Language, ageing and neurodegenerative disease.

UNLABELLED: Until recently brain-behavior relationships in healthy ageing and neurodegenerative disease were based on studies of the state of the brain after its final outcome, death. Direct in vivo imaging of dynamic cognitive systems at different disease stages offers an unprecedented opportunity to gain insight into evolving cognitive dysfunctions and changing brain systems. In this talk we will present new data on how this semantic system is affected by healthy ageing, lesions and neurodegenerative disease. 1. Age: One of the principal cognitive consequences of normal ageing is a decline of episodic memory while semantic memory is preserved. Despite the fact that semantic task performance remains at equal levels, the underlying semantic brain network shows clear alterations: The gradient between left and right prefrontal cortex is significantly decreased, principally due to a decrease of left prefrontal activation. 2. Focal brain lesions: In a patient who suffered from an ischemic lesion that is confined to the right anterior fusiform gyrus, associative semantics were still performed at a high level while drawing from memory and pseudo-object decision task were severely impaired. The right anterior fusiform group activation coincided with the lesion. In this patient the mirror left fusiform region was significantly more active during picture semantics than under normal circumstances. A case with a lesion in the mirror left fusiform region will also be discussed. 3. Neurodegenerative disease: We will contrast two patient groups: Patients with a progressive word finding and semantic memory deficit (primary progressive aphasia, most often due to frontotemporal degeneration) and patients with an isolated episodic memory deficit (incipient Alzheimer's disease, mild cognitive impairment). In patients with primary progressive aphasia different components of the semantic network, i.e. inferior frontal sulcus, superior temporal sulcus and anterior temporal pole, show less activity than in healthy controls. The activity levels correlate with performance on off-line picture naming tasks. Interestingly, the right medial temporal lobe, classically implicated in episodic memory functions, shows higher activity in primary progressive aphasics than in healthy controls, suggesting that patients make use of non-verbal episodic memory strategies to compensate for their semantic deficit. In contrast, patients with mild cognitive impairment clinically have only an isolated episodic memory deficit and perform within the normal range on semantic tasks. Despite normal performance the semantic system for words and pictures show profound alterations, including among other differences decreased activity in Wernicke's area (posterior middle temporal gyrus) on the left compared to age-matched controls. CONCLUSION: cognitive brain systems for semantic memory change with increasing age. These changes are qualitatively different from those found in incipient Alzheimer's disease or in primary progressive aphasia. The degree to which brain systems adapt in a plastic way to pathogenetic processes at multiple levels, is a determinant of disease manifestation and an important target for current and future therapies.