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.

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=frontc

over#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

– 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 sleepof 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.

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

Definitions of Dementia

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

DSM-5 Major and Mild Neurocognitive Disorders

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

• 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

The Three Stages of Alzheimer’s Disease

Prevalence of Dementia

Prevalence of Dementia in the United States: The Aging, Demographics, and Memory StudyNeuroepidemiology 2007;29:125–132

PET scan showing metabolic activity

People with Alzheimer’s Show Structural Changes in the BrainBasal forebrain nuclei disappearNeurofibrillary tangles, which are abnormal whorls of neurofilaments, including the tau protein. Amyloid “Senile” plaques form by β-amyloid buildup.

Imaging Amyloid Plaques in the BrainPET 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– e3/e3 55%

– e3/e4 25%

– e3/e2 15%

– e4/e4 1–2%

– e2/e2 1–2%

– e4/e2 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• 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• 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.

• 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 diseaseUnlikely 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

– 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– 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 – 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– 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.pone.0045232