Transcript Types of dementia - Occidental College

Learning and Memory Change as We Age (6)
• Some memory impairment in elderly
– Elderly: old or aging person, 65 years of age
– “conscious recollection that require effort, and rely primarily on internal
generation of the memory rather than on external cues”
– Formation of new declarative memory
– Formation of new episodic memory
– Decreases in spatial memory and navigational skills.
– Decline in working memory
– Executive function starts to decline at age 40
– Impairments of coding and retrieval
• However long term episodic and sematic memory are stable
Active Brain Regions during Encoding and Retrieval
Tasks in Young and Old People
Changes to the nervous system (3)
• Loss of neurons and or neural connections
• Loss of Betz cells in the motor cortex
• Some parts of the brain lose a larger proportion of volume
• Septal complex and basalis of Meynert
• Shrinkage of the hippocampus
• Shrinkage of the Supratemporal gyrus
• Overall shrinkage of the brain starting at age 30
• The good news
• No change in brainstem neurons
• Normal cerebral metabolism (in healthy adults)
Hippocampal Shrinkage Correlates with Memory Decline in Aging
The Brain Continues to Change as We Grow Older
• Accepted understanding of aging effects on cognition
– “ … and a progressive decline in many of our abilities.” (2, 3)
• A decline in sensory such as vision, hearing, olfaction, touch
• A decline in motor such as strength, reaction time, coordination
• A decline in cognitive functions
• However, this Is Not a Progressive Decline in cognitive function
– Note that I am contradicting our textbook
– Appears progressive if using averages across many individuals
– Most of the decline is from non-normative events such as
• Physical Disease
• Traumatic events
• See “Handbook of the Clinical Psychology of Ageing” pages 35 – 39
• http://books.google.com/books?id=FiNDwdHI3rQC&printsec=frontco
ver#v=onepage&q&f=false
• There is a great deal of individual differences
The Brain Continues to Change as We Grow Older
• Cognitive decline is neither inevitable nor progressive
– “It is now clear that significant cognitive decline is not an inevitable
consequence of advancing age.” (1)
– “For many people, aging is associated with relatively little cognitive decline
( “healthy” or “successful” aging).” (1)
– “Many medical scientists and physicians believe that all changes in
senescence are but the cumulative effects of injury and disease.” (2)
– “So lifelong environmental enrichment may have strongly protective effects
on cognitive functions, such as memory, later in life.” (4)
– “…patients with frontal lesions also reveals an array of strange impairments
in their behavior, especially in the realm of executive function, …” (5)
Individual Differences In Cognitive Decline
• Some individual remain healthy with only small changes in
cognition up through 90 years of age.
– Examples from Nun Study (8)
– See fig. 2 Nyberg (2012) (6)
– Reserve hypothesis:
• even with brain pathology some individuals retain cognitive abilities
• their brains have extra circuits and efficiently process information
• can build up reserve through years of education and experiences
– Maintenance hypothesis:(6)
• some individuals have very little brain pathology
• lifestyle factors such as
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low stress
effective coping
regular exercise
healthy diet
adequate sleep
• in combination with genetic predispositions
• preservation of neurochemical, structural and functional brain integrity
Cognitive Decline Related to Aging
• Cognitive functions decline (2), however
– Less decline on the verbal scale
• vocabulary and comprehension
– More decline in performance scale tasks
• block design, reversal of digits, picture arrangement, object assembly, and
the digit symbol task
• Selective decline in memory (3)
– Declarative-episodic, spatial and working memory show decline
– Declarative-semantic, autobiographical are stable
– Age of onset is 60-65, see figure 1 from Nyberg (2012) (7)
• These differences are clearly related to the function of hippocampal
circuits, cortical circuits and caudate circuits
Cognitive Decline Related to Brain Structure
• Aging is associated with changes in brain integrity, with volume
shrinkage and white-matter pathologies accelerate as a function of
age
• Individuals differ in rate of structural brain changes so brain
integrity is relatively well preserved in some older adults.
– Volume of hippocampus see fig. 3 Nyberg (2012) (7)
• Related to episodic, spatial and working memory
– Thickness of cortex see fig. 4 Nyberg (2012) (7)
• Thinning of cortex from lower density of dendrites, synapses, cell
shrinkage, and cortical myelin loss
• Cortical thickness related to executive function as seen in WCST
performance
The Typical Pattern of Sleep in
an “Unhealthy” Elderly Person
“This decline in stage 3 sleep with age may be related to diminished cognitive
capabilities, since an especially marked reduction in 3 SWS characterizes the sleep
of people who suffer from senile dementia (Kondratova and Kondratova, 2012).”
