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Introduction This clinical trial aimed to determine whether in‐car video feedback about unsafe driving events (UDE) to cognitively impaired older drivers and family members leads to a reduction in such driving behaviors. Methods We randomized 51 cognitively impaired older drivers to receive either (1) a weekly progress report with recommendations and access to their videos, or (2) video monitoring alone without feedback over 3 months. Results UDE frequency/1000 miles was reduced by 12% in feedback (rate ratio [RR] = 0.88, 95% confidence interval [CI] = .58–1.34), while remaining constant with only monitoring (RR = 1.01, 95% CI = .68–1.51). UDE severity/1000 miles was reduced by 37% in feedback (RR = 0.63, 95% CI = .31–1.27), but increased by 40% in monitoring (RR = 1.40, 95% CI = .68–2.90). Cognitive impairment moderated intervention effects (P = .03) on UDE frequency. Discussion Results suggest the potential to improve driving safety among mild cognitively impaired older drivers using a behavior modification approach aimed at problem behaviors detected in their natural driving environment.

Author(s): Korthauer, Laura E; Denby, Charles; Molina, David; Wanjiku, Janet; Daiello, Lori A; Drake, Jonathan D; Grill, Josh D; Ott, Brian R | Abstract: IntroductionThe goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting.MethodsPrimary care providers (PCPs; Nn=n6) referred patients (Nn=n94; Mn=n63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification.ResultsCompared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes.DiscussionA referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry.

Background Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer’s disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1–4, 2017). Previously, we established the scopolamine challenge test (SCT) as a “cognitive stress test” screening measure to identify individuals at risk for AD (Alzheimer’s & Dementia 10(2):262–7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. Methods Older adults (N = 63, aged 55–75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. Results Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. Conclusions Cognitive response to the SCT (Alzheimer’s & Dementia 10(2):262–7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Objectives: Patients with Alzheimer’s disease (AD) demonstrate deficits in cross-cortical feature binding distinct from age-related changes in selective attention. This may have consequences for driving performance given its demands on multisensory integration. We examined the relationship of visuospatial search and binding to driving in patients with early AD and elderly controls (EC). Methods: Participants (42 AD; 37 EC) completed search tasks requiring either luminance-motion (L-M) or color-motion (C-M) binding, analogs of within and across visual processing stream binding, respectively. Standardized road test (RIRT) and naturalistic driving data (CDAS) were collected alongside clinical screening measures. Results: Patients performed worse than controls on most cognitive and driving indices. Visual search and clinical measures were differentially related to driving behavior across groups. L-M search and Trail Making Test (TMT-B) were associated with RIRT performance in controls, while C-M binding, TMT-B errors, and Clock Drawing correlated with CDAS performance in patients. After controlling for demographic and clinical predictors, L-M reaction time significantly predicted RIRT performance in controls. In patients, C-M binding made significant contributions to CDAS above and beyond demographic and clinical predictors. RIRT and C-M binding measures accounted for 51% of variance in CDAS performance in patients. Conclusions: Whereas selective attention is associated with driving behavior in EC, cross-cortical binding appears most sensitive to driving in AD. This latter relationship may emerge only in naturalistic settings, which better reflect patients’ driving behavior. Visual integration may offer distinct insights into driving behavior, and thus has important implications for assessing driving competency in early AD. (JINS, 2018, 24, 486–497)

Introduction Links between preclinical Alzheimer's disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. Methods One hundred four OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries, and self-reported their driving habits. Results Higher values of cerebrospinal fluid (CSF) tau/Aβ 42 and phosphorylated tau (ptau 181 )/Aβ 42 ratios, but not uptake on Pittsburgh compound B amyloid imaging ( P = .12), predicted time to a rating of marginal or fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70–19.53), P = .005 for CSF tau/Aβ 42 ; 6.19 (1.75–21.88), and P = .005 for CSF ptau 181 /Aβ 42 . Discussion Preclinical AD predicted time to receiving a marginal or fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.

