Mild Cognitive Impairment and Early Detection of Alzheimer`s Disease. A Positron Emission Tomography Study

Alzheimer`s disease (AD) is characterised neuropathologically by the presence of extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss. The pathological changes in AD are believed to start even decades before clinical symptoms are detectable. AD gradually affects episodic memory, cognition, behaviour and the ability to perform everyday activities. Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia disorders, especially AD. The predictive accuracy of the current and commonly used MCI criteria devide this disorder into amnestic (aMCI) and non-amnestic (naMCI) MCI. It seems that many individuals with aMCI tend to convert to AD. However many MCI individuals will remain stable and some may even recover. At present, the principal drugs for the treatment of AD provide only symptomatic and palliative benefits. Safe and effective mechanism-based therapies are needed for this devastating neurodegenerative disease of later life. In conjunction with the development of new therapeutic drugs, tools for early detection of AD would be important. In future one of the challenges will be to detect at an early stage these MCI individuals who will convert to AD. Methods which can predict which MCI subjects will convert to AD will be much more important if the new drug candidates prove to have disease-arresting or even disease–slowing effects. These types of drugs are likely to have the best efficacy if administered in the early or even in the presymptomatic phase of the disease when the synaptic and neuronal loss has not become too widespread. There is no clinical method to determine with certainly which MCI individuals will progress to AD. However there are several methods which have been suggested as predictors of conversion to AD, e.g. increased [11C] PIB uptake, hippocampal atrophy in MRI, low CSF A beta 42 level, high CSF tau-protein level, apolipoprotein E (APOE) ε4 allele and impairment in episodic memory and executive functions. In the present study subjects with MCI appear to have significantly higher [¹¹C] PIB uptake vs healthy elderly in several brain areas including frontal cortex, the posterior cingulate, the parietal and lateral temporal cortices, putamen and caudate. Also results from this PET study indicate that over time, MCI subjects who display increased [¹¹C] PIB uptake appear to be significantly more likely to convert to AD than MCI subjects with negative [¹¹C] PIB retention. Also hippocampal atrophy seems to increase in MCI individuals clearly during the conversion to AD. In this study [¹¹C] PIB uptake increases early and changes relatively little during the AD process whereas there is progressive hippocampal atrophy during the disease. In addition to increased [¹¹C] PIB retention and hippocampal atrophy, the status of APOE ε4 allele might contribute to the conversion from MCI to AD.

Neural correlates of language learning in adults

The human language-learning ability persists throughout life, indicating considerable flexibility at the cognitive and neural level. This ability spans from expanding the vocabulary in the mother tongue to acquisition of a new language with its lexicon and grammar. The present thesis consists of five studies that tap both of these aspects of adult language learning by using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) during language processing and language learning tasks. The thesis shows that learning novel phonological word forms, either in the native tongue or when exposed to a foreign phonology, activates the brain in similar ways. The results also show that novel native words readily become integrated in the mental lexicon. Several studies in the thesis highlight the left temporal cortex as an important brain region in learning and accessing phonological forms. Incidental learning of foreign phonological word forms was reflected in functionally distinct temporal lobe areas that, respectively, reflected short-term memory processes and more stable learning that persisted to the next day. In a study where explicitly trained items were tracked for ten months, it was found that enhanced naming-related temporal and frontal activation one week after learning was predictive of good long-term memory. The results suggest that memory maintenance is an active process that depends on mechanisms of reconsolidation, and that these process vary considerably between individuals. The thesis put special emphasis on studying language learning in the context of language production. The neural foundation of language production has been studied considerably less than that of perceptive language, especially on the sentence level. A well-known paradigm in language production studies is picture naming, also used as a clinical tool in neuropsychology. This thesis shows that accessing the meaning and phonological form of a depicted object are subserved by different neural implementations. Moreover, a comparison between action and object naming from identical images indicated that the grammatical class of the retrieved word (verb, noun) is less important than the visual content of the image. In the present thesis, the picture naming was further modified into a novel paradigm in order to probe sentence-level speech production in a newly learned miniature language. Neural activity related to grammatical processing did not differ between the novel language and the mother tongue, but stronger neural activation for the novel language was observed during the planning of the upcoming output, likely related to more demanding lexical retrieval and short-term memory. In sum, the thesis aimed at examining language learning by combining different linguistic domains, such as phonology, semantics, and grammar, in a dynamic description of language processing in the human brain.