Dying neurons typically display little activity, but Alzheimer’s disease researchers have puzzled over a strange surge of hippocampal firing in some seniors at the cusp of mental decline. A functional brain imaging study in the November 30 Journal of Neuroscience links this paradoxical hyperactivity with an established marker of neurodegeneration—atrophy in a network of functionally connected AD brain areas. The correlation showed up not only in older people with mild cognitive impairment, but also in those who seemed cognitively normal. The research, led by Reisa Sperling at Brigham and Women’s Hospital in Boston, suggests that hippocampal hyperactivation in seniors with normal or slightly impaired cognition could be an early sign of AD-related neurodegeneration.

Functional and structural imaging evidence continues to push back the start of Alzheimer’s disease by years, even decades, before memory problems emerge. Just before the steady decline in hippocampal activation that occurs as dementia sets in, this brain region shows a surprising frenzy of activity. With functional magnetic resonance imaging (fMRI), Sperling and others have seen hippocampal hyperactivation in seniors with MCI (Dickerson et al., 2005; Hämäläinen et al., 2007; Kircher et al., 2007; Yassa et al., 2010) or mildly impaired memory (ARF related news story on Miller et al., 2008), people with familial or genetic AD risk (Bondi et al., 2005; Bassett et al., 2006), and even in young adults (ARF related news story on Filippini et al., 2009). Research presented at the recent Society for Neuroscience meeting in Washington, DC, also suggests that brain changes revealed by functional imaging could signal future dementia (see ARF related news story).

Meanwhile, structural MRI studies have identified a network of functionally connected cortical regions that thin out in MCI patients on the wane toward AD dementia (Bakkour et al., 2009; Dickerson et al., 2009), and in some cognitively normal adults (Dickerson et al., 2011). In the current study, first author Deepti Putcha and colleagues wondered if hippocampal hyperactivity correlated with cortical thinning in these AD signature areas.

The researchers used functional and structural MRI to analyze 18 cognitively intact seniors and 16 with “early MCI.” The latter came from a cohort, recruited for the second phase of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), deemed not quite normal but not impaired enough to meet amnestic MCI criteria, Sperling told ARF. Compared to the control group, early MCI participants did worse on the Rey auditory verbal learning task and showed modest deficiencies in Clinical Dementia Rating (CDR) and Mini-Mental State Exam scores. And, consistent with previous work, the early MCI group showed hippocampal hyperactivity relative to controls during the fMRI memory task. The new piece in the present study was the connection to atrophy in AD signature areas shown by structural MRI. “The more the hippocampus showed this paradoxical hyperactivity, the greater the cortical thinning in these functionally connected regions,” Sperling said of the early MCI group. The signature areas included the medial temporal lobe, the angular gyrus, and the inferior temporal gyrus. The association also appeared in the control group, albeit only in a subset of these cortical regions.

“I think this hyperactivity is a harbinger of imminent clinical decline. This study links it to neurodegeneration, not just in the hippocampus but in a distributed network of AD signature regions,” Sperling said. Her findings seem to jibe with recent reports of increased neuronal excitotoxicity (ARF related news story on Palop et al., 2007) and abnormally high calcium influx (ARF related news story) in the hippocampus and associated cortical regions in AD mouse models.

Though she concedes that fMRI is an indirect measure of neuronal activity—“much removed” from the direct recordings done in animal studies—Sperling thinks excitotoxicity could be driving the paradoxical hyperactivity she and others have observed in mildly impaired seniors, and even some who appear normal. “One of the early things that may happen in AD before cells die is that they have this aberrant increase in activity. When they’re firing in an abnormal way, that may be a sign that they are dying,” she said. Longitudinal studies are underway to see if this hypothesis bears out.—Esther Landhuis


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News Citations

  1. Deactivation Flaws Predict Memory Troubles
  2. ApoE4 Linked to Default Network Differences in Young Adults
  3. DC: Do Measurable Changes in Brain Function Herald Dementia?
  4. Do "Silent" Seizures Cause Network Dysfunction in AD?
  5. Hyperactive Neurons and Amyloid, Side by Side

Paper Citations

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  2. . Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging. 2007 Dec;28(12):1889-903. Epub 2006 Sep 25 PubMed.
  3. . Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding. J Neurol Neurosurg Psychiatry. 2007 Aug;78(8):812-8. PubMed.
  4. . High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242-52. PubMed.
  5. . Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2181-6. PubMed.
  6. . fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology. 2005 Feb 8;64(3):501-8. PubMed.
  7. . Familial risk for Alzheimer's disease alters fMRI activation patterns. Brain. 2006 May;129(Pt 5):1229-39. PubMed.
  8. . Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7209-14. PubMed.
  9. . The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology. 2009 Mar 24;72(12):1048-55. PubMed.
  10. . The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb Cortex. 2009 Mar;19(3):497-510. PubMed.
  11. . Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology. 2011 Apr 19;76(16):1395-402. PubMed.
  12. . Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

External Citations

  1. Alzheimer’s Disease Neuroimaging Initiative

Further Reading

Primary Papers

  1. . Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults. J Neurosci. 2011 Nov 30;31(48):17680-8. PubMed.