the microtubules)
    • when processed incorrectly, tau molecules clump together, form tangles, microtubules disintegrate
    • normally tau is found in healthy brains in these microtubules that are involved in the trasport of nutrients
    • for some reason the tau disintegrates and forms these tangles, the microtubules collapse
  • Tangles interfere with normal cell function
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14
Q

Biomarkers:

Alzheimer’s disease

A
  • Low CSF Abeta
    • low levels of amyloid beta in cerebrospinal fluid (because they accumulate in the brain)
  • Elevated tau in CSF (because the tau disintegrates from the microtubules)
  • Amyloid beta imaging on PET
  • Decreased fluorodeoxy-glucose (FDG) uptake on PET – measure of brain metabolism
  • Disproportionate atrophy (loss volume) in temporal lobe (in particular hippocampus)
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15
Q

Biomarker of AD:

¨Decreased fluorodeoxy-glucose (FDG) uptake on PET – measure of brain metabolism

A

FDG-PET - reduced glucose metabolism in temporal and parietal regions in patients with MCI and Alzheimer’s disease

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16
Q

Biomarkers of AD:

Amyloid beta imaging on PET

A

Red and yellow areas high concentrations of PiB, suggesting high amounts of amyloid deposits

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17
Q

¨Alzheimer’s disease

Risk factors:

A
  • Age (biggest risk factor)
  • Family history
    • causative genes
    • susceptibility genes
  • Sex (women at higher risk to develop AD)

Further possible risks, include TBI, obesity, smoking, not smoking, diabetes, chronic stress, alcohol….

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18
Q

Alzheimer’s disease

Genetic risks:

A

Causative genes:

  • Causative: person with mutation will develop AD if they live until middle or old age. Persons who do not develop disease, do not carry the mutation
  • 3 causative mutations known
    • Mutations amyloid precursor protein gene, Presenilin 1 gene and Presenilin 2 gene
    • account for 5% of AD cases
    • all associated with early onset dementia (meaning onset before age 65)
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19
Q

Genetic risks

Susceptibility genes:

A
  • Genetic mutations increase the risk for AD (but not necessarily lead to AD)
    • Not all persons with AD carry the gene
  • Best known: apolipoprotein E (APOE) gene
  • Different forms APOE: epsilon 2 (E2), epsilon 3 (E3), epsilon 4 (E4).
  • E2 form reduced risk for AD
  • E4 form increased risk for late-onset AD.
  • Apolipoprotein E (APOE) gene: everyone inherits one gene form from their parents
    • one E4 allele, risk to develop AD ≈ 4x higher than for persons who do not carry this form
    • both E4 alleles, risk ≈ 16x higher
    • exact added risk still uncertain, therefore reluctance to tell APOE genotype
20
Q

¨Prevalence Alzheimer’s disease:

A
  • 0.5-1% of persons age 60-64 yrs
  • 10-30% of those over 85 yrs (WHO Dementia Report, 2012)
  • Number of persons with AD worldwide estimated at 27 million in 2006, expected to rise to 107 million worldwide in 2050.
21
Q

Prevalence of AD relative to gender:

A
  • AD more prevalent in women than men (roughly 2:1)
    • Women: overall 70% of woman with dementia have AD
    • Men over 80: proportion with AD similar as in women

Picture: Proportion types of dementia among women

22
Q

Picture: Proportion types of dementia among men

A
23
Q

AD fatal disease

Expected survival time after diagnosis:

(Brookmeyer et al., 2002)

A

Expected survival time after diagnosis varies with age at time of diagnosis:

  • e.g. diagnosis at 65 – median survival time ± 8 years; diagnosis at 90 – median survival time ±3 years
  • Survival time shorter for men than for women
24
Q

Theories of etiology (3 main theories)

Alzheimer’s disease

A
  1. Choline hypothisis
  2. Amyloid cascade hypothesis
  3. Vascular theory
25
Q

Choline hypothesis:

