Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline.
BACKGROUND
Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses.


METHODS
We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data.


RESULTS
Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status.


CONCLUSIONS
Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.
O'Brien
J L
JL
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
O'Keefe
K M
KM
LaViolette
P S
PS
DeLuca
A N
AN
Blacker
D
D
Dickerson
B C
BC
Sperling
R A
RA
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000523:psychology; D015331:Cohort Studies; D003704:Dementia / Q000175:diagnosis / Q000378:metabolism* / Q000523:psychology; D005500:Follow-Up Studies; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000639:trends*; D009483:Neuropsychological Tests; D013997:Time Factors
J Neurosci. 2006 May 31;26(22):6069-76
16738250
Nat Rev Neurosci. 2004 May;5(5):347-60
15100718
Neurochem Int. 2004 Oct;45(5):583-95
15234100
J Magn Reson Imaging. 2009 May;29(5):1021-6
19388128
Neuropsychologia. 2008;46(6):1624-35
18206188
Ann Neurol. 2004 Jul;56(1):27-35
15236399
J Neurol Neurosurg Psychiatry. 2003 Jan;74(1):44-50
12486265
Hum Brain Mapp. 2001 Nov;14(3):129-39
11559958
Radiology. 2006 Jul;240(1):177-86
16684919
Neurobiol Aging. 2007 Mar;28(3):404-13
16530885
Ann Neurol. 1999 Apr;45(4):466-72
10211471
Neurobiol Aging. 2009 Nov;30(11):1737-48
18325636
AJNR Am J Neuroradiol. 2009 Feb;30(2):411-6
19001543
J Intern Med. 2004 Sep;256(3):183-94
15324362
J Neurol Neurosurg Psychiatry. 2008 Jun;79(6):630-5
17846109
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):455-60
11756667
Arch Neurol. 2004 Jan;61(1):59-66
14732621
Arch Neurol. 2000 May;57(5):675-80
10815133
Neurobiol Aging. 2007 Dec;28(12):1889-903
16997428
Brain. 2009 May;132(Pt 5):1310-23
19042931
Neuron. 2007 Sep 6;55(5):697-711
17785178
PLoS One. 2007 Oct 31;2(10):e1104
17971867
J Neurol Neurosurg Psychiatry. 2007 Aug;78(8):812-8
17287238
Brain. 2006 May;129(Pt 5):1229-39
16627465
Neurochem Res. 2003 Nov;28(11):1743-56
14584828
Brain. 2009 May;132(Pt 5):1355-65
19339253
Neurology. 2005 Feb 8;64(3):501-8
15699382
J Neurosci. 2006 Oct 4;26(40):10222-31
17021177
Neurology. 2003 Aug 26;61(4):500-6
12939424
Hum Brain Mapp. 2009 Dec;30(12):4033-47
19492301
Neurology. 2005 Aug 9;65(3):404-11
16087905
N Engl J Med. 2000 Aug 17;343(7):450-6
10944562