Functional neurobiology in normal aging, mild cognitive impairment and Alzheimer's disease : focus on on visuospatial processing using functional magnetic resonance imaging

With the proportional increase of the aging population in the coming decades as well as a continuously augmenting life expectancy, the effects of neurodegeneration on brain function are a topic of increasing importance. Of special interest are tools that probe the functional consequences of neurodegenerative processes and possible compensatory mechanisms that might emerge. This thesis uses functional magnetic resonance imaging, fMRI to investigate visuospatial processing in early adulthood, old age and during different stages in the course of Alzheimer s disease, AD (including mild cognitive impairment, MCI), with the aim to relate the functional activation changes in aging and dementia to the task demand (assessed by reaction time, RT), and task performance (% correct responses).

Using an angle discrimination task with varying task demand we could demonstrate that all groups engaged a visuospatial network including bilateral core regions in parietal, occipital, and frontal cortex as well as basal ganglia. In these regions a general pattern of a linear relationship (either by using correlation analysis (study I) or by incorporating a reaction time dependent hemodynamic response predictor in the statistical model (study II-V)) between cortical activation and behavioral performance could be observed, reflecting increased cortical processing due to increased task demand.

However, t he processing efficiency or relative contribution of the components in this network differed depending on age and disease . In study III we found an age-related task demand dependent change of activation, suggesting that age modulates the utilization of cerebral networks, which has bearing on the behavioral response in the elderly subjects. The results of a weaker relation between task demand and brain activity in several areas of the visuospatial network in elderly compared to young subjects indicate that age-related decrease in processing speed is related to a decline in the neural correlates of processing efficiency. In study V we found an enhanced parietal activation (especially left sided) pattern in patient that later progressed to AD compared to patients that remained stable (SMCI) and controls. This could reflect a reduced neuronal efficacy due to accumulating AD pathology, in which the increased activation could serve as a compensatory role for PMCI patients to achieve the same level of behavioral task performance as the controls and SMCI. However, as the pathological changes progress in AD, abnormal brain function was observed in the parietal cortices. A weak and sometimes absent increase in BOLD signal with increasing task demand was demonstrated in study IV in several regions in the dorsal visual pathway in AD patients compared to controls, suggesting a failure to modulate the neural response to increased task demand.

Further, it was shown that the groups also differed with respect to the general BOLD signal increase of activation irrespective of task demand. In study III-IV, an age- and disease related reduction in occipital activity was discovered. These findings could be due to a decline in sensory processing due to age which is worsening further by the neurodegenerative disease. However, in study III we also found an age-related increase in several prefrontal regions, which was interpreted to reflect a compensatory pathway in which older brains may apply a different strategy in order to solve the task with similar task performance as the younger subjects. A similar compensatory effect could be demonstrate in the PMCI patients (study V), reflected as an increase of activation in left precuneus (as compared to SMCI and controls). In study IV, AD patients demonstrated a weaker general increase in BOLD signal in these areas (e.g. left precuneus, and prefrontal cortex) suggesting that the above reported compensatory pathways are limited in AD patients. Instead, we found a n increased activation in the right ventral pathway, which might reflect a potential secondary compensatory mechanism for the reduced functional capacity of the parietal regions in AD patients.

A proposed integrative model that applies to the functional activation studies of both healthy aging and Alzheimer s disease and its precursors is presented. This model reveals that alterations in the visuospatial network, independently of its cause, lead to changes in functional activation which seems to follow similar rules in aging and dementia. Thus, the findings presented in this thesis are providing one step in the unraveling of the physiological and pathophysiological mechanisms behind age- and disease related cognitive decline.

List of scientific papers

I. Vannini P, Almkvist O, Franck A, Jonsson T, Volpe U, Kristoffersen Wiberg M, Wahlund LO, Dierks T (2005). Task demand modulations of visuospatial processing measured with functional magnetic resonance imaging. Neuroimage. 21(1): 58-68
https://pubmed.ncbi.nlm.nih.gov/14741642

II. Lehmann C, Vannini P, Wahlund LO, Almkvist O, Dierks T (2006). Increased sensitivity in mapping task demand in visuospatial processing using reaction-time-dependent hemodynamic response predictors in rapid event-related fMRI. Neuroimage. 31(2): 505-12.
https://pubmed.ncbi.nlm.nih.gov/16564707

III. Vannini P, Lehmann C, Almkvist O, Jonsson T, Kiefer C, Menzi C, Wahlund LO, Dierks T (2007). When things are getting difficult: Brain basis of age-related slowing in visuospatial processing. [Submitted]

IV. Vannini P, Lehmann C, Dierks T, Viitanen M, Wahlund LO, Almkvist O (2007). Failure to modulate neural response to increased task demand in mild Alzheimers disease: fMRI study of visuospatial processing. [Submitted]

V. Vannini P, Almkvist O, Dierks T, Lehmann C, Wahlund LO, (2007). Reduced neuronal efficacy in progressive mild cognitive impairment: A prospective fMRI study on visuospatial processing. Psychiatry Research: Neuroimaging. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/17719211