Disintegration at the Syntax-Semantics Interface in Prodromal Alzheimer's Disease: New Evidence from Complex Sentence Anaphora in Amnestic Mild Cognitive Impairment (aMCI).

Although diverse language deficits have been widely observed in prodromal Alzheimer's disease (AD), the underlying nature of such deficits and their explanation remains opaque. Consequently, both clinical applications and brain-language models are not well-defined. In this paper we report results from two experiments which test language production in a group of individuals with amnestic Mild Cognitive Impairment (aMCI) in contrast to healthy aging and healthy young. The experiments apply factorial designs informed by linguistic analysis to test two forms of complex sentences involving anaphora (relations between pronouns and their antecedents). Results show that aMCI individuals differentiate forms of anaphora depending on sentence structure, with selective impairment of sentences which involve construal with reference to context (anaphoric coreference). We argue that aMCI individuals maintain core structural knowledge while evidencing deficiency in syntax-semantics integration, thus locating the source of the deficit in the language-thought interface of the Language Faculty.

Language Decline Characterizes Amnestic Mild Cognitive Impairment Independent of Cognitive Decline.

Purpose This research investigated the nature of cognitive decline in prodromal Alzheimer's disease (AD), particularly in mild cognitive impairment, amnestic type (aMCI). We assessed language in aMCI as compared with healthy aging (HA) and healthy young (HY) with new psycholinguistic assessment of complex sentences, and we tested the degree to which deficits on this language measure relate to performance in other general cognitive domains such as memory. Method Sixty-one individuals with aMCI were compared with 24 HA and 10 HY adults on a psycholinguistic measure of complex sentence production (relative clauses). In addition, HA, HY, and a subset of the aMCI participants (n = 22) were also tested on a multidomain cognitive screen, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and on a verbal working memory Brown-Peterson (BP) test. General and generalized linear mixed models were used to test psycholinguistic results and to test whether ACE-R and BP performance predicted performance on the psycholinguistic test similarly in the aMCI and HA groups. Results On the psycholinguistic measure, sentence imitation was significantly deficited in aMCI in comparison with that in HA and HY. Experimental factorial designs revealed that individuals with aMCI had particular difficulty repeating sentences that especially challenged syntax-semantics integration. As expected, the aMCI group also performed significantly below the HY and HA groups on the ACE-R. Neither the ACE-R Memory subtest nor the BP total scores predicted performance on the psycholinguistic task for either the aMCI or the HA group. However, the ACE-R total score significantly predicted psycholinguistic task performance, with increased ACE-R performance predicting increased psycholinguistic task performance only for the HA group, not for the aMCI group. Conclusions Results suggest a selective deterioration in language in aMCI, specifically a weakening of syntax-semantics integration in complex sentence processing, and a general independence of this language deficit and memory decline. Results cohere with previous assessments of the nature of difficulty in complex sentence formation in aMCI. We argue that clinical screening for prodromal AD can be strengthened by supplementary testing of language, as well as memory, and extended evaluation of strength of their relation.

Reversing Ribot: does regression hold in language of prodromal Alzheimer's disease?

We consider the regression or retrogenesis hypothesis, which argues that order of acquisition in development is reversed in neurodegeneration or pathology. Originally proposed as a regression hypothesis for the study of memory disorders, specifically retrograde amnesia, by Ribot (1881), it has been extended to the study of brain aging and pathology and to language. We investigate this hypothesis in a new study of language development, aging, and pathology. Through interuniversity collaboration using a matched experimental design and task, we compare production of complex sentences containing relative clauses by normal monolingual children during normal development, healthy young adults, healthy aging adults, and aging adults diagnosed with mild cognitive impairment, a recognized potential harbinger of Alzheimer's disease. Our results refute the regression hypothesis in this area and lead to potential syntactic markers for prodromal Alzheimer's disease and predictions for future brain imaging analyses.

Ultrabithorax protein expression in breakpoint mutants: localization of single, co-operative and redundant cis regulatory elements.

The correct function of homeotic genes depends on their correct spatial deployment which is regulated at the level of transcription by a number of cis regulatory elements. The localisation of cis regulatory regions has been difficult because of the enormous length of the homeotic genes. Here we try to find new cis regulatory elements by analysing Ultrabithorax expression in a number of breakpoint mutations spanning the whole Ultrabithorax gene. Most mutations breaking in the transcription unit give rise to RNAs that translate into mutant protein products. These can be detected with an antibody directed against the part of the protein encoded by the 5' exon of the gene. Using this antibody we have studied how breakpoints both upstream and downstream of the Ubx promoter affect the distribution of UBX protein. We define localised regions of DNA which are required to drive spatial expression in parasegment 5 and in the posterior compartment of parasegment 6. In contrast, our results suggest that the Ubx regulatory elements for parasegments 7-12 are highly redundant since (1) double mutants affecting both the up-stream and down-stream regulatory regions have a synergistic effect in these parasegments, and (2) in some cases, lack of Ubx expression in early development caused by the absence of certain elements is overcome by the later activity of the remaining cis elements. Our analysis of mutations breaking upstream of the transcription unit reveals that ectodermal and mesodermal Ubx expression in the posterior abdomen is regulated by co-operative cis regulatory elements. We also show that, at least, some of these cis regulatory elements are germ layer specific and not parasegment specific.