Vulnerability to Proactive Semantic Interference and Progression to Dementia among Older Adults with Mild Cognitive Impairment

David A. Loewenstein a–c Amarilis Acevedo b, c, e Joscelyn Agron b, c, e Ranjan Duara a, c, d

a Wein Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Fla. , b Center on Aging and Departments of c Psychiatry and Behavioral Sciences, and d Medicine, Miller School of Medicine, University of Miami School of Medicine, Miami, Fla. , e Johnnie Byrd Alzheimer’s Disease Clinical and Research Center, Tampa, Fla. , USA

Abstract There is evidence that vulnerability to proactive semantic interference may be an early manifestation of early Alzheimer’s disease and other neurodegenerative disorders. At present, there is a paucity of data regarding the extent to which such deficits relate to the progression of cognitive deficits and to clinically significant endpoints such as dementia. In this study, we followed 76 older adults, initially diagnosed with mild cognitive impairment, for a period of up to 3 years. Twenty-seven of these individuals (35.5%) progressed from mild cognitive impairment to dementia. An examination of baseline neuropsychological performance indicated lower baseline scores for object memory among those progressing to dementia. However, baseline Mini-Mental State Examination scores, delayed memory for passages, delayed visual memory, letter fluency, category fluency, Trails B and Block Design did not differ among study groups. In contrast, the Semantic Interference Test, a measure susceptible to vulnerability to proactive semantic interference showed the greatest baseline differentiation between those who progressed and those who did not progress to dementia. Further, scores on this measure predicted future progression to dementia with high accuracy. Vulnerability to proactive interference may be an early manifestation of an early dementing process and may have utility in predicting future progression to dementia.

Introduction There has been an increasing emphasis on the detection of early manifestations of mild cognitive impairment (MCI) in the elderly. Since some persons with MCI may progress to greater degrees of impairment while others do not, it is important to determine predictors of important endpoints such as dementia. Performance on list learning and semantic memory tests assessing immediate and delayed recall has been the most predictive of progression to dementia among older adults who do not meet criteria for dementia upon initial evaluation [1–4] and among initially normal community-dwelling elders [5] . However, nonmemory tests such as information and animal fluency [6] , attention and executive function [7] and psychomotor speed [8] have also been found to be predictive of progression to dementia. This raises the issue that the earliest cognitive symptoms of an underlying degenerative process may be variable and that it may correspond to specific areas of the brain that may be initially affected.

With the promise of newer pharmacological agents on the horizon, investigators have turned to other paradigms in an attempt to identify the earliest cognitive manifestations of MCI and neurodegenerative disease. In an attempt to elucidate these early mechanisms, our group has found that increased vulnerability to semantic interference may be an early manifestation of cognitive impairment among elderly patients with early Alzheimer’s disease (AD). After learning an initial list of items over several trials, susceptibility to proactive interference for other semantically related targets had a high degree of sensitivity and specificity in distinguishing mildly impaired AD patients, patients with prodromal AD who did not meet criteria for dementia, and normal elderly controls [9, 10] .

The fact that mean group differences persisted after controlling for overall memory performance suggests that susceptibility to proactive interference may reflect impaired inhibitory processes and potential dysfunction that extends beyond memory impairment [9] . More recent work suggests that susceptibility to semantic interference may not be limited to AD but may be observed among patients with other neurological conditions such as multiple cerebral infarctions, which commonly affect executive function [11] . While vulnerability to semantic interference may be an effective marker of early cognitive impairment, little is known about the utility of such measures to predict those persons who might be more susceptible to cognitive decline and progression to dementia. In this study, we followed 76 subjects with MCI for up to 3 years. The primary goal of the study was to assess the extent to which baseline vulnerability to semantic interference and performance on other neuropsychological measures could differentiate persons who would progress to dementia from those who would not progress to dementia.

Vulnerability to Proactive Semantic Interference and Progression to Dementia among Older Adults with Mild Cognitive Impairment

David A. Loewenstein a–c Amarilis Acevedo b, c, e Joscelyn Agron b, c, e Ranjan Duara a, c, d

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