A
  • loss of cholinergic cells in brain
  • Nucleus basalis of Meynert, important producer of acetylcholine (ACh) in the brain, atrophied in AD.
  • Reduced levels of ACh would result in impairments in memory and learning
  • Most current medication AD developed to increase ACh levels
    • Acetylcholinesterase – inhibitors
  • Acetylcholinesterase – donepezil, galantamine, rivastigmine
    • can have positive effect on cognition
      • Improvements ADAS-Cog
    • effects medication are temporary
    • no cure, slow down progression
      • treatment may come too late
      • degeneration nucleus Meynert and reduction ACh levels would be aspect of late stage AD
26
Q

Amyloid cascade hypothesis:

A
  • Misprocessing (misfolding) amyloid precursor protein (APP) → amyloid fragments (beta amyloid) that accumulate in brain.
  • beta amyloid forms plaques
  • Plaques produce mild inflammatory response
  • plaques and inflammation toxic to neurons
  • toxic reactions → release tau and formation of neurofibrillary tangles
27
Q

Critiques amyloid cascade hypotheses:

A
  • Amyloid plaques also found in cognitively healthy persons
  • No convincing evidence toxicity of plaques
  • Implications: reducing beta-amyloid should lead to improvement symptoms.
    • AD patients in whom amyloid clearance was successful, little or no effect on symptoms
28
Q

Vascular theory:

A
  • Beta amyloid also accumulates in blood vessels brain
  • Amyloid in small blood vessel walls in almost all cases of AD - cerebral amyloid angiopathy (CAA)
  • CAA would play role causing symptoms of AD (Arvanitakis et al. 2011):
    • Levels CAA correlated with cognitive deficits
      • More severe CAA pathology – poorer episodic memory, slower reaction times
  • Unlikely to be an complete explanation of AD
29
Q

Timing of neuropathological changes:

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

A
  • Neuropathological changes AD start long before clinical symptoms
  • Distribution of neuropathology tends to follow typical pattern,
    • neurofibrillary tangles (NFT) first medial temporal lobe (entorhinal cortex, hippocampus)
    • spreads to frontal, parietal and other parts temporal cortex
30
Q

Etiology/ Neuropathology

Neurofibrillary tangles: twisted protein fibres within nerve cells. Sequence.

A
  • Appear first in medial temporal lobe and limbic structures (entorhinal cortex, hippocampus)
  • neurofibrillary tangles basis for Braak & Braak neuropathology staging system for AD
31
Q

Neurofibrillary changes in AD.

Famous study: (Braak & Braak, 1991)

different stages

A
  • NFT (neurofibrillary tangles) found in entorhinal cortex in young – middle aged adults (22-46) = Braak stage I
  • Stage I and II – probably preclinical – no obvious AD symptoms
  • stage V and VI - moderate to severe dementia
32
Q

Famous study: (Braak & Braak, 1991)

different stages

Similar pattern Beta amyloid​:

A
  • starts at temporal and medial-temporal areas andd spreads throughout the cortex
33
Q

Neuropathological changes and cognitive impairments

  • Progression areas affected reflected in cognitive impairments observed?
A
  • Early impairment in memory in line early neuropathology in medial temporal lobes in AD
  • structures crucial for learning and recall new information
34
Q

Alzheimer’s disease

  • Cognitive impairments:
A
  • Key impairment: episodic memory – impairment learning and retaining new information
    • Smith & Bondi (2013): anterograde amnesia
  • Impaired episodic memory first and most salient cognitive impairment in AD
  • Memory impairment prerequisite for diagnosis AD
35
Q

Episodic memory in AD:

  • Impairment episodic memory tests (Salmon & Bondi, 2009)
A
  • Persons with AD particularly impaired on delayed recall and recognition - information can not be retrieved, despite presence of recall cues (Salmon & Bondi, 2009)
  • Both free recall and recognition impaired
    • retrieval deficit unlikely
    • abnormally rapid forgetting (storage)/ or information never getting properly encoded
36
Q

Anterograde Amnesia:

A

Anterograde amnesia is a loss of the ability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact.

