age-related cognitive declineage-related cognitive decline • changes in cognitive abilities with...
TRANSCRIPT
![Page 1: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/1.jpg)
Age-Related Cognitive Decline
Marilyn S. Albert, PhDProfessor of Neurology
Johns Hopkins University
![Page 2: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/2.jpg)
Age-Related Cognitive Decline
• Changes in cognitive abilities with age in humans – focus on episodic memory
• Changes in episodic memory in animal models – non-human primates and rodents
• Brain changes that may underlie alterations in cognitive abilities with age
• Future Directions
![Page 3: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/3.jpg)
Question to be Answered:
Are there changes in cognitive ability as individuals get older, in the absence of disease?
![Page 4: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/4.jpg)
OPTIMALLY HEALTHY SUBJECTSVS. AVERAGE SUBJECTS
![Page 5: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/5.jpg)
Memory
• Ability to learn and retain new information over time
• Has been studied for a long time at multiple levels of analysis• humans and non-humans• individuals and populations• brain structure and function• data on potential interventions in
humans and animal models
![Page 6: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/6.jpg)
Anna Thompson of South Boston, employed as a scrub woman in an office building, reported at the city hall station that she had been held up the night before on State Street and robbed of fifteen dollars. She had four little children, the rent was due, and they had not eaten for two days. The officers, touched by the woman’s story made up a purse for her.
The American Liner New York struck a mine near Liverpool Monday evening. In spite of a blinding snow storm and darkness, the sixty passengers including 18 women were all rescued though the boats were tossed about like corks in the heavy sea. They were brought into port the next day by a British steamer.
Stories to Learn & Remember
![Page 7: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/7.jpg)
* **
Albert et al, 1987
Differences in Delayed Recall with Age(subjects 30 – 79 years old)
![Page 8: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/8.jpg)
Paired Associate Learning (errors)– Computerized Task (n=1444)
![Page 9: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/9.jpg)
-0.02-0.01
00.010.020.030.040.050.060.070.08
20-30's 40's 50's 60's 70+
Rate of Change in Visual Memory with Age
****
**
Age
-Reg
ress
ed E
rror
Slo
pes
Age at Initial Testing
**p<.01
NIA-BLSA
![Page 10: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/10.jpg)
Changes in Memory with Age
• Humans• Monkeys• Rodents
![Page 11: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/11.jpg)
Studies of Optimally Healthy Rhesus Monkeys
25 year old Male5 year old Male
![Page 12: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/12.jpg)
Delayed Recognition Span TestSpatial condition
Courtesy M. Moss
![Page 13: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/13.jpg)
*
Moss et al, 1988
*
Differences in Delayed Recognition with Age
(Monkeys 4 – 32)
![Page 14: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/14.jpg)
Studies of Optimally Healthy Rodents
Young Rat Old Rat
![Page 15: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/15.jpg)
Morris Water Maze
Morris, 1984
![Page 16: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/16.jpg)
After 8 training days and 4 probe trials
Assessment of Memory in Water Maze
Memory Index = Proximity of Animal to Hidden Platform on Each Probe TrialMeasurement is integrated over 4 probe trials;Weighting scheme gives credit for early learning; Automated image tracking permits measurement in x,y coordinates
8 training days, same platform location (3 trials/day)1 probe trial every other training day = 4 probe trials
Gallagher et al., 1993
![Page 17: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/17.jpg)
100
120
140
160
180
200
220
240
260
280
6-9 Months 12-14 Months 16-18 Months 24-28 MonthsAge
Beha
vior
al In
dex
Differences in Memory Performance on Water MazeWith Age
(Rats 6-28 months)
*
*
Courtesy of M. Gallagher
![Page 18: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/18.jpg)
Variability in Memory Performance with Age
• Humans• Non-human primates• Rodents
![Page 19: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/19.jpg)
Delayed Recall of Stories
0
5
10
15
30 40 50 60 70 80 90
HumansAge
![Page 20: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/20.jpg)
Recognition Memory Performance
Rhesus Monkeys
Relationship between Cognition and Agein the Non-Human Primate
0
20
40
60
80
100
120
140
0 5 10 15 20 25 30 35
Age
![Page 21: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/21.jpg)
Memory Performance in Water Maze
100
150
200
250
300
350
12-14 Months
16-18 Months
24-28 Months
4-6 Months Rats
![Page 22: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/22.jpg)
Memory Performance in Water Maze
100
150
200
250
300
350
12-14 Months
16-18 Months
24-28 Months
4-6 Months Rats
Age impaired
Age unimpaired
![Page 23: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/23.jpg)
• Cognitive changes with age - declines occur at middle age with respect to memory (declines in other domains occur at varying ages)
• Variability with advancing age in all species studied – some preserve function well
• Mechanisms – why do some decline?
Neuropsychological Manifestations of Brain Aging
![Page 24: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/24.jpg)
Question to be Answered:
What brain mechanisms underlie alterations in cognitive abilities (memory) with advancing age?
