Investigating Compensatory Brain Activity in Older Adults with Subjective Cognitive Decline

Abstract

Background: Preclinical Alzheimer’s disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain. Objective: To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD. Methods: 52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-β and phosphorylated tau (pTau181) measures. Results: Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at p < 0.001. This finding was not replicated in a subset of 23 biomarker positive individuals. Conclusion: Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored.

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

“…CSF biomarkers of plasticity include: neurogranin, a postsynaptic protein involved in synaptic plasticity and LTP [37], whose levels are usually higher in AD patients [38]; synaptosome-associated protein-25 (SNAP-25), which participates in the control of synaptic plasticity [39] and is usually higher in AD patients [40]; brain-derived neurotrophic factor (BDNF), essential for memory formation and structural plasticity [41] Measuring neuroplasticity in human subjects is obviously precluded by ethical and methodological considerations, calling for the use of proxy measures. Thus, measuring neuroplasticity was for many years restricted to the use of neuropsychological tests [30], such as the Battery of Learning Potential for Assessing Dementia [31] or the re-adapted Auditory Verbal Learning Test [32], and indirect biomarkers in serum and cerebrospinal fluid (CSF) [33][34][35][36]. CSF biomarkers of plasticity include: neurogranin, a postsynaptic protein involved in synaptic plasticity and LTP [37], whose levels are usually higher in AD patients [38]; synaptosome-associated protein-25 (SNAP-25), which participates in the control of synaptic plasticity [39] and is usually higher in AD patients [40]; brain-derived neurotrophic factor (BDNF), essential for memory formation and structural plasticity [41] and which is lower in MCI and AD patients [42,43]; and vascular endothelial growth factor (VEGF), a protein involved in the growth of blood vessels and delivery of glucose that has a role in enhancing neurogenesis and synaptic plasticity [33] (see Table 1).…”