37
Q

Semantic memory (Alzheimer’s disease).

A

Semantic memory deficit in AD – general loss of knowledge

  • category or semantic fluency more impaired than letter or phonemic fluency in AD
    • access semantic information/knowledge
  • naming impairments, e.g. Boston Naming Test
    • deficit can be due to language deficit rather than semantic deficit
    • pattern of naming errors in AD suggests semantic deficit
  • in healthy people this is barely affected
38
Q

Semantic memory

  • Persons with AD (n=52) > semantic-associative and superordinate errors healthy controls (n = 52) (Hodges et al., 1991)
  • 22 AD patients followed up over 3 years
A
  • Semantic superordinate errors: ‘vegetable’ for asparagus; ‘animal’ for rhinoceros
  • Semantic associative errors: ‘painting’ or ‘artist’ for easel, ‘ice’ for igloo, ‘desert‘ for camel
  • 22 AD patients followed up over 3 years
    • Overall naming performance declined
    • % semantic associative errors increased
    • % visual errors increased (“spear” or “snake” for asparagus)
39
Q

Remote memory/retrograde amnesia (AD)

A

Memory for public events and famous persons (Salmon, 2008):

  • 11 probable AD, 23 matched healthy older controls
  • Remote memory battery:
    • famous faces test – 15 faces from each decade
    • Public events questionnaire – 15 questions for each decade
  • AD recalled fewer names and events than HC
  • AND performed worse for more recent decades
  • Retrieval all decades impaired in AD
    • Combination of episodic and semantic memory impairments
    • Impairment episodic memory - temporal gradient
      • more recent information - no longer stored or never learned (because of the anterograde amnesia)
40
Q

Remote memory/retrograde amnesia

AD: temporal gradient in recall

Memory for public events and famous persons (Salmon, 2008):

A
  • AD: temporal gradient in recall, better recall from early epoch (40s, 50s) than later epochs.
  • Proportion correct: number correct from each life epoch relative to number correct overall
  • ¨Remote memories retrieved relatively better in AD
    • disruption in consolidation process
      • stores information for long term/permanently in cortical areas outside the hippocampus
    • more remote memory less affected by hippocampus damage
  • Retrieval all decades impaired in AD
41
Q

Autobiographical memory performance in Alzheimer’s disease depends on retrieval frequency (Müller et al, 2016)

A
  • memories from early childhoods were more accurate than those of recent events
  • if frequency of retrievla was low, retrieval information were less accurate
  • memory from childhood were also those that had been retrieved most frequently
42
Q

Procedural memory in AD

Mirror tracing skills (Albert, 2008)

A

Mirror tracing skills:

  • AD patients who were able to perform the task: normal improvement with practice and retained skill as well as HC subjects across a 30 min. delay
  • AD patients generalize skill to new figure (from 4 point star to 6 point star) as well as HC
  • so, procedural memory was relatively intact; still ability to learn
43
Q

Implicit memory in AD.

A

Implicit memory tasks would not rely on hippocampus, but on frontal or posterior cortical areas.

44
Q

Implicit memory in AD.

Word stem completion in AD (Salmon 2008):

A

Word stem completion in AD (Salmon 2008):

  • Words presented one at a time: e.g. MOTEL, ABSTAI
  • Participants rated how much they liked the wor
  • Word stems, half of words from study list (e.g. MOT, ABS), half of other words
  • Complete stem with first word that comes to mind
  • Normal pattern: complete stems with words from study list
    • AD: little effect of priming
  • Deficits word stem completion in AD replicated by several studies
  • Other studies found intact priming AD on word stem completion
    • Implicit memory can be intact in AD
45
Q

Implicit memory in AD.

Review Fleischmann (2007):

A
  • Priming intact in normal ageing
  • AD: priming more compromised when priming based on accuracy scores compared to priming based on reaction times

Neuropsychology of Ageing (12 decks)

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