References
• 1. Cognition in Aging and Age-Related Disease Elizabeth A. Kensinger in
Handbook of the Neuroscience of Aging edited by Patrick R. Hof, Charles
V. Mobbs. Academic Press, 2010
• 2. Adams and Victor’s Principles of Neurology, (2005) Ropper, Chapter 29
The Neurology of Aging, p. 206
• 3. Biological Psychology 7th Edition by Breedlove, Watson & Rosenzweig,
2013, p. 212-213, 556
• 4. Biological Psychology 7th Edition by Breedlove, Watson & Rosenzweig,
2013, p. 557
• 5. Biological Psychology 7th Edition by Breedlove, Watson & Rosenzweig,
2013, p. 590
• 6. Biological Psychology 7th Edition by Breedlove, Watson & Rosenzweig,
2013, p. 555
• 7. Memory aging and brain maintenance (2012) Lars Nyberg, Trends in
Cognitive Sciences Vol. 16, No. 5
• 8. Healthy Aging and Dementia: Findings from the Nun Study (2003)
David A. Snowdon, Ann Intern Med. 139:450-454.
Definitions of Dementia
Age-Associated Memory Impairment (AAMI) is a normal decline
in memory due to aging for someone at least 50 years old
Mild Cognitive Impairment (MCI) is memory decline which is
more severe or consistent then AAMI – this is not Dementia
Dementia: is a group of symptoms including a chronic deterioration
of intellectual function and other cognitive skills severe enough to
interfere with the ability to perform activities of daily living. So
Dementia isn't a specific disease.
Senile dementia a neurological disorder of the aged that is
characterized by progressive behavioral deterioration including
personality change in profound intellectual decline. It includes but is
not limited to Alzheimer’s disease
DSM-5 Major and Mild Neurocognitive Disorders
DSM-5 criteria for mild neurocognitive disorder, an individual must
have evidence of modest cognitive decline, but the decline does not
interfere with everyday activities
DSM-5 criteria for major neurocognitive disorder an individual must
have evidence of significant cognitive decline and the cognitive
decline must interfere with independence in everyday activities
Types of Dementia
• Primary - Progressive dementia which worsens over time and does
not result from any other disease
– Alzheimer's disease (AD)
• 40-70 percent of dementia ?
• plaques and tangles
• Age related
– Vascular dementia (VaD)
• 20-40 percent of dementia ?
• Brain damage from stroke, including “mini” and “silent” strokes
– Lewy body dementia (DLB)
• 20 percent of dementia ?
• abnormal clumps of protein
• Age related
– Frontotemporal dementias include several disorders (FTLD)
• A small percent of dementias
• Pick's disease has tangles made up of the tau protein
• Motor neuron disease inclusion dementia and corticobasal degeneration (CBD)
• Secondary dementia occurs as a result of a physical disease or injury such as
depression, delirium, side effects from medications, thyroid problems, certain
vitamin deficiencies and excessive use of alcohol
The Three Stages of Alzheimer’s Disease
• 2011 Criteria and Guidelines Proposed by National Institute on
Aging (NIA) & Alzheimer’s Association (AA)
• Preclinical Alzheimer’s disease
• Biomarkers: changes in the brain, cerebrospinal fluid and/or blood
• have not yet developed noticeable symptoms such as memory loss
• Mild cognitive impairment (MCI) due to Alzheimer’s disease
• mild but measurable changes in thinking abilities
• do not affect the individual’s ability to carry out everyday activity
• Dementia due to Alzheimer’s disease
• Quite noticeable memory, thinking and behavioral
• impair a person’s ability to function in daily life
See: 2014 Alzheimer’s Disease Facts and Figures
Prevalence of Dementia
Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study
Neuroepidemiology 2007;29:125–132
PET scan showing metabolic activity
People with Alzheimer’s Show Structural Changes in the Brain
Basal forebrain nuclei disappear
Neurofibrillary tangles, which are abnormal whorls of neurofilaments, including the
tau protein. Amyloid “Senile” plaques form by β-amyloid buildup.
Imaging Amyloid Plaques in the Brain
PET scan showing Pittsburg Blue (PiB) dye used to mark Beta-Amyloid
One Hypothesis of Alzheimer’s Disease
Role of ApoE
Frequency of ApoE
• Estimated human genotype frequency of ApoE
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e3/e3
e3/e4
e3/e2
e4/e4
e2/e2
e4/e2
55%
25%
15%
1–2%
1–2%
1–2%
• Risk for Alzheimer’s Disease
– e4/e4 20 times more likely
– Any e4 ?????
– e4 does not determine Alzheimer’s Disease
• 30% with Alzheimer’s have no e4
• Some e4/e4 do not get Alzheimer’s
– Not related to early onset Alzheimer’s
Representative Glial Cells
Role of Microglial and Astrocytes in Neurodegeneration
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Senile plaques and tangles are a prominent pathological feature of Alzheimer's disease
(AD)
– development is associated with activated astrocytes and microglia
– astrocytosis and microgliosis increased linearly throughout the disease course
– microglial responses correlated positively with tangle burden
• migrate into and congregate within neuritic and dense-core plaques
• convert Abeta within plaques to the fibrillar form
– astrocytosis correlated negatively with cortical thickness
• debris-clearing role in response to local neurodegeneration
• overburdened with these internalized materials can eventually undergo lysis
– Microglial responses increased linearly around existing plaques and in the vicinity of tangles
– Interactions between microglia and astrocytes production of
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• interleukin-1β
• tumor necrosis factor-α
• transforming growth factor-β
• neurotrophic molecules such as NGF and bFGF
Reactive glia might contribute to the ongoing neurodegeneration.
