Florbetapir F18 has been approved by the Food and Drug Administration for in vivo assessment of amyloid pathology in patients undergoing evaluation for Alzheimer disease (AD). The aim of this study was to determine the impact of amyloid imaging on the diagnoses and management of patients undergoing evaluation for cognitive decline. Patients were recruited to participate at 19 clinical sites. The site physician provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plan for diagnostic evaluation and management both before and after receiving the results from amyloid imaging with florbetapir F18. Analyses compared the frequency of AD and non-AD diagnoses, plans for ancillary testing, and intended patient management before and after florbetapir imaging. A total of 229 patients participated in the trial (113 amyloid positive, 116 amyloid negative). After receiving the results of the florbetapir scan, diagnosis changed in 125/229, or 54.6% [95% confidence intervals (CI), 48.1%-60.9%], of cases, and diagnostic confidence increased by an average of 21.6% (95% CI, 18.3%-24.8%). A total of 199/229 or 86.9% (95% CI, 81.9%-90.7%) of cases had at least 1 change in their management plan. Intended cholinesterase inhibitor or memantine treatment increased by 17.7% (95% CI, 11.8%-25.8%) of all cases with positive scans and decreased by 23.3% (95% CI, 16.5%-31.8%) of all those with negative scans. Among subjects who had not yet undergone a completed work up, planned brain structural imaging (computed tomographic/magnetic resonance imaging) decreased by 24.4% (95% CI, 17.5%-32.8%) and planned neuropsychological testing decreased by 32.8% (95% CI, 25.0%-41.6%). In summary, amyloid imaging results altered physician's diagnostic thinking, intended testing, and management of patients undergoing evaluation for cognitive decline.

Objective To examine differences in lower-extremity function in cognitive healthy older persons, older persons with mild cognitive impairment (MCI), and older persons with Alzheimer’s disease (AD). Design Descriptive study. Setting University Alzheimer’s disease clinical and research program. Participants Older persons (N=66) were studied (mean age, 76.7y); 22 were cognitively normal, 22 were diagnosed with probable MCI, 22 were diagnosed with probable AD. Interventions Not applicable. Main Outcome Measures Lower-extremity function was assessed by the four-meter walk test (4MWT), Timed Up & Go (TUG) test, and sit-to-stand (STS) test. Results Analysis of variance, adjusting for covariates, revealed that performance on the 4MWT was significantly lower in the MCI and AD groups as compared with controls. TUG test performance was worse in the AD group compared with controls. No significant group differences were found for STS performance. Conclusions These results suggest an association between cognitive impairment and lower-limb function in older persons Walking speed could be evaluated for its possible utility in screening older persons at risk for cognitive impairment and falls.

Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f2 = 0.137) and memory decline (p = 0.006, Cohen’s f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited ante-mortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16.93% increase per year) for the proband, and -30.75 ml/year (2.77% decrease per year) and +5.01 ml/year (3.11% increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.

Measures of episodic memory are often used to identify Alzheimer's disease (AD) and mild cognitive impairment (MCI). The Neuropsychological Assessment Battery (NAB) List Learning test is a promising tool for the memory assessment of older adults due to its simplicity of administration, good psychometric properties, equivalent forms, and extensive normative data. This study examined the diagnostic utility of the NAB List Learning test for differentiating cognitively healthy, MCI, and AD groups. One-hundred fifty-three participants (age: range = 57-94 years, M = 74 years, S. D. = 8 years; sex: 61% women) were diagnosed by a multidisciplinary consensus team as cognitively normal, amnestic MCI (aMCI; single and multiple domain), or AD, independent of NAB List Learning performance. In univariate analyses, receiver operating characteristics curve analyses were conducted for four demographically-corrected NAB List Learning variables. Additionally, multivariate ordinal logistic regression and five-fold cross-validation was used to create and validate a predictive model based on NAB List Learning test T-scores. At optimal cutoff scores, univariate sensitivity values ranged from .58 -.92 and univariate specificity values ranged from .52 -.97. Multivariate ordinal regression produced a model that classified individuals with 80% accuracy and good predictive power. KeywordsDementia; Sensitivity and Specificity; Differential Diagnosis; Neuropsychology; Neuropsychological Tests; Memory Address correspondence to: Robert A. Stern, Associate Professor of Neurology, Co-Director, Alzheimer's Disease Clinical and Research Program, Boston University School of Medicine, Robinson 7800, 72 East Concord Street, Boston, MA 02118-2526, phone: 617-638-5678, fax: 617-414-1197, email: bobstern@bu.edu. Robert A. Stern is one of the developers of the NAB and receives royalties from its publisher, Psychological Assessment Resources Inc.Portions of this manuscript were presented at the International Conference on Alzheimer's Disease, Chicago, July 2008. With this exception, the information in this manuscript and the manuscript itself has never been published either electronically or in print.A scoring program based on the multiple ordinal regression model reported in this manuscript is available as an electronic addendum to this manuscript. et al., 1989). List learning tests have been shown to possess adequate sensitivity and specificity in differentiating participants with MCI (Mdn: sensitivity = .67, specificity = .86) (Ivanoiu et al., 2005;Karrasch et al., 2005;Schrijnemaekers et al., 2006;Woodard et al., 2005) and AD (Mdn: sensitivity = .80, specificity = .89) from controls (Bertolucci et al., 2001;Derrer et al., 2001;Ivanoiu et al., 2005;Karrasch et al., 2005;Kuslansky et al., 2004;Salmon et al., 2002;Schoenberg et al, 2006), as well as AD from MCI (Mdn: sensitivity = .85, specificity = .83) (de Jager et al., 2003). NIH Public AccessThe current study was undertaken in order to evaluate the diagnostic utility of a new list learning ...