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Introduction: Manual motor problems have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the specific aspects that are affected, their neuropathology, and potential value for classification modeling is unknown. The current study examined if multiple measures of motor strength, dexterity, and speed are affected in MCI and AD, related to AD biomarkers, and are able to classify MCI or AD., Methods: Fifty-three cognitively normal (CN), 33 amnestic MCI, and 28 AD subjects completed five manual motor measures: grip force, Trail Making Test A, spiral tracing, finger tapping, and a simulated feeding task. Analyses included (1) group differences in manual performance; (2) associations between manual function and AD biomarkers (PET amyloid β, hippocampal volume, and APOE ε4 alleles); and (3) group classification accuracy of manual motor function using machine learning., Results: Amnestic MCI and AD subjects exhibited slower psychomotor speed and AD subjects had weaker dominant hand grip strength than CN subjects. Performance on these measures was related to amyloid β deposition (both) and hippocampal volume (psychomotor speed only). Support vector classification well-discriminated control and AD subjects (area under the curve of 0.73 and 0.77, respectively) but poorly discriminated MCI from controls or AD., Conclusion: Grip strength and spiral tracing appear preserved, while psychomotor speed is affected in amnestic MCI and AD. The association of motor performance with amyloid β deposition and atrophy could indicate that this is due to amyloid deposition in and atrophy of motor brain regions, which generally occurs later in the disease process. The promising discriminatory abilities of manual motor measures for AD emphasize their value alongside other cognitive and motor assessment outcomes in classification and prediction models, as well as potential enrichment of outcome variables in AD clinical trials., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain understudied, especially with how they compare to biomarkers of AD., Objective: The current study sought to add to this growing literature., Methods: Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 status., Results: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons., Conclusion: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.

Recently, two new recognition subtests for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were developed and initially validated in a cohort of older adults who were cognitively intact or classified as amnestic Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD). The current paper extends that validation by comparing the recall and recognition subtests of the RBANS, including the existing and recently developed scores, to three commonly used biomarkers in AD in an expanded sample from the initial validation. One hundred fifty-four older adults (65 intact, 46 MCI, 43 AD) were administered the RBANS, which included the recently developed subtests for Story Recognition and Figure Recognition (hits, false positives, total correct), as part of a study on memory and biomarkers. Participants also completed magnetic resonance imaging to obtain hippocampal volumes, positron emission tomography to obtain amyloid plaque deposition, and a blood draw to obtain APOE ε4 status. Whereas correlations between recall scores and biomarkers tended to be moderate (average r = ±0.48), these correlations were comparable across the three recognition total scores (average r = ±0.42), but tended to be lower for recognition hits (average r = ±0.28) and false positives (average r = ±0.38). These results further validate the existing and recently developed recognition scores on the RBANS as providing useful information about brain and genetic pathology in older adults with intact and impaired cognitive functioning.

Background: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer's disease (AD), including brain amyloid plaque density. However, less is known about if changes in the RBANS across time are also related to brain amyloid deposition. The current study sought to expand on prior work by examining the relationship between changes over time on the RBANS and amyloid deposition via positron emission tomography (PET)., Method: One-hundred twenty-six older adults with intact or impaired cognition and daily functioning underwent repeat assessment with the RBANS across nearly 16 months, as well as had a baseline amyloid PET scan., Results: In the entire sample, amyloid deposition was significantly related to change on all five Indexes and the Total Scale score of the RBANS, with greater amyloid being associated with worsening cognition. This pattern was also observed in 11 of 12 subtests., Conclusions: Whereas prior studies have identified a relationship between baseline RBANS and amyloid status, the current findings support that changes in the RBANS are also indicative of AD brain pathology, even if these findings are mediated by cognitive status. Although replication in a more diverse sample is needed, these results continue to support the use of the RBANS in AD clinical trials.

