# Presentation: 248178

## Cognitive and Brain Aging in the Baltimore Longitudinal Study of Aging 

- Susan M. Resnick, Ph.D.
- Laboratory of Personality and Cognition
- National Institute on Aging

- Cognitive and Brain Aging in Older Adults

- What is the background upon which drug abuse is superimposed?
- Which aspects of cognition show age-related decline in individuals without dementia?
- How does the brain change with age?
*Structural changes*
*Functional changes*
*fMR probes of specific regions*

## Baltimore Longitudinal Study of Aging

**BLSA**

**	**Study initiated in 1958
- 	Women studied since 1978
- 	Highly educated community-dwelling sample
- 	GRC visits every 2 years for 2 1/2 days
- 	Behavioral and physical assessments
- 	Prospective diagnoses of dementia
-        Information on alcohol and smoking but no systematic 	information on other substance abuse

## Age Effects Vary Across Specific Cognitive Functions

- Some abilities are preserved throughout the lifespan, e.g. over-learned skills such as Vocabulary

- Vocabulary

## Age Effects Vary Across Specific Cognitive Functions

- Other specific functions show declines
- Different abilities may begin declining at different ages
- Different abilities may decline at different rates

**B**enton **V**isual **R**etention **T**est BVRT

## Age Differences and Longitudinal Changes on the BVRT

- Cross-sectional

- Longitudinal

## California 

- California
- Verbal
- Learning
- Test

## Longitudinal Change in Delayed Verbal Memory

- N = 266
- N = 345

- Neurology 2003

**Notes:**
Long Delay Free Recall without initial score

## CVLT Long Delay Free Recall:

- Rates of Change are Variable Across Individuals

- Age _>_ 60
- Mean 72.3

## LPC Neuroimaging Study

**Annual Evaluation**

**Men and Women (Age 55-85)**

**MRI**

**Brain Structure**

**Ischemic Change**

**PET-CBF**

**Rest**

**Verbal Memory**

**Figural Memory**

**Neuropsychological**

**Testing**

**LPC Neuroimaging Study**
- Early Markers of Alzheimer’s Disease and Cognitive Decline

**Without Prior Neurologic or **
**Severe Cardiovascular Disease**

## LPC Neuroimaging Assessments: 

**LPC Neuroimaging Assessments: **
**2/10/94 through 6/03/04**

- ASSESSMENT	MEN	WOMEN  TOTAL
**	****1****	****  ****	****94*****	****     69*****	****      163**
**	****2****	****  ****	****88****	****     63****	****      151**
**	****3****	****   ****	****82****	****     59          141  **
**	****4****	****  ****	****77****	****     59          136**
**	****5****	****   ****	****73****	****     57****	****      130****	**
**	****6****	****   ****	****71****	****     55****	****      126**
**	****7****	****  ****	****68****	****     53****	****      121**
**	****8****	****   ****	****61****	****     45****	****      106 **
**	****9****	****     ****	****48****	****     38****	****        86**
**           ****10****	****	****16****	****     13****	****        29****	**
**          ****TOTAL****	****           678****	****    511****	****      1189**

- Goals

- To determine the rates of structural and functional brain changes as a prerequisite for identification of disease.
- To determine whether some regions are more vulnerable to tissue loss and functional changes.
- To identify brain changes that predict cognitive impairment and dementia.
- To identify factors that modify brain-behavior associations in aging.

## Variability in BLSA Brain Morphology (N = 18)

## MR Image Processing Using RAVENS

- 1

- 2

- 3

- 4

- Original

- Automated Skull-Stripping

- Manual Editing

- Segmentation

- 158 Average

- Model

## Cross-sectional:  Both Gray and White Matter Volumes Are Negatively Correlated with Age

**Gray Volume**

**White Volume**

**300**

**400**

**500**

**600**

**700**

**50**

**60**

**70**

**80**

**90**

**cm****3**

**AGE**

**r = -.23**

**300**

**400**

**500**

**600**

**700**

**50**

**60**

**70**

**80**

**90**

**cm****3**

**AGE**

**r = -.29**

**WOMEN**

**MEN**

- Resnick et al. *Cerebral Cortex* 2000;10:464

**N = 116; Mean Age 70.4 (7.5)**

## Longitudinal:  Brain and CSF Volumes are Measured with High Reliability over Four Years

**Brain (G+W)**

**Ventricles**

- (n = 92, Mean Age= 70.4)

## Annual Changes in Brain Volumes over 4 Years 

- Annual Changes in Brain Volumes over 4 Years
- Resnick et al.  J Neuroscience 2003