Objective: This study aimed to compare the sensitivity and specificity of a modified version of the Minnesota Cognitive Acuity Screen (MCAS-m), by adding learning and recognition memory components, to the original version MCAS to distinguish amnestic mild cognitive impairment (aMCI) from healthy controls (HCs). Methods/Design: A total of 30 individuals with aMCI and 30 HCs underwent neuropsychological testing, neurologic examination, laboratory, and brain imaging tests. Once diagnosis was confirmed, participants completed the MCAS and MCAS-m in counterbalanced order. Results: The average administration time was 12.6 minutes for the MCAS and 13.5 minutes for the MCAS-m. Receiver operating characteristic curve analyses showed that the MCAS-m demonstrated 97% sensitivity and 97% specificity for distinguishing between aMCI and HC versus 97% and 87%, respectively, for the original MCAS in this sample. Conclusions: Both the MCAS and the MCAS-m were highly sensitive when distinguishing between normal cognition and aMCI; however, the MCAS-m demonstrated a 10% increase in specificity compared to the original version. Improved specificity is particularly relevant to screening in larger community samples with lower base rates of MCI than clinic populations. This modified screening measure presents a brief and cost-effective tool for identifying MCI. Given the risk of progression from aMCI to Alzheimer disease dementia (AD), the MCAS-m represents a modest improvement in telephone-administered methods for the early detection of AD.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Introduction Postmortem studies suggest that fibrillar brain amyloid places people at higher risk for hazardous driving in the preclinical stage of Alzheimer's disease (AD). Methods We administered driving questionnaires to 104 older drivers (19 AD, 24 mild cognitive impairment, and 61 cognitive normal) who had a recent 18 F-florbetapir positron emission tomography scan. We examined associations of amyloid standardized uptake value ratios with driving behaviors: traffic violations or accidents in the past 3 years. Results The frequency of violations or accidents was curvilinear with respect to standardized uptake value ratios, peaking around a value of 1.1 (model r 2 = 0.10, P = .002); moreover, this relationship was evident for the cognitively normal participants. Discussion We found that driving risk is strongly related to accumulating amyloid on positron emission tomography, and that this trend is evident in the preclinical stage of AD. Brain amyloid burden may in part explain the increased crash risk reported in older adults.

Background Identifying effective and accessible interventions for dementia caregivers is critical as dementia prevalence increases. Objective Examine the effects of a telephone-based intervention on caregiver well-being. Design Randomized, controlled trial. Setting Academic medical center. Participants Two hundred and fifty distressed, family, dementia caregivers. Intervention Caregivers randomized to receive 16 telephone contacts over 6 months of either the Family Intervention: Telephone Tracking—Caregiver (FITT-C) or Telephone Support (TS). Outcome Primary outcome variables were family caregivers' depressive symptoms, burden, and reactions to care recipients' behavior problems at 6 months. Results The FITT-C intervention resulted in significantly improved caregiver depressive symptoms ( P = .003; 27% net improvement) and less severe reactions to care-recipient depressive behaviors ( P = .009; 29% net improvement) compared with the control condition (TS). Conclusion An entirely telephone-based intervention improves caregivers' depressive symptoms and reactions to behavior problems in the care recipient and is comparable with reported results of face-to-face interventions.

Despite their growing use, few studies have examined the associations between patients' performance on brief telephone-based cognitive assessments and their functional status. The purpose of this study was to examine the relationship between the Minnesota Cognitive Acuity Screen (MCAS), a very brief telephone-based dementia screening instrument, and functional impairment as rated by the Clinical Dementia Rating (CDR) scale in a sample of 176 individuals diagnosed with mild cognitive impairment or dementia. Results showed lower MCAS scores were correlated with poorer daily function as measured by CDR global scores and domain scores, and the MCAS orientation subscale was one of the strongest subscales in predicting functional status as it was uniquely predictive of all CDR domains. Findings suggest the MCAS appears to be useful in predicting patients' level of daily function and may be useful for quickly and easily monitoring patients' cognitive and functional status over time.