Background: The Quick Dementia Rating System (QDRS) is a brief, informant-reported dementia staging tool that approximates scores on the Clinical Dementia Rating Scale in patients with Alzheimer's disease (AD)., Objective: The current study sought to examine change in the QDRS across time, which is necessary for clinical and research efforts., Methods: One-hundred ten older adults (intact, mild cognitive impairment [MCI], mild AD, classified with Alzheimer's Disease Neuroimaging Initiative criteria) were rated on the QDRS by an informant and had an amyloid positron emission tomography scan at baseline. The informant re-rated each participant on the QDRS after one year. Dependent t-tests compared the entire sample and various subgroups (e.g., cognitive status, amyloid status) on baseline and follow-up QDRS scores., Results: In the entire sample, the Total score on the QDRS significantly increased (i.e., worsened) on follow-up (p < 0.001). When subgroups were analyzed, the MCI and mild AD subjects showed increasing (i.e., worsening) QDRS Total scores (both p < 0.001), but the intact subjects remained stable over time (p = 0.28). Additionally, those classified as being amyloid positive at baseline showed significantly increased QDRS Total scores at follow-up (p < 0.001) compared to those who were amyloid negative at baseline, whose QDRS Total scores remained stable over time (p = 0.63)., Conclusion: The QDRS can potentially demonstrate worsening functioning status across one year, especially in those who have MCI or mild AD and those who are amyloid positive. Therefore, the current results preliminarily suggest that the QDRS may provide an efficient tool for tracking progression in clinical trials in AD.

Background: Despite reports of gross motor problems in mild cognitive impairment (MCI) and Alzheimer's disease (AD), fine motor function has been relatively understudied., Objective: We examined if finger tapping is affected in AD, related to AD biomarkers, and able to classify MCI or AD., Methods: Forty-seven cognitively normal, 27 amnestic MCI, and 26 AD subjects completed unimanual and bimanual computerized tapping tests. We tested 1) group differences in tapping with permutation models; 2) associations between tapping and biomarkers (PET amyloid-β, hippocampal volume, and APOEɛ4 alleles) with linear regression; and 3) the predictive value of tapping for group classification using machine learning., Results: AD subjects had slower reaction time and larger speed variability than controls during all tapping conditions, except for dual tapping. MCI subjects performed worse than controls on reaction time and speed variability for dual and non-dominant hand tapping. Tapping speed and variability were related to hippocampal volume, but not to amyloid-β deposition or APOEɛ4 alleles. Random forest classification (overall accuracy = 70%) discriminated control and AD subjects, but poorly discriminated MCI from controls or AD., Conclusions: MCI and AD are linked to more variable finger tapping with slower reaction time. Associations between finger tapping and hippocampal volume, but not amyloidosis, suggest that tapping deficits are related to neuropathology that presents later during the disease. Considering that tapping performance is able to differentiate between control and AD subjects, it can offer a cost-efficient tool for augmenting existing AD biomarkers.

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer's disease (AD). However, prior studies have typically utilized small and poorly characterized samples, and they have not analyzed the subtests of the RBANS. The current study sought to expand on prior work by examining the relationship between the Indexes and subtest scores of the RBANS and three AD biomarkers: amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and APOE ε4 status., One-hundred twenty-one older adults across the AD continuum (intact, amnestic Mild Cognitive Impairment, mild AD), who were mostly Caucasian and well-educated, underwent assessment with the RBANS and collection of the three biomarkers., Greater amyloid deposition was significantly related to lower scores on all five Indexes and the Total Scale score of the RBANS, as well as 11 of 12 subtests. For bilateral hippocampal volume, significant correlations were observed for 4 of the 5 Indexes, Total Scale score, and 9 of 12 subtests, with smaller hippocampi being related to lower RBANS scores. Participants with at least one APOE ε4 allele had significantly lower scores on 3 of the 5 Indexes, Total Scale score, and 8 of the 12 subtests., In this sample of participants across the dementia spectrum, most RBANS Indexes and subtests showed relationships with the amyloid deposition, hippocampal volumes, and APOE status, with poorer performance on the RBANS being associated with biomarker positivity. Although memory scores on the RBANS have traditionally been linked to biomarkers in AD, other Index and subtest scores also hold promise as indicators of AD. Replication in a more diverse sample is needed.

