Faculty Bibliography

INTRODUCTION: The Severe Impairment Battery (SIB) is validated for assessing cognition in patients with severe dementia. The current analysis aimed to further investigate the cognitive efficacy of rivastigmine capsules, as assessed by SIB factor scores, in patients with moderately severe-to-severe Alzheimer's disease (AD). METHODS: This was a retrospective analysis of a 26-week, multicenter, randomized, double-blind, placebo-controlled study of oral rivastigmine conducted in Spain. Previously reported outcome measures included the full SIB. Current analyses examined calculated scores and effect sizes for the change from baseline at Week 26 on: newly defined SIB subscales (derived by a factor analysis of the 40 SIB items, using the PROC FACTOR function (SAS)); previously defined memory, language and praxis subscales (derived by previous analysis of the nine SIB domains); and the individual SIB items. Treatment differences were assessed. RESULTS: SIB data were provided by 104 rivastigmine-treated patients and 106 patients receiving placebo (Intent-To-Treat Last Observation Carried Forward population). Significantly less decline was observed on the previously defined memory and language subscales, and the newly defined working memory/memory subscale in rivastigmine-treated patients (all P < 0.05 versus placebo). Calculation of effect sizes demonstrated numerically greater efficacy of rivastigmine versus placebo on each of the subscales, and a broad range of SIB items; greatest effect sizes were observed on SIB items assessing the current month (effect size = 0.30) and digit span series (effect size = 0.33). CONCLUSIONS: These data suggest the observed efficacy of rivastigmine in moderately severe-to-severe AD is likely a cumulative effect across a range of tasks. Rivastigmine demonstrates broad cognitive efficacy in this patient population.

The measurement of effort is now considered to be an important component of neuropsychological assessment. In addition to stand-alone measures, built-in, or embedded measures of effort have been derived for a limited number of standard neurocognitive tests. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used brief battery, employed as a core diagnostic tool in dementia and as a neurocognitive screening battery or tracking/outcome measure in a variety of other disorders. An effort index (EI) for the RBANS has been published previously (Silverberg, N. D., Wertheimer, J. C., & Fichtenberg, N. L. 2007. An EI for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical Neuropsychology, 21 (5), 841-854), but it has been reported to result in high false positive rates when applied to patients with "true" amnesia (e.g., Alzheimer's disease). We created a new effort scale (ES) for the RBANS based on the observation of patterns of free recall and recognition performance in amnesia versus inadequate effort. The RBANS ES was validated on a sample of patients with amnestic disorders and a sample of mild traumatic brain injury participants who failed a separate measure of effort. The sensitivity and specificity of the new ES was compared with the previously published EI. Receiver-operating characteristic analyses demonstrated much better sensitivity and specificity of the ES, with a marked reduction in false positive errors. Application and limitations of the RBANS ES, including indications for its use, are discussed.

Background: Biomarkers such as amyloid beta (e.g. Ab42) and hyperphosphorylated tau (e.g. pTau181) in cerebral spinal fluid (CSF) and hippocampal volume loss measured by magnetic resonance imaging (MRI) are useful for identifying cognitively normal elderly likely to have "preclinical" Alzheimer's disease (AD), but such methods are invasive and/or expensive. We investigated whether cognitive tasks dependent on brain regions affected in early AD can serve as proxies of AD biomarkers. Research indicates that the hippocampal formation (Hipp), particularly CA3/dentate gyrus (CA3/DG) and the entorhinal cortex (EC) are affected in preclinical AD. Therefore, we hypothesized that performance on a CA3/DG-dependent spatial pattern separation task (PST) and a Hipp/ EC-dependent discrimination and generalization task (DGT) would be impaired in cognitively normal individuals with biomarker evidence for AD. Methods: We collected initial data on our tasks from 31 cognitively normal NYU Alzheimer's Disease Center/Center for Brain Health participants who had MRI and who also provided CSF for longitudinal studies. In the PST, participants discriminated between two identical dots, one in a previously viewed location and one in a new location. In the DGT, participants learned to discriminate pairs of stimuli determined by shapes or colors in a discrimination phase, then had to generalize the "preferred" shapes and colors to novel stimuli in a generalization phase. Results: Linear regression analyses (with age and years of education as covariates) were used to determine whether task performance correlates with bilateral Hipp volume (used as a surrogate for CA3/DG and controlled for total intracranial volume) and CSF biomarkers. Performance on the PST correlates with bilateral Hipp volume (n = 31; R 2 = 0.151, P = 0.004) and CSF Ab42/pTau181 ratio (n = 26; R 2 = 0.182, P = 0.026). Performance on generalization correlates with Ab42 (R 2 = 0.182, P = 0.026) and marginally with Ab42/pTau181 ratio (R 2 = 0.119, P = 0.079). Performance on discrimination correlates with Ab42/ pTau181 ratio only (R 2 = 0.159, P = 0.039). A standard memory test (NYU Paragraph Recall) shows no significant correlations. Conclusions: These preliminary results are consistent with our hypothesis that cognitive tasks dependent on brain regions affected by early AD pathology may provide a non-invasive and cost-effective method to identify and track change in clinically normal individuals at high risk for progressing to theMCI and dementia stages of AD