Background Patients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E ( APOE ) genotype are associated with the rate of functional decline in MCI. Methods Participants were 164 healthy controls, 258 MCI patients, and 103 patients with mild Alzheimer's disease (AD), enrolled in the Alzheimer's Disease Neuroimaging Initiative. They underwent brain MRI scans, APOE genotyping, and completed up to six biannual Functional Activities Questionnaire (FAQ) assessments. Random effects regressions were used to examine trajectories of decline in FAQ across diagnostic groups, and to test the effects of ventricle-to-brain ratio (VBR) and APOE genotype on FAQ decline among MCI patients. Results Rate of decline in FAQ among MCI patients was intermediate between that of controls and mild AD patients. Patients with MCI who converted to mild AD declined faster than those who remained stable. Among MCI patients, increased VBR and possession of any APOE ɛ4 allele were associated with faster rate of decline in FAQ. In addition, there was a significant VBR by APOE ɛ4 interaction such that patients who were APOE ɛ4 positive and had increased atrophy experienced the fastest decline in FAQ. Conclusions Functional decline occurs in MCI, particularly among patients who progress to mild AD. Brain atrophy and APOE ɛ4 positivity are associated with such declines, and patients who have elevated brain atrophy and are APOE ɛ4 positive are at greatest risk of functional degradation. These findings highlight the value of genetic and volumetric MRI information as predictors of functional decline, and thus disease progression, in MCI.

This study examined the ability of computerized maze test performance to predict the road test performance of cognitively impaired and normal older drivers. The authors examined 133 older drivers, including 65 with probable Alzheimer disease, 23 with possible Alzheimer disease, and 45 control subjects without cognitive impairment. Subjects completed 5 computerized maze tasks employing a touch screen and pointer as well as a battery of standard neuropsychological tests. Parameters measured for mazes included errors, planning time, drawing time, and total time. Within 2 weeks, subjects were examined by a professional driving instructor on a standardized road test modeled after the Washington University Road Test. Road test total score was significantly correlated with total time across the 5 mazes. This maze score was significant for both Alzheimer disease subjects and control subjects. One maze in particular, requiring less than 2 minutes to complete, was highly correlated with driving performance. For the standard neuropsychological tests, highest correlations were seen with Trail Making A (TrailsA) and the Hopkins Verbal Learning Tests Trial 1 (HVLT1). Multiple regression models for road test score using stepwise subtraction of maze and neuropsychological test variables revealed significant independent contributions for total maze time, HVLT1, and TrailsA for the entire group; total maze time and HVLT1 for Alzheimer disease subjects; and TrailsA for normal subjects. As a visual analog of driving, a brief computerized test of maze navigation time compares well to standard neuropsychological tests of psychomotor speed, scanning, attention, and working memory as a predictor of driving performance by persons with early Alzheimer disease and normal elders. Measurement of maze task performance appears to be useful in the assessment of older drivers at risk for hazardous driving.

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be safe and to have beneficial effects on cognition, function, behavior, and global patient status in patients with Alzheimer’s disease (AD) in studies lasting 3–6 months. It is approved in the U.S. and Europe for the treatment of moderate to severe AD and is currently under investigation for mild to moderate AD. To evaluate the long-term safety of memantine in patients with mild to moderate AD and to investigate the tolerability of once-daily dose administration. This 28-week study enrolled 314 patients with mild to moderate AD who had completed a 24-week, double-blind, placebo-controlled lead-in clinical trial of memantine in AD. Following an 8-week double-blind dose titration phase (used to assess the tolerability of different dosing regimens), subjects were assigned to continuous open label memantine (10 mg, bi.d.) treatment for 20 weeks. Safety outcome measures included treatment-emergent adverse events (AEs), deaths, vital signs, electrocardiograms, and laboratory parameters. During the 28-week study (Phase A + Phase B), the most common AEs were falls and other injuries (both 10.8%). AEs resulted in treatment discontinuation in 6.7% of patients. Discontinuations due to AEs were similar in the once-daily dosing groups compared to the twice-daily dosing groups. During dose titration, completion rates were greater than 90% for both groups. Conversion to once-daily dosing in patients already receiving twice-daily doses of memantine was also well tolerated. Memantine monotherapy in patients with mild to moderate AD is safe and well tolerated for at least one year. Once-daily dosing during titration and short-term maintenance therapy is safe and well tolerated.

