Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] Innovations in CLINICAL NEUROSCIENCE 33 commonly used memory measures for e arly AD include the following: A) they focus on passive rather than active encoding strategies, B) they are susceptible to attentional issues, C) they are influenced by level of education and c ognitive reserve, D) they do not address vulnerabilities of AD patients to semantic interference, 14–16 and E) they do not dissociate between memory deficits and deficits in utilizing semantic cues. 17– 18 Commonly utilized tests typically focus on retrospective memory as opposed to prospective memory (remembering to remember intended actions), a type of memory increasingly found to be implicated in MCI. 20 Measures of prospective memory may be as sensitive, or more sensitive than, traditional measures of retrospective memory in MCI patients. 21,22 An alternative possibility for prevention trials is the deployment of novel tests to select samples in preclinical states. To this end, there has been a focus on the development of neuropsychological tests that tap into abilities such as 1) associative memory necessary for "binding" representations of two or more stimuli, 2) pattern separation necessary to distinguish between two similar memory representations, and 3) prospective memory required to remember a delayed intention to act at a certain time in the future. At least two of these types of tests (face-name associative memory and pattern separation) have been shown to be related to AD imaging biomarkers (Pittsburgh Compound B [PiB] imaging and functional magnetic resonance imaging [fMRI], respectively) and are being incorporated as secondary measures into the A4 prevention trial. 23 More recent developments in biomarker imaging data suggests that beta amyloid deposition may have a predilection for areas within the anterior and posterior cingulate, precuneus, and selected regions of the frontal, temporal, and parietal lobes, which can be visualized earlier than medial temporal lobe atrophy. This may give rise to subtle dysfunction in specific aspects of memory, efficiency of cognitive processing, and executive function that may not be detectable with typical clinical trials outcome measures. L oewenstein et al 2 4 r ecently developed several measures sensitive to impairments in otherwise unimpaired preclinical individuals. One of these, the Loewenstein-Acevedo Scales of S emantic Interference and Learning (LASSI-L 24 ) has been shown to have good psychometric properties and robust sensitivity and specificity in differentiating normal controls from preclinical states identified with MRI. The LASSI-L has high re-test reliability in more impaired patients using National Institute on Aging–Alzheimer's Association (NIA-AA) criteria for MCI due to AD (MCI-AD 24 ). Similar findings were evident for mildly demented AD patients. 25,26 Discriminative validity studies were conducted to distinguish between 34 MCI and 47 cognitively normal subjects using step-wise logistic regression, yielding a sensitivity of 87.9 percent, a specificity of 91.5 percent, and an overall correct classification rate of 90.0 percent. This far exceeded classification rates from traditional neuropsychological measures, such as delayed recall of passages and category fluency. 2 6 The LASSI-L also correlated with MRI measures of medial temporal atrophy and with high amyloid load in the precuneus and posterior cingulate and temporal regions. 24 Recent findings by Loewenstein et al 2 6 have shown that the inability to recover from the effects of proactive interference is highly predictive of regional and total amyloid load among community-dwelling elders with no clinical diagnosis of MCI and normal scores on traditional neuropsychological measures. Similarly, Parra et al 27,28 have developed a short-term visual memory binding test (SVMB) that incorporates a paradigm measuring the ability to determine a change in features, such as shape or color, or changes in shape- color binding. They have found that the SVMB test was able to identify impairments among asymptomatic carriers of the E280A single presenilin-1 mutation, which causes autosomal dominant AD. 28 Moreover, the SVMB test is sensitive to early AD, 27 and can distinguish between early AD and other neurodegenerative conditions, as well as between AD and depression. 27–29 A r elationship between SVMB test performance and early changes in the hippocampus and surrounding medial temporal regions has been described. 30 Moreover, because the shape–color c ombinations in the SVMB test are quickly overwritten in short-term visual memory, they are not susceptible to practice effects. Given that the SVMB test has been shown to be able to detect memory-binding deficits in asymptomatic carriers of Presenilin 1 mutations, it may be sensitive to memory changes among preclinical subjects who have elevated amyloid load. Finally, the use of non-verbal information and reliance only on change detection makes the SVMB test promising for studies in multicultural groups. ASSESSMENT OF FUNCTIONAL SKILLS AND OUTCOMES There is recent evidence to suggest that subtle but measureable and detectable functional impairment may occur in the early phases of AD. The traditional clinical view in the Alzheimer's dementia field has been that functional impairment first emerges in the formal dementia stage. However, the intriguing proposition that detectable functional change actually commences much earlier in the AD disease process, in MCI, and possibly as early as the preclinical stage, is receiving increasing attention. 31–34 Prior research by several groups 35–39 has shown that complex functional skills (independent activities of daily life, or IADLs) show impairment in patients with MCI and continue to decline over time. 36 In particular, financial capacity is a higher order functional skill that is highly sensitive to MCI and mild AD. 36,37,39 The vulnerability of financial capacity in MCI and AD raises the possibility that measurable financial decline may also occur and is detectable in persons with preclinical AD. 34 Performance-based measures have been found to be sensitive to treatment effects for both pharmacological and rehabilitation interventions in severe mental illness. Further, several studies have shown that performance-based

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