##  Longitudinal Brain Changes are Evident in Younger and Older Individuals

**Annual Rate of Change (cm3)**

** **Longitudinal Brain Changes are Evident in Younger and Older Individuals

- ***

***** p < .001**

## 4-year Gray Matter Loss in Specific Regions

- Longitudinal Decreases *and* Increases in GM

- Qualitative Changes in Tissue Composition Measured by Signal Intensity

## Age Effects on Tissue Composition:

- Decreased Gray-White Signal Contrast

**Tissue Contrast**

*********p < .001**

- Cross-sectional

- Longitudinal

- Age Differences and Age Changes in
- Regional Cerebral Blood Flow (rCBF)

## 						Men		Women
N				    		46		37
Age (yrs)				70.9 ± 7.3 	70.6 ± 7.9
ApoE e4 (No. -/+)     		34/12		24/13
Mild memory loss* 
(No. -/+)	 			 41/5              31/6
*Clinical Dementia Rating (CDR) >  0.5

- PET Sample Characteristics

**	****	****	****	****	****	****Men****	****	****Women**
**N****	****	****	****	****    ****	****	****46****	****	****37**
**Age (yrs)****	****	****	****	****70.9 ± 7.3 ****	****70.6 ± 7.9**
**ApoE e4 (No. -/+)     ****	****	****34/12****	****	****24/13**
**Mild memory loss* **
**(No. -/+)****	**** ****	****	****	**** ****41/5              31/6**
- *Clinical Dementia Rating (CDR) _>_  0.5

## PET Results:  Cross-sectional Effects ofAge on Resting rCBF

- Older compared with younger individuals show selective decreases in rCBF in insular (INS), cingulate (CG), and inferior temporal (IT) regions.

## Longitudinal Age Changes in Resting rCBF

- Longitudinal declines in rCBF over 4 years are observed in bilateral superior temporal, right middle temporal, inferior parietal and midline occipital regions.

## Age Influences the RATE of rCBF Decline in the Mesial Temporal Lobe

- Older individuals show faster *rates* of decline in mesial temporal rCBF.

## Functional Brain Changes with PET

- Regional decreases in resting rCBF are observed in older individuals, with the greatest differences apparent in insular, cingulate and temporal regions, including hippocampus.
- These changes reflect a combination of structural and functional brain changes.
- With increasing longitudinal interval, we are investigating associations between specific brain and cognitive changes.

- fMR Probes
- for Regions Vulnerable to Aging

## fMR OFC Sample

**	****	****	****	****Younger Adults****	****Older Adults**
**n****	****	****	****	****20 (10M/10F)****	****	****20 (10M/10F)**
**Age (yrs)****	****	****28.7 (6.4)****	****	****69.3 (5.2)**
**	****    ****(range)****	****	****20-40****	****	****	****60-80**
**Education (yrs)****	****15.2  (2.4)****	****	****15.0  (3.6)**
**MMSE****	****	****	****29.4  (1.0)****	****	****28.9  (1.6)**
**CESD****	****	****	****  7.5  (4.1)****	****	****  4.7  (5.2)**
**	**

## Younger Adults Activate Predicted OFC RegionsLamar, Yousem, Resnick NeuroImage 2004

- Medial OFC (p<.01)

- Lateral OFC (p=.01)

**Match - NonMatch**

**NonMatch - Match**

## Older Adults Activate Posterior RegionsLamar, Yousem, Resnick NeuroImage 2004

**Match - NonMatch**

**NonMatch - Match**

- Association Cortices (ns)

- DLPFC (p=.006)

**Notes:**
Match-Nonmatch ns but largest areas: all association cortices in temporal and parietal regions; interestingly, older had more PFC BA 9 (working memory) activation in match whereas young had it in nonmatch

NonMatch-Match 
Based on a heightened threshold of .01 and a 15 voxel extent threshold; cluster p-uncorrected <.05
Shown here is BA 9&10 (DLPFC) R>L 
Also activated is: Dorsomedial thalamic activation (VOI); temporal and parietal association cortices; caudate

- Conclusions

- Cognitive and brain changes associated with drug abuse in the elderly will be superimposed upon a changing brain.
- Some but not all cognitive functions show age changes.
- Many but not all individuals show age changes in cognition and brain structure and function.

- BLSA Cognition and Neuroimaging Study:
- Possibilities for Studies of Drug Abuse

- Assessments of older adults continue and neuroimaging studies will be expanded with the NIA IRP MRI facility.
- Potential to include additional assessments.
- Abuse of prescription medications, including pain-killers will be most informative in this sample.