The Learning Ratio (LR) is a novel learning score examining the proportion of information learned over successive learning trials relative to information available to be learned. Validation is warranted to understand LR's sensitivity to Alzheimer's disease (AD) pathology. One-hundred twenty-three participants across the AD continuum underwent memory assessment, quantitative brain imaging, and genetic analysis. LR scores were calculated from the HVLT-R, BVMT-R, RBANS List Learning, and RBANS Story Memory, and compared to total hippocampal volumes, 18 F-Flutemetamol composite SUVR uptake, and APOE ε4 status. Lower LR scores were consistently associated with smaller total hippocampal volumes, greater cerebral β-amyloid deposition, and APOE ε4 positivity. This LR score outperformed a traditional learning slope calculation in all analyses. LR is sensitive to AD pathology along the AD continuum - more so than a traditional raw learning score - and reducing the competition between the first trial and subsequent trials can better depict learning capacity.

Cortical amyloid deposition is one of the hallmark biomarkers of Alzheimer's disease (AD). However, given how cost- and time-intensive amyloid imaging can be, there is a continued need for a low-cost, non-invasive, and accessible enrichment strategy to pre-screen individuals for their likelihood of amyloid prior to imaging. Previous work supports the use of coordinated limb movement as a potential screening tool, even after controlling for cognitive and daily function. Thirty-six patients diagnosed with amnestic mild cognitive impairment over the age of 65 underwent 18F-Flutemetamol amyloid-positron emission tomography (PET) imaging and then completed a timed motor task involving upper limb coordination. This task takes ∼5 minutes to administer and score. Multivariate linear regression and receiver operator characteristic analyses showed that including motor task performance improved model prediction of amyloid burden. Results support the rationale for including functional upper extremity motor assessment as a cost- and time-effective means to screen participants for amyloid deposition.

Introduction: The Quick Dementia Rating System (QDRS) is a brief, patient-reported dementia staging tool that has approximated scores on the Clinical Dementia Rating Scale in patients with Alzheimer's disease (AD). However, no studies have examined its relationship with AD-related biomarkers., Methods: One-hundred twenty-one older adults (intact, amnestic mild cognitive impairment, mild AD) completed the QDRS, and three biomarkers (amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and apolipoprotein [APOE] ε4 status)., Results: The Total score on the QDRS was statistically significantly related to all three biomarkers (after controlling for age, education, sex, and race), with greater levels of dementia severity being associated with greater amyloid deposition, smaller hippocampi, and having copies of APOE ε4 allele., Discussion: In participants across the cognitive spectrum, the QDRS showed modest relationships with amyloid deposition, hippocampal volumes, and APOE status. Therefore, the QDRS may offer a cost-effective screening method for clinical trials in AD., (© 2022 S. Karger AG, Basel.)

Introduction: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated, to varying degrees, with commonly used biomarkers of Alzheimer's disease (AD). Given the ease of RBANS administration as a screening tool for clinical trials and other applications, a better understanding of how RBANS performance is associated with presence of APOE ε4 allele[s], cerebral amyloid burden, and hippocampal volume is warranted., Method: One hundred twenty-one older adults who were classified as intact, amnestic Mild Cognitive Impairment, or mild AD underwent cognitive assessment with the RBANS, genetic analysis, and quantitative brain imaging. APOE ε4 carrier status, 18 F-Flutemetamol composite standardized uptake value ratio (SUVR), and hippocampal volume were each regressed on demographic variables and RBANS Total Scale score, Index scores, and subtest scores., Results: Lower RBANS Total Scale score or Delayed Memory Index (DMI) predicted the presence of APOE ε4 allele[s], higher cerebral amyloid burden, and lower hippocampal volumes. DMI was a slightly better predictor than Total Scale score for most AD biomarkers. No demographic variables consistently contributed to these models., Conclusions: The RBANS - DMI in particular - is sensitive to AD pathology. As such, it could be used as a predictive tool, particularly in clinical drug trials to enrich samples prior to less accessible AD biomarker investigation.

