Sensitive and non-invasive methods of screening for early-stage Alzheimer’s disease (AD) are urgently needed. The digital clock drawing test (DCTclockTM) is an established and well-researched neuropsychological tool that can aid in early detection of dementia. Other simple, yet sensitive, neuropsychological measures able to detect early stages of AD include Trail Making Tests (TMT). We investigated the psychometric properties of DCTclockTM with TMT-A and TMT-B. We then sought to understand the degree to which neuropsychological tools (i.e., DCTclockTM, TMT-A, and B) versus the Montreal Cognitive Assessment (MoCA) predict beta-amyloid (Aß) positron emission tomography (PET) status (positive or negative) in cognitively normal individuals.

Participants included a sample of cognitively normal older adults (n= 59, M age = 69.2, F = 64%) recruited from the Butler Memory and Aging Program. The Linus Health DCTclockTM uses a digital pen to capture traditional clock drawing test performance and advanced analytics to evaluate the drawing process for indicators of cognitive difficulty. DCTclockTM may have overlapping cognitive properties with TMT measures, like efficiency, processing speed, and spatial reasoning. We compared latency measures (i.e., process efficiency, clock face speed, average latency, and processing speed) and spatial reasoning of the DCTclockTM to z-scores of TMT-A and TMT-B to detect any overlapping psychometric properties. Verbal fluency was included for discriminant validity. We then ran logistic regressions on a subset of the sample to compare neuropsychological tests (DCTclockTM total score [score that captures overall performance], TMT-A/B, and verbal fluency) to the MoCA, a commonly used cognitive screening tool, in determining PET status.

Highly correlated (r > .7) DCTclockTM variables were excluded. We found statistically significant correlations between some DCTclockTM measures and TMT-A/B, like DCTclockTM drawing process efficiency and TMT-A and TMT-B (r= .45, p< .001, r=.29, p< .026, respectively), and DCTclockTM average latency and TMT-A and TMT-B (r=.3, p< .024, r= .26, p< .044, respectively). No statistically significant associations were found between any DCTclockTM measures and verbal fluency, or between DCTclockTM spatial reasoning and TMT-A/B. We then investigated the effect of these neuropsychological tests (DCTclockTM total score, TMT-A/B, verbal fluency) and age on the likelihood of PET positivity (subset of sample, total PET, n=31). The model was statistically significant (x2 (5) = 15.35, p< .01). The model explained 53% (Nagelkerke R2) of the variance in PET status and correctly classified 74.2% of cases. DCTclockTM was the only significant predictor (p< .02), after controlling for TMT-A, TMT-B, verbal fluency, and age. Comparatively, there was no effect of MoCA and age (total PET, n= 29) on the likelihood of PET positivity.

Overall, these results suggest psychometric convergence on elements of DCTclockTM and TMT-A/B, while there was no association in spatial operations between DCTclockTM and TMT measures. Further, when compared to the MoCA, DCTclockTM and these commonly used neuropsychological tests (verbal fluency and TMT-A/B) were better predictors of PET status, primarily driven by the DCTclockTM. Digitized neuropsychological tools may provide additional metrics not captured by pen-and-paper tests that can detect AD-associated pathology.

Individuals with Down syndrome (DS) experience intellectual disability, such that measures of cognitive and adaptive functioning are near the normative floor upon evaluation. Individuals with DS are also at increased risk for Alzheimer's disease (AD) beginning around age 40; and test performances and adaptive ratings at the normative floor make it difficult to detect change in cognition and functioning. This study first assessed the range of raw intelligence scores and raw adaptive functioning of individuals with DS at the normative floor. Next, we assessed whether those raw intelligence scores were predictive of raw adaptive functioning scores, and by association, whether they may be meaningful when assessing change in individuals with a lower baseline of cognitive functioning.

Participants were selected from a cohort of 117 adults with DS in a longitudinal study examining AD risk. Participants (n=96; M=40.9 years-old, SD=10.67; 57.3% female) were selected if they had both a completed measure of IQ (Kaufmann Brief Intelligence Test; KBIT2) and informant ratings of adaptive functioning (Vineland Adaptive Behavior Scales; VABS-II). Multiple regression was conducted predicting VABS-II total raw score using K-BIT2 total raw score, while controlling for age.