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Nagele (2004) Neurobiol Aging. May-Jun;25(5):663-74.
Serrano-Pozo (2011) Am J Pathol. Sep;179(3):1373-84
Minagar (2002) Journal of the Neurological Sciences Volume 202, Issues 1–2, 15
Differential Diagnosis for Alzheimer's disease
Unlikely Alzheimer's disease: The patient presents a dementia syndrome with a
sudden onset, focal neurologic signs, or seizures or gait disturbance early in the
course of the illness.
Possible Alzheimer's disease: There is a dementia syndrome with an atypical onset,
presentation or progression; and without a known etiology; but no co-morbid
diseases capable of producing dementia are believed to be in the origin of it.
Probable Alzheimer's disease: Dementia has been established by clinical and
neuropsychological examination. Cognitive impairments also have to be
progressive and be present in two or more areas of cognition. The onset of the
deficits has been between the ages of 40 and 90 years and finally there must be an
absence of other diseases capable of producing a dementia syndrome.
Definite Alzheimer's disease: The patient meets the criteria for probable
Alzheimer's disease and has histopathologic evidence of AD via autopsy or
biopsy.
Treatment of Alzheimer’s disease
• Cholinesterase Inhibitors
– Tacrine, Aricept (donepezil), Exelon (rivastigmine) and Reminyl
(galantamine).
• Beta-secretase inhibitor: NIC5-15
– prevents amyloid plaque formation
• Symptomatic therapy for specific
behavioral/psychiatric disturbances
Risk Factors for Alzheimer’s Dementia
• Age (Just getting older puts you at risk?)
• Genetics
– Direct: a gene directly linked to the disorder
• Mutations on presenilin1 & 2 genes
(rare)
– Indirect: genetic predisposition (APOE4)
– Family history: a combination of genetics and environment
• Head injury (TBI) {a serious problem in contact sports}
• Cardiovascular
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High blood pressure
Heart disease
Stroke
Diabetes
High Cholesterol
• Low level of education
• Gender: higher rates in females
• In general a more stressful environment
The Nun Study
• Longitudinal study of 678 Catholic sisters 75 to 107 years of age
who are members of the School Sisters of Notre Dame
congregation.
• Data include
– early and middle-life risk factors
– annual cognitive and physical function evaluations
– postmortem neuropathologic evaluations of the participants’ brains
• Among participants in the Nun Study with dementia who have
died and been neuropathologically evaluated
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33.9% had mixed dementia (both Alzheimer disease and stroke present)
43.2% had Alzheimer disease
2.5% had vascular dementia
20.4% had other causes of dementia
• Lewy bodies, meningioma, primary hydrocephalus, and contusions)
Healthy Aging and Dementia: Findings from the Nun Study
Ann Intern Med. 2003;139:450-454
Three Case Histories from the Nun Study
• A centenarian (104)
– a model of healthy aging
– cognitively and physically intact
– almost no neuropathology
• A 92-year-old
– with dementia
– clinically significant Alzheimer disease neuropathology
– vascular lesions
• An 85-year-old
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with well preserved cognitive and physical function
a genetic predisposition to Alzheimer disease
an abundance of Alzheimer disease lesions
this is asymptomatic or clinically silent Alzheimer’s disease
Nun Study – Clinically Silent AD
• The Nun Study: Clinically silent AD, neuronal hypertrophy, and
linguistic skills in early life. Neurology September 1, 2009 vol.
73 no. 9 665-673
• Results
– Asymptomatic Alzheimer’s disease
• A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and
nucleoli (+80.2%) in the CA1 neurons
• higher idea density scores in early life were observed
• Conclusions
– Neuronal hypertrophy
• early cellular response to Alzheimer disease (AD) pathology
• or reflect compensatory mechanisms that prevent cognitive impairment
Healthy Aging
• Strategies for overall healthy aging
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keep your weight within recommended guidelines
avoid tobacco
avoid excess alcohol
avoid head trauma
stay socially connected
exercise both your body and mind
use good stress coping strategies
• Will keep the brain healthy and Protect against Alzheimer’s
and other dementias
Genetics of Longevity
• There are important genetic contributions to longevity
– Twin studies show that 25% of the overall variation in human
lifespan can be attributed to genetic factors
– becomes more relevant after 60 years of age
– genetic of longevity related to
• stress response signaling
• DNA repair
• storage and the use of nutrients
– “In particular, the variability and the expression of the genes involved in the
storage and the use of the nutrients showed to influence both longevity and the
quality of the aging.”
• Bitter Taste Receptor Polymorphisms and Human Aging. Daniele Campa (2012)
PLoS ONE 7(11)
• http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.p
one.0045232