Convergent validation of a verbal incidental learning (IL) task from the WAIS-IV using neuroimaging biomarkers is warranted to understand its sensitivity to Alzheimer's disease (AD) pathology. Fifty-five memory clinic patients aged 59 to 87 years received neuropsychological assessment, and measures of IL and quantitative brain imaging. Worse IL-Total Score and IL-Similarities performances were significantly associated with smaller hemispheric hippocampal volumes. IL measures were not significantly correlated with cerebral β-amyloid burden, though a trend was present and effect sizes were mild. These hippocampal volume results suggest that this IL task may be sensitive to AD pathology along the AD continuum.

Screen failure rates in Alzheimer's disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50-83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.

Objective: Several studies have suggested that cancer is associated with a reduced risk of the development of Alzheimer's disease (AD). This study seeks to improve our understanding of the association between cancer and the development of AD by showing how mortality selection alters this relationship., Method: A retrospective cohort study was carried out examining 92,425 individuals (47,873 women and 44,552 men) from the Utah Population Database with and without a history of any primary cancer identified by the Utah Cancer Registry. All individuals were aged 65-79 years and free of dementia in 1992 and followed for upwards of 18 years (1992-2009) for AD ascertainment, which was identified using diagnostic information from Medicare claims data., Results: We replicate previous results suggesting that cancer is associated with reduced risk of subsequent AD under specific statistical model specifications. However, these results should not be interpreted as evidence of an etiological association. We conclude that higher rates of overall mortality among individuals with cancer relative to those without cancer induce the widely reported putative protective association with cancer., Conclusion: Careful consideration of model specification and the profound effects of mortality selection in the older adult population is essential when investigating the relationship between aging-related diseases such as cancer and AD. We show that cancer does not provide protection from AD as previously described in the literature. Social scientists seeking to understand social disparities in disease outcomes among older adults may therefore want to strongly consider the role of mortality selection which, if uncorrected, may generate biased associations., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clinical trials in Alzheimer disease are moving toward prevention studies in prodromal individuals with amyloid burden. However, methods are needed to identify individuals expected to be amyloid positive for these studies to be feasible and cost-effective. The current study sought to determine whether short-term practice effects on cognitive tests can identify those with notable uptake on amyloid imaging. Twenty-five, nondemented older adults (15 cognitively intact, 10 with mild cognitive impairment) underwent amyloid imaging through F-flutemetamol and 2 cognitive testing sessions across 1 week to determine practice effects on a visual memory test. Results indicated that, whereas F-flutemetamol uptake showed little association with baseline performance on a visual memory test (r=-0.04, P=0.85), it was significantly correlated with practice effects across 1 week on that same memory measure (r=-0.45, P=0.02), with greater uptake being associated with lower practice effects. The odds ratio of notable F-flutemetamol uptake was 5 times higher in individuals with low practice effects compared with high practice effects. Although these preliminary results need to be replicated in larger samples, short-term practice effects on cognitive tests may provide an affordable screening method to identify individuals who are amyloid positive, which could enrich samples for preventative clinical trials in Alzheimer disease.