Alzheimer's disease (AD) is the most common and most studied cause of dementia. Significant advances have been made since the first set of clinical criteria for AD were put forth in 1984 that are now captured in the new criteria for AD published in 2011. Key features include recognition of a broad AD spectrum (from preclinical to mild cognitive impairment to AD dementia) and requirement of AD biomarkers for diagnosis. Correctly diagnosing dementia type is increasingly important in an era when potential disease-modifying agents are soon to be marketed. The typical AD dementia syndrome has at its core, an amnestic syndrome of the hippocampal type, followed by associated deficits in word-finding, spatial cognition, executive functions and neuropsychiatric changes. Atypical presentations of AD have also been identified that are presumed to have a different disease course. It can be difficult to distinguish between the various dementia syndromes given the overlap in many common clinical features across the dementias. The clinical difficulty in diagnosis may reflect the underlying pathology, as AD often co-occurs with other pathologies at autopsy, such as cerebrovascular disease or Lewy bodies. Neuropsychological evaluation has provided clinicians and researchers with profiles of cognitive strengths and weaknesses that help to define the dementias. There is yet no single behavioral marker that can reliably discriminate AD from the other dementias. The combined investigation of cognitive and neurobehavioral symptoms coupled with imaging markers could provide a more accurate approach for differentiating between AD and other major dementia syndromes in the future

The authors characterized the cognitive, adaptive, and behavioral sequelae of Coffin-Siris (CS) syndrome and epilepsy in a 7.5-year-old child. Little is known about the early neurobehavioral presentation of CS. Clinical features consistent with this genetic anomaly include underdeveloped tips and nails of the fifth fingers, extended infranasal depression, and craniofacial abnormalities. MRI findings often reveal callosal agenesis. The authors conducted a neuropsychological evaluation and obtained parental ratings of behavioral and adaptive functioning. Attentional abilities were limited. As assessed by the Mullen Scales of Early Learning, receptive language abilities (age equivalent [AE]: 3-3) were relatively stronger than expressive skills (AE: 1-4). Adaptive functioning was low across all domains (Vineland Adaptive Behavior Composite AE: 1-9). On the Behavior Assessment for Children (BASC-2), social skills dysfunction, stereotyped and self-stimulatory behaviors, restricted interests, ritualistic play, and inappropriate object usage were noted. No significant mood disturbances were endorsed. Study findings indicate a diffuse pattern of neurobehavioral deficits in a child with CS and epilepsy. Further clinical assessment and research should include multidimensional assessment techniques, including evaluation of adaptive behavior, in an effort to capture the full range developmental sequelae in children with CS

Effort assessment is of particular importance in pediatric epilepsy where neuropsychological findings may influence treatment decisions, especially if surgical interventions are being considered. The present investigation examines the Test of Memory Malingering (TOMM) in 60 children and adolescents with epilepsy. The overall pass rate for the sample was 90%. TOMM scores were unrelated to age, though there was a significant correlation between TOMM Trial 2 scores and intelligence estimates. Overall, the TOMM appears to be a valid measure of effort in young epilepsy patients, though caution should be used when interpreting scores for those with very low IQ, especially if behavioral problems are also evident. Caution should also be exercised in interpreting scores in children with ongoing interictal epileptiform activity that may disrupt attention

Individuals with amnestic mild cognitive impairment (aMCI) often complain of difficulty remembering to carry out intended actions, consistent with findings of impaired prospective memory (PM) in this population. In this study, individuals with aMCI (N = 27) performed worse than healthy controls (N = 27) on the Memory for Intentions Screening Test (Raskin, 2004), including on time- and event-based subscales, and recognition of the intentions. The aMCI participants made more errors overall, but the proportion of the various error types did not differ between the two groups. Across all error types, both groups made more retrospective than prospective errors, especially on event-based PM tasks. Overall, the findings suggest that PM impairment in aMCI is associated with deficient cue detection involving both automatic (as in event-based tasks) and more strategic detection (as in time-based tasks) processes. These difficulties are likely due to a combination of problematic retrospective episodic memory (e.g., reduced encoding and/or consolidation of cue-intention pairings) and executive functions (e.g., decreased self-initiation, attention switching, and/or inhibition on memory tasks). Formal assessment of PM may help characterize the nature of the memory impairment among individuals with aMCI in clinical neuropsychological evaluations