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Hippocampal atrophy and neocortical dysfunction in early Alzheimer’s disease
  1. J-C Baron
  1. Department of Neurology, Box 83, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
  1. Correspondence to:
 Professor J-C Baron;
 jcb54{at}cam.ac.uk

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Is there a relationship between medial temporal lobe atrophy and brain dysfunction in Alzheimer’s disease?

Although it would appear straightforward that neuronal loss in and by itself explains the cognitive deficits in Alzheimer’s disease (AD), things are considerably more complicated as shown by Garrido et al (this issue pp 508–16).1 In this elegant study of nine patients with very mild AD, the authors assessed the relationships between hippocampal volume (assessed with structural magnetic resonance imaging (MRI) and voxel based morphometry), and the changes in cerebral perfusion (mapped with single photon emission computed tomography (SPECT)) during a verbal recognition memory task. Increasing hippocampal atrophy was associated with reduced activation of the extensive left sided network normally engaged by this episodic task, but also with increased activation in several frontal regions. They interpret these findings as suggesting that medial temporal lobe (MTL) pathology negatively modulates structures belonging to this network and reciprocally connected with the hippocampus, while also positively modulating activity in non-specific executive control centres—also indirectly connected to the hippocampal complex—probably reflecting an attempt by the AD brain to maintain performance by increased attentional/strategic load.

Although this study has some acknowledged limitations, the results are convincingly robust. Furthermore, they are entirely consistent with other work. Using positron emission tomography, Meguro et al reported a significant correlation between the degree of hippocampal atrophy and the severity of resting state glucose hypometabolism in the ipsilateral parietotemporal association cortex (PACx).2 This correlation remained significant even after controlling for degree of dementia, thus ruling out a simple effect of disease severity. This suggested that the striking PACx hypometabolism present from the very early stages of AD may not simply reflect the degree of local pathology but also in part a remote effect of MTL tau pathology. This clinical study followed an earlier work in baboons, which documented that excitotoxic damage to the rhinal cortex (the MTL area earliest affected in AD) induces significant resting hypometabolism in several PACx areas.3 The fact that this hypometabolism was correlated to the severity of declarative memory impairment suggests that these remote functional effects may have clinical relevance. Recently, Prvulovic et al4 found that the degree of atrophy in the left superior parietal lobule was correlated not only to the reduction in activation of this area during a visuospatial task, but also to increased activation of the left occipitotemporal cortex, suggesting the visual ventral stream got engaged in the task so as to compensate (efficiently, as shown by preserved performance) for dorsal stream dysfunction.

Thus, the AD brain demonstrates its abnormal function in two ways, firstly a reduced capacity of normally engaged networks, and secondly, in an attempt to compensate for this, an increased activation of some less affected cortical areas. Importantly, both remote functional effects appear to be modulated by the degree of atrophy in targeted areas. Although the mechanism underlying this modulatory activity remains to be addressed, it may involve altered neurotransmitter balance, for example, glutamate/GABA, at distant synaptic relays.

What are the clinical implications of these emerging concepts? First, they suggest that the functional impairment in AD is not just related to local pathology, but partly reflects dysfunction elsewhere. Second, the AD brain possesses considerable functional plasticity in areas still relatively spared by the pathology. Third, and finally, activation in those remote areas may be partially restored by—for example, appropriate manipulation of neurotransmission or re-establishment of function in the MTL, while activation of the compensatory areas may be further enhanced by targeted cognitive training. Although still entirely speculative, these interventions could be both guided and monitored by functional imaging.

Is there a relationship between medial temporal lobe atrophy and brain dysfunction in Alzheimer’s disease?

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