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what is dementia?

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A significant deterioration of cognition in an alert person
Deterioration is not necessarily diffuse or global
• often multifocal, affecting multiple domains of intellectual function, while sparing others.
• An acquired disorder with evidence of decline from a previous level of function
• as demonstrated by history or cognitive testing.
• At least two domains of function, one of which is
memory, should be affected:
language perception visuospatial function calculation judgment abstraction

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NINCDS/ADRDA Criteria for AD

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dementia established by clinical examination and documented by the Mini-Mental Test; Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests;
• deficits in two or more areas of cognition;
• progressive worsening of memory and other cognitive
functions;
• no disturbance of consciousness;
• onset between ages 40 and 90, most often after age 65;
and
• absence of systemic disorders or other brain diseases
that in and of themselves could account for the progressive deficits in memory and cognition

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Probable AD

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dementia established by clinical examination and documented by the Mini-Mental Test; Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests;
• deficits in two or more areas of cognition;
• progressive worsening of memory and other cognitive
functions;
• no disturbance of consciousness;
• onset between ages 40 and 90, most often after age 65;
and
• absence of systemic disorders or other brain diseases
that in and of themselves could account for the progressive deficits in memory and cognition

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Possible AD

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Established dementia • Deficits in 1 cognitive
domain
• Onset and/or course
atypical
• The presence of other systemic or brain disorders that might account for decline but cannot be the sole cause of deficits

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Older compared to younger adults show

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greater ventricular or sulcal cerebrospinal fluid (CSF)
• increase an average of 1500 mm3 per year
• smaller volumetric estimates of brain tissue
• specific regional changes in hippocampus, frontal and temporal lobes

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As we age the ratio of ventricle to brain ratio is

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increased

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Age is negatively correlated with brain volume because

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As we age brain volume goes down..men show greater decrease

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Gray and white matter volumes comparisson

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both negatively correlated with age. Both types of tissue decrease with age: white and gray matter

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Older compared to younger individuals show greatest age-related differences in:

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parietal regions
• gray matter of
• orbital frontal cortex
• mesial temporal

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Some medical parameters are the normal change with age.
Overall brain volume change over time and the people with the most risk is those with

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some medical conditions

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4year gray matter loss was shown in specific regions

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cingulate
Inferior/Mes temporal
Orbitofrontal

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Special area that shows a lot of atrophy in AD patients

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hippocampus

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As we age hippocampus does atrophy, but the level of atrophy in Alzheimer is

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greatly increased.

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Mild cognitive impairment is

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state of cognitive function (typically memory functioning)
• abnormal for age and education

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MCI does not meet criteria for AD but

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is at least 1-1.5 SD below age-peers
• Might be a prodromal phase of the disorder

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Predictors of transition to AD

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NEUROANATOMICAL:
Hippocampal volume at time of diagnosis Rates of change in hippocampal volume COGNITIVE:
Inability to benefit from semantic cues
• Especially during recall
Deficits in a 2nd cognitive function
• Particularly executive functioning

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Not everyone at mci progressed to dementia. Some fell into mci and then bounce back to normal. Those with brain change in volume were likely to developed mci but those with a second problem

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could go to dementia

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Amnestic MCI may progress to

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AZ's disease

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mci affecting multiple domains and with mild impairments may progress to

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AZ's disease
Vascular dementia
Normal aging

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Single non-memory domain MCI may progress to

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Frontotemporal dementia
Lewy body dementia
Primary progressive aphasia
vascular dementia

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Criteria for aMCI vs MCI

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Subjective memory complaints
• Corroboration by an informant optimal
• Normal general cognitive functions
• If impaired it doesn’t lead to ADL declines
• Impaired memory functioning for age/educ
• Do not meet criteria for probable AD

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Importance of transtional states

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Individuals with MCI tend to progress to clinically probable AD at a rate of 10-15% per year
If we can determine who will convert to dementia then treatments can target those individuals regardless of dementia type.

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Role of vascular risk relies heavily on the presence of

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cerebrovascular disease and/or vascular
burden
• Vascular risk factors (e.g., HTN, IDDM)

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Vascular risk involves

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Impaired non-memory functioning
• Executive and/or information processing
speed

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Infractions in the white matter and the more you get the more

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cognition problems

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Mmse scores go down if

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LA increase in white matter

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LA and infarctions appear to have a synergistic impact on

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risk for and development of dementia

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Large-scale epidemiological and autopsy studies suggest that there is more overlap in the dementias than

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originally thought

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The more white matter damage the more chance of

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dementia

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PET Ligand studies pattern of beta amyloid deposition

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A useful method of visualizing and studying chemical activity in brain
HC
AD
• PIB – allows for
the visualization
of amyloid
deposits in
patients with AD

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Those who convert to ad show like of they had ad even before they show magnification..the ones who don't transition look like

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healthy brains

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Amyloid burden may be important for

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driving MRI structural changes
• Studies have not shown longitudinal increases in 2-year follow-up studies

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Accuracy of PIB-PET higher than

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FDG-PET
• Some evidence to suggest superior even in older subjects (>80YO)

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cerebral regions with coherent default network activity under resting conditions in young adults. These resemble areas of both increased amyloid plaque deposition assessed by molecular imaging modalities such as PET (middle) and of cortical atrophy measured by morphological MR- imaging (right). The similarity might be explained by

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steady increased baseline activity in default networks leading to an increased pathology with subsequent neurodegeneration

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aMCI – amnestic

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(memory related) cognitive impairment

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c. Dementia is Significant

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cognitive impairment – memory + one other domain (language, calc, prob solving, etc.)

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a. Difference btwn MCI and dementiai.

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i. Dementia is significant deterioration of cognition in an alert persons. At least in two domains of fxn, one of which is memory.
ii. MCI is a state of cognitive fxn, does not meet criteria at least 1-1.5 SD below age peers which they are abnormal for age and education. but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and dementia.

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b. Various forms of MCI – esp amnestic form of MCI has only one domain affected whereas dementia

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needs more than one

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amyloid

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hey are actually aggregates of fibrous protein and not amyloid at all.

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Whats the possible problem in AD?

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amyloid plaques are the source of the problem with AD. A-β is toxic to neurons grown in petri dishes. Furthermore, A-β can impair the development of long-term potentiation (LTP) as well as the memory for a maze in rodents

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iv. The final major pathology of AD is

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the intracellular neurofibrillary tangles. The neurofibrillary tangles come from the proteins on the microtubules of the neuron. The tau proteins bind to the microtubules and provide stability. The problem seems to start with the hyperphosphorylation of the tau proteins. Too many phosphates attached to the tau proteins cause them to detach from the microtubules. It is these detached proteins that clump together and form the neurofibrillary tangles, which in turn clog the neuron's axons and dendrites and cause the cell to die. What causes the hyperphosphorylation remains unclear but seems to be initiated by β-amyloid

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Areas affected by AD

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i. Atrophy of hippocampus
ii. Language area decreases
iii. Ventricles bigger and gray matter decrease

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How is estrogen involved with AD?

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f. Estrogen helps AD and lose the edge to AD during menopause or removal of ovaries.