Although amyloid deposition remains a marker of the development of Alzheimer's disease, results linking amyloid and cognition have been equivocal. Twenty-five community-dwelling non-demented older adults were examined with (18)F-flutemetamol, an amyloid imaging agent, and a cognitive battery, including an estimate of premorbid intellect and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the first model, (18)F-flutemetamol uptake significantly correlated with the Delayed Memory Index of the RBANS (r = -.51, p = .02) and premorbid intellect (r = .43, p = .03). In the second model, the relationship between (18)F-flutemetamol and cognition was notably stronger when controlling for premorbid intellect (e.g., three of the five RBANS Indexes and its Total score significantly correlated with (18)F-flutemetamol, r's = -.41 to -.58). Associations were found between amyloid-binding (18)F-flutemetamol and cognitive functioning in non-demented older adults. These associations were greatest with delayed memory and stronger when premorbid intellect was considered, suggesting that cognitive reserve partly compensates for the symptomatic expression of amyloid pathology in community-dwelling elderly.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG-PET) thus far rarely has been used to advance the development of new treatments for Alzheimer's disease (AD). Now that FDG-PET with standard acquisition protocols for dementia is widely available, change in cerebral glucose metabolism is a feasible outcome variable for clinical drug trials. Individual analysis of FDG-PET results also might prove valuable. FDG-PET can detect metabolic changes very early in the course of AD and identify subjects for earlier treatment. FDG-PET reliably distinguishes AD from frontotemporal dementia so that only those most likely to benefit are enrolled in trials. Finally, objectively identifying phenotypic variations of AD with FDG-PET might have pathogenic and prognostic implications that can be used for personalized treatment approaches. The judicious use of FDG-PET is needed to accelerate the evaluation of promising new drugs and more rationally target treatments for dementing diseases.

Objective: The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism., Methods: This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography., Results: At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2., Conclusion: Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

Functional neuroanatomical correlates subserving maintenance rehearsal relative to a reading control task were investigated with positron emission tomography imaging of cerebral blood flow in 6 healthy older participants and 6 patients with mild Alzheimer's disease (AD). Rehearsal and reading rates and number of unique words rehearsed did not differ significantly for the 2 groups. The right dorsolateral prefrontal cortex was activated in both groups during rehearsal, highlighting this region's role in short-term maintenance of verbal information. A shift in cortical processing resources to more anterior brain regions with increased rehearsal list length was seen, likely reflecting greater demands on frontal cortex as cognitive load grows. Whereas controls showed unilateral right frontal activation during rehearsal, AD patients demonstrated bilateral frontal activation, possibly reflecting compensatory recruitment of neural resources.

Objective: Local cerebral metabolic rates for glucose were compared between patients with familial Alzheimer's disease (FAD), sporadic Alzheimer's Disease (SAD), and normal controls (NC) to determine if FAD is associated with a unique pattern of brain metabolism., Design: Case-control study matched to convenience sample of FAD., Methods: Subjects in the three diagnostic groups were scanned using fluorodeoxyglucose and the Positron Emission Tomographic (PET) technique. The criterion standard of a detailed clinical history and examination were compared to scan results., Setting: Patients in a university hospital., Subjects: Ambulatory controls and Alzheimer's patients, both sporadic (n = 8) and familial (n = 7). The two groups were similar in severity of cognitive dysfunction., Results: FAD and SAD patients did not significantly differ in terms of local cerebral metabolic rates for glucose.

Alzheimer disease is a common neurodegenerative disorder consisting of memory impairment and intellectual function that produces not only profound disabilities in the patient, but a significant cost to society as well. The biochemical basis for Alzheimer disease is not completely understood, but both positron-emission tomography and single-photon-emission computed tomography provide insights into the in vivo biochemistry associated with this disease. Both techniques show characteristic brain abnormalities, which consist of reductions in temporal-parietal metabolism that progress in severity and extent as the disease itself shows clinical progression. Such noninvasive biochemical assays may ultimately prove to be of assistance in clinical management, and are clearly helpful in understanding the pathophysiologic mechanisms associated with the production of this disease.

Alzheimer's disease (AD) is becoming an increasingly important public health problem. The clinical diagnosis of AD continues to be problematic and costly. [18F]-fluorodeoxyglucose-position emission tomography (FDG-PET) can assist with the diagnosis of AD at an early stage. The utility of FDG-PET in AD may also be extremely useful in the future when objective physiologic monitoring of drug effects and therapy are required.