The purpose of this article is to review the literature on the ability of individuals with dementia to drive an automobile. Based on a review of the literature, several factors were identified that may be useful in differentiating between people with dementia who presently remain safe drivers from those who have progressed to impaired driving. These factors include disease duration and severity, sex, patient self-assessment, family assessment, neuropsychological measures, findings on road evaluations, and driving simulator testing. The approach of the physician to driving and dementia is addressed, including in-office screening, referral for on-road driving assessments, and the potential for physician reporting to state agencies.

The authors previously reported that subcortical hyperintensity (SH) and whole-brain volume (WBV) each covary with different subscale scores of the Mattis Dementia Rating Scale (MDRS) among vascular dementia (VaD) patients. The present longitudinal analysis examined these relationships for change. The authors found that SH volume increased and WBV decreased significantly over 12 months. At baseline, SH volume accounted for significant variance in MDRS total score and every subscale score, except Memory. WBV was unrelated to any MDRS measure. After 12 months, SH volume was related only to the Construction subscale score, whereas WBV accounted for the majority of variance in Attention and Memory subscale performance. These findings indicate that although SH volume increases with disease progression, the relative impact of SH volume on cognitive status decreases among patients with advanced VaD.

The relationship between MRI findings (i.e., subcortical hyperintensities; SH, whole brain volume) and the cognitive dysfunction of vascular dementia (VaD) was examined. Participants included 24 persons that met NINDS-AIREN criteria for VaD (MMSE = 19.9 ± 4.2) and underwent comprehensive neuropsychological assessment and MRI brain imaging. The volume of subcortical hyperintensities (SH) was strongly associated with executive–psychomotor performance, but not with performance across other cognitive domains or global cognitive functional level. Conversely, WBV was strongly associated with global cognitive functioning and performance across most cognitive domains (memory, language, visual integration), but not with executive–psychomotor functioning. The failure of SH to account for either the global dementia evident in these VaD patients or impairments across most cognitive domains suggests that deep subcortical white matter disease may only indirectly contribute to the global cognitive dysfunction of VaD. That WBV emerged as a stronger correlate of dementia raises further questions regarding the cerebral mechanisms that contribute to the development of VaD. (JINS, 2002, 8, 743–752.)

The relationship of behavioral disturbance and dementia severity to activities of daily living (ADLs) in vascular dementia (VaD) was examined in baseline data for 29 VaD patients. A series of stepwise regression analyses was conducted to examine the extent to which dementia severity, apathy, disinhibition, and executive dysfunction predict ADLs (total, basic, and instrumental). For total ADLs, apathy accounted for 36% of the variance and dementia severity accounted for an additional 15%. For basic ADLs, apathy accounted for 27% of the variance. Dementia severity, executive dysfunction, and disinhibition were not significantly associated with basic ADLs. For instrumental ADLs, dementia severity accounted for 37% of the variance and apathy accounted for an additional 14%. These findings highlight the importance of apathy as an independent factor associated with functional independence beyond general cognitive abilities.

teristics (i.e. demographics), primary stressors (i.e. participants’ cognitive, functional and behavioural decline over time), subjective stressors (i.e. distress due to participant’s behavioural symptoms and burden related to helping with everyday tasks), secondary role strains (i.e. caring for others), protective factors (i.e. coping) and personal stressors (i.e. self-rated health and quality of life). Over four years 37 participants developed dementia (7%), while 133 (24%) met Winblad criteria for mild cognitive impairment (35% incident cases). Our model fitted the data well (c 2/df1⁄42.517; CFI1⁄4.934; PCFI1⁄4.799; SRMR1⁄4.069; RMSEA1⁄4.052; PCLOSE1⁄4.172). Although change on all variables was subtle and informants overall did not experience significant increases in distress longitudinally (slope mean1⁄4-.03, p1⁄4.410), there was significant interindividual variability with respect to distress trajectories (slope variance1⁄4.10, p

Background Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." Methods Healthy older adults ( n = 26, aged 55–75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. Results There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite ( d ≈ 0.50) that were all unrelated to body mass. Conclusions A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (T max ) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.