## Collaborators: Neuroimaging Project

_**NIA**_**	****	****	****	**_**JHU**_
- Alberto Goldszal, PhD 		Christos Davatzikos, PhD
- Dzung Pham, PhD		Michael Kraut, MD, PhD
- Melissa Lamar, PhD		R. Nick Bryan, MD, PhD
- Scott Moffat, PhD 		Jerry Prince, PhD
- Stephanie Golski, PhD
**	****	****	****	**_**JHU PET Facility**_
- 				Robert Dannals, PhD
- 				Hayden Ravert, PhD

**Neuroimaging Participant Selection**

**Inclusion:**
**	****Age 55-85**
**	****Prior cognitive and memory assessment**
**Exclusion:**
**	****Existing neurologic disease, including dementia**
*	**(mild cognitive decline is not exclusionary)*
**	****Severe cardiovascular disease **
*	**(hypertension alone is not exclusionary)*
**	****Metastatic cancer**
**	****Weight greater than 300 lbs or other factors precluding ****	****	****neuroimaging assessment**

## 4-

**-4.0**

**-3.5**

**-3.0**

**-2.5**

**-2.0**

**-1.5**

**-1.0**

**-0.5**

**0.0**

**0.5**

**1.0**

******4-**

******4+**

**Annual Rate of Change (%)**

**Risk Factor:  APOE ********4 ****genotype is associated with accelerated hippocampal volume loss**

- Neurology 2000;55:134-136.

**N = 13**

**N = 13**

**Notes:**
Alzheimer’s disease is increased in people have have the Apolipoprotein E epsilon 4 gene.  We have shown that this risk factor is also associated with accelerated loss of hippocampal volume, even in people who do not yet show memory impairment.

Moffat et al. Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype.  Neurology 2000;55:134-136.

## Increases in Temporal Horn Volumes Predict Mild Cognitive Impairment by CDR Score

**Temporal Horn**

**Brain**

**N = 82**

**N = 12**

**N = 82**

**N = 12**

- ***

**Increases in Temporal Horn Volumes Predict Mild Cognitive Impairment by CDR Score**

##  Annual percentage changes from baseline, respectively for brain, gray, white, and ventricular volumes:  

-  Annual percentage changes from baseline, respectively for brain, gray, white, and ventricular volumes:
- entire sample -0.55 (0.5), -0.42 (0.9), -0.67 (1.5), 4.82 (2.5); subgroup with some medical problems -0.62 (0.5), -0.50 (0.9), -0.73 (1.6), 4.97 (2.7);
- very healthy -0.36 (0.4), -0.19 (0.8), -0.48 (1.4), 4.39 (1.5).

- Automated analysis of specific regions with HAMMER and brain atlas*

**Template brain**
- (*regional outlines provided by Noor Kabani)

**BLSA brain**

- Gray

- White

## Age Differences and Age Changes in Spatial Rotation: Card Rotations Test

- Age Effects on Regional White Matter Signal Intensities

**Age differences**

**4-year decline**

- Davatzikos and Resnick.  Cerebral Cortex 2002;12:767-771

- Analysis of 4-Year Change in MRI Volumes:
- Sample Characteristics

- 			        **MEN****	****     WOMEN****	****      TOTAL****N****	****	****	****	****50****	****	****42****	****	****92****	****	****Age (yrs)****	****	****	****70.5 ± 6.4****	****70.4 ± 7.7****	****70.4 ± 7.0 ****Education (yrs)****	****	****16.0 ± 3.2****	****16.2 ± 2.4****	****16.1 ± 2.8**** ****	****	****Handedness (R:L)****	****	**** ****47:3****	****	****40:2****	****	****87:5 **
**Race (White:**
**	****Nonwhite)****	****	**** ****48:2****	****	****36:6****	****	****84:8**

## 
IMAGE PROCESSING AND STATISTICAL ANALYSIS:
Preprocessing using SPM99 and the STAR algorithm for elastic stereotaxic normalization
Voxel-based statistical analysis using customized SPM99 software 
Cross-sectional analysis:  mean CBF across Years 1, 3, and 5
Longitudinal analysis:  rates of change over time
Significance threshold:  p < .01 and cluster size > 35

**PET Analysis**

**IMAGE PROCESSING AND STATISTICAL ANALYSIS:**
- Preprocessing using SPM99 and the STAR algorithm for elastic stereotaxic normalization
- Voxel-based statistical analysis using customized SPM99 software
- Cross-sectional analysis:  mean CBF across Years 1, 3, and 5
- Longitudinal analysis:  rates of change over time
- Significance threshold:  p < .01 and cluster size _>_ 35

- Summary:
- Age-Related Structural Changes

- Regional brain structure can be measured reliably over time.
- Both gray and white matter volumes show longitudinal declines even in the healthy elderly.
- Increases in ventricular volumes are greater in older than younger individuals.
- There are regional patterns to both tissue loss and qualitative changes in tissue composition.