![Page 25: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/25.jpg)
Potential Explanations for Declines in Cognitive Abilities with Age
• Loss of nerve cells diffuselythroughout the brain
• Loss of nerve cells in highly selective regions in the brain
• Changes in physiological mechanisms that modulate brain function
![Page 26: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/26.jpg)
![Page 27: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/27.jpg)
Hippocampal Complex• CA1• CA2 - 3 • Dentate (granule cells)• Entorhinal Cortex
• CA4• Subiculum
0 - 5 %
35 %Gomez-Isla et al., 1996West et al, 1993Peters et al., 1996Merrill et al., 2000Rapp & Gallagher, 1996
Neuronal Loss with AgeHuman, Monkey and Rat Studies
Unbiased Stereology
![Page 28: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/28.jpg)
Normal
MCI
AD
![Page 29: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/29.jpg)
Alterations in Gray Matterwith Age
• Minimal loss of neurons in cortexstriate cortex motor cortexfrontal cortex
• Alterations in dendrites in layer 1 of cortex
• Minimal accumulation of lipofuscin in cortex
Tigges et al., 1992Peters et al., 1994Peters et al., 2001Unbiased Stereology
![Page 30: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/30.jpg)
Subcortical Nuclei
• Nucleus Basalis - 50%• Substantia Nigra - 35 - 40 %• Raphe Nucleus - 35 - 40 %
Rosene 1993Arnsten et al., 1995Kemper, et al, 1997
Neuronal Loss with AgeHuman and Monkey Studies
neurotransmitters that influence plasticity and learning in adult brain
![Page 31: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/31.jpg)
![Page 32: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/32.jpg)
Alterations in White Matter with Age
• Degeneration of myelin (e.g., split sheaths, debris within sheath)
• Membranous inclusions• Substantial accumulation of
lipofuscin in neuroglia
Peters et al., 1994Peters et al., 1996Nielson & Peters, 2000
![Page 33: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/33.jpg)
Alterations in Myelinated Fibers of White Matter
Young8 Yrs
Old25 Yrs
Cortical Gray Matter Subcortical White Matter
Young5 Yrs
Old25 Yrs
![Page 34: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/34.jpg)
Functional Changes with AgeHippocampal Complex
Synaptic number• Synaptic number altered in some regions
(e.g., dentate gyrus)
Plasticity• LTP, LTD, NMDA receptor function altered
Connectional integrity• Layer II entorhinal neurons altered
Rosensweig & Barnes, 2003Gallagher et al., 2003
![Page 35: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/35.jpg)
LTP Differences with AgeWater Maze Performance
ESPS
A
MPL
ITU
DE
(Mv)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1Month 10 Months 25 MonthsAGE
*
Barnes et al., 2000Barnes et al., 2000Barnes et al., 1992
Correlation with performance
![Page 36: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/36.jpg)
Current Explanations for Decline in Cognitive Abilities with Age
• Loss of nerve cells diffuselythroughout the brain does NOT occur
• Loss of nerve cells in highly selective regions in the brain
• Changes in physiological mechanisms that modulate brain function
![Page 37: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/37.jpg)
• Likely explanations for variability in performance among healthy individuals– Some do NOT demonstrate age-related
declines in structure and function
– Some may activate adaptive mechanisms
Neurobiology of Preservation of Cognitive Function
![Page 38: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/38.jpg)
Increased fMRI Activation Successful Memory Task Performance
Young Older
10
5
1correct high confidence successful responses > fixation
Sperling et al., 2005Cabeza et al., 2004
![Page 39: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/39.jpg)
Neurobiological Manifestations of Brain Aging
• Preservation of cognitive ability with age likely results from both:
– Absence of age-related declines in function– Activation of adaptive mechanisms
• Neuronal loss limited: If neuronal loss is limited in the normal aging brain, then therapies (i.e., behavioral or drug therapies) might be targeted at promoting cell health and function, rather than at recreating cells in appropriate regions
• Genetic factors: Is optimal function related entirely to genetic factors?
![Page 40: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/40.jpg)
Genetic Influences on LearningStudies of Identical Twins Reared Together & Apart
• Swedish Adoption Twin Study of Aging– Heritability: 32%-44% (mean age 66)
• Minnesota Twin Study – Heritability: 50%-60% (mean age 67)
• Octo Twin Study – Heritability: 37%-49% (mean age 83)
Pedersen et al., 1992Finkel & McGee, 1993Johnsson et al., 1999
![Page 41: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/41.jpg)
Neurobiological Manifestations of Brain Aging
• Genetic factors can explain part, but not all, of the variance
• Appropriate to examine life-style factors that may modify age-related cognitive decline
![Page 42: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/42.jpg)
Future Directions
• Examination of Adaptive Mechanisms –neurobiological underpinnings and possibility of promoting adaptation
• Age-related change vs. disease related change - change within normal limits vs. change that is harbinger of progression to impairment
![Page 43: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/43.jpg)
Future Directions
• Role of Early Experience – do cohort differences in nutrition, infections, etc influence cognitive decline in later life
• Potential for Modification – life style factors that may be modified (intensity of intervention, timing of intervention, multiplicity of interventions)
![Page 44: Age-Related Cognitive DeclineAge-Related Cognitive Decline • Changes in cognitive abilities with age in humans – focus on episodic memory • Changes in episodic memory in animal](https://reader035.vdocuments.mx/reader035/viewer/2022062603/5f0f70597e708231d4442a63/html5/thumbnails/44.jpg)