Neurology -- Correspondence for Bondi et al., 64 (3) 501-508

Correspondence published:

fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease: Nikolaos Scarmeas, Yaakov Stern (26 May 2005)

Reply to Scarmeas et al: Mark W. Bondi, S. Duke Han (26 May 2005)

fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease 26 May 2005

Nikolaos Scarmeas,
Columbia University Medical Center
622 W168th, PH 19th Floor, New York, NY, 10032,
Yaakov Stern
Send Correspondence to journal:
Re: fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease

ns257{at}columbia.edu Nikolaos Scarmeas, et al.

We read the recent article by Bondi et al [1] with great interest. The authors review previous studies suggesting that BOLD brain responses during performance of memory tasks are of greater magnitude and more diffuse in patients with early Alzheimer's disease (AD) than in normal older individuals. They also review previous studies demonstrating an increase in the intensity and extent of brain activation for non-demented E4 carriers.
Using an elegant fMRI experiment, they conclude that elderly E4 carriers require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding. The authors suggest that the observed greater magnitude and extent of activations is consistent with the compensatory hypothesis.
There is also strong evidence for reporting brain regions with decreased activation in E4 carriers. Using H₂¹⁵O PET, we have demonstrated decreased activation for healthy young (Scarmeas et al. JNNP, in press), healthy elderly [2] and AD [3] E4 carriers during non-verbal memory tasks. Decreased activation for E4 carriers has been also demonstrated with fMRI by other investigators during visual naming and verbal fluency tasks. [4, 5] Even in Bondi et al's study, there were clusters in the left hippocampal and parahippocampal areas where E4 carriers had lower activation, as compared to their E3 counterparts. The interpretation of either increased or decreased activation is not straightforward, as it is not always readily apparent which directionality reflects the �optimal� response. Decreased activation for E4 carriers may be equally important.
In many previous studies involving either AD patients or healthy elderly, decreased activation in certain brain regions has been associated with more efficient processing while an increase has been associated with less effective cognitive strategies. Demonstration of significant correlations with aspects of task performance is one way to determine whether increased or decreased activation constitutes a beneficial or compensatory response.
References
1.Bondi MW, Houston WS, Eyler LT, Brown GG. fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology 2005;64:501-508.
2.Scarmeas N, Habeck C, Anderson KE, et al. Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the E4 Allele). Am. J. Geriatr. Psychiatry 2004;12:596-605.
3.Scarmeas N, Anderson KE, Hilton J, et al. APOE-dependent PET patterns of brain activation in Alzheimer disease. Neurology 2004;63:913-915.
4.Smith CD, Andersen AH, Kryscio RJ, et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology 1999;53:1391-1396.
5.Smith CD, Andersen AH, Kryscio RJ, et al. Women at risk for AD show increased parietal activation during a fluency task. Neurology 2002;58:1197-1202.
The authors report no conflicts of interest.

Reply to Scarmeas et al 26 May 2005

Mark W. Bondi,
UCSD & VA San Diego Healthcare System
VASDHS (116B), 3350 La Jolla Village Drive, San Diego CA 92161,
S. Duke Han
Send Correspondence to journal:
Re: Reply to Scarmeas et al

mbondi{at}ucsd.edu Mark W. Bondi, et al.

We thank Scarmeas and Stern for their interest in our study and cogent commentary. They point out that interpretation of directionality of activation in functional imaging studies is not straightforward. In other words, �optimal� performance may be reflected either in decreases or increases in activation within a given region.
Although not explicitly stated by Scarmeas and Stern, another implication is that both may occur within a functional system such as episodic memory encoding. That is, an increase in one region may be best complemented by a decrease in activation within another region of this cognitive system. [1] Advancing methodologies in functional connectivity, including efforts to combine different imaging techniques, will help elucidate such relationships. [2]
The authors close by suggesting that demonstration of significant correlations with aspects of task performance is one way to determine whether increased or decreased activation may constitute a beneficial or compensatory response. Again, we agree and refer back to our article�s correlations of brain response in the hippocampi with two different measures of task performance: (a) recognition memory for the pictures and (b) the California Verbal Learning Test�s [3] summary learning variable. Both measures demonstrated different patterns of correlation between the two APOE genotype groups. The APOE E3 group demonstrated positive associations between BOLD response in the hippocampus and task performance, whereas the APOE E4 group demonstrated either negative or no associations.
Based on these correlations, we suggested that the APOE E4 group may be invoking bilateral medial temporal brain resources in an aberrant manner as an attempt to facilitate encoding.
Although we fully acknowledge that these correlations are preliminary, they anchor the BOLD response to behavioral measures of interest. In response to Scarmeas and Stern�s review of visual naming and verbal fluency studies suggesting a different pattern of activation according to APOE genotype, we argue that tasks of episodic memory, such as the one employed for the current study, would differentially activate hippocampal and other regions within a broadly distributed network and thus are difficult to compare to one another.
Scarmeas and Stern are correct to stress the cautionary stance with which investigators should approach directionality of activation within fMRI research. Given our preliminary evidence supporting a compensation hypothesis, more studies are needed to further clarify the underlying mechanisms of such a phenomenon.
References
1. Ragland JD, Gur RC, Valdez J, et al. Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia. American Journal of Psychiatry 2004; 161: 1004- 1015.
2. Ramnani N, Behrens TEJ, Penny W, et al. New approaches for exploring anatomical and functional connectivity in the human brain. Biological Psychiatry 2004; 56(9): 613-619.
3. Delis DC, Kramer JH, Kaplan E, Ober BA. The California Verbal Learning Test. 1987. New York: Psychological Corporation.