A slight majority (57.3%) of the sample had a standardized IQ score of 40 with the majority (95.7%) having a standardized score at or below 60. Additionally, 85.3% of the sample had a standard VABS-II score at or below 60. Within the normative floor for the KBIT2 (IQ=40), there was a normal distribution and substantial range of both KBIT2 raw scores (M = 31.19, SD = 13.19, range: 2 to 41) and VABS-II raw scores (M = 406.33, SD = 84.91, range: 198 to 569). Using the full sample, age significantly predicted raw VABS-II scores (ß = -.283, p = .008). When KBIT2 raw scores were included in the model, age was no longer an independently significant predictor. KBIT2 raw scores significantly predicted raw VABS-II scores (ß = .689, p < .001). Age alone accounted for 8.0% of variance in VABS-II raw scores and KBIT2 raw scores accounted for 43.8% additional variance in VABS-II raw scores. This relationship was maintained when the sample was reduced to individuals at the normative floor (n = 51) where KBIT2 raw scores accounted for 23.7% of the variance in raw VABS-II scores (ß = .549, p < .001).

The results indicate that meaningful variability exists among raw intelligence test performances that may be masked by scores at the normative floor. Further, the variability in raw intelligence scores is associated with variability in adaptive functioning, such that lower intelligence scores are associated with lower ratings of adaptive functioning. Considering this relationship would be masked by a reduction of range due to norming, these findings indicate that raw test performances and adaptive functioning ratings may have value when monitoring change in adults with DS at risk for AD.

Preclinical Alzheimer disease (AD) has been associated with subtle deficits in memory, attention, and spatial navigation (Allison et al., 2019; Aschenbrenner et al., 2015; Hedden et al., 2013). There is a need for a widely distributable screening measure for detecting preclinical AD. The goal of this study was to examine whether self- and informant-reported change in the relevant cognitive domains, measured by the Everyday Cognition Scale (ECog; Farias et al., 2008), could represent robust clinical tools sensitive to preclinical AD.

Clinically normal adults aged 56-93 (n=371) and their informants (n=366) completed memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the ECog. Reliability and validity of these subsections were examined using Cronbach’s alpha and confirmatory factor analyses (CFA). The hypothesized CFA assumed a three-factor structure with each subsection representing a separate latent construct. Receiver operating characteristics (ROC) and area under the curve (AUC) analyses were used to determine the diagnostic accuracy of the ECog subsections in detecting preclinical AD, either defined by cerebrospinal fluid (CSF) ptau181/Aß42 ratio >0.0198 or hippocampal volume in the bottom tertial of the sample. Hierarchical linear regression was used to examine whether ECog subsections predicted continuous AD biomarker burden when controlling for depressive symptomatology, which has been previously associated with subjective cognition (Zlatar et al., 2018). Lastly, we compared the diagnostic accuracy of ECog subsections and neuropsychological composites assessing the same or similar cognitive domains (memory, executive function, and visuospatial ability) in identifying preclinical AD.

All self- and informant-reported subsections demonstrated appropriate reliability (a range=.71-.89). The three-factor CFA models were an adequate fit to the data and were significantly better than one-factor models (self-report x2(3)=129.511, p<.001; informant-report X2(3)=145.347, p<.001), suggesting that the subsections measured distinct constructs. Self-reported memory (AUC=.582, p=.007) and attention (AUC=.564, p=.036) were significant predictors of preclinical AD defined by CSF ptau181/Aß42 ratio. Self-reported spatial navigation (AUC=.592, p=.022) was a significant predictor of preclinical AD defined by hippocampal volume. Additionally, self-reported attention was a significant predictor of the CSF ptau181/Aß42 ratio (p<.001) and self-reported memory was a significant predictor of hippocampal volume (p=.024) when controlling for depressive symptoms. Informant-reports were not significant predictors of preclinical AD (all ps>.074).

There was a nonsignificant trend for the objectively measured executive function AUC to be higher than for self-reported attention in detecting preclinical AD defined by CSF ptau181/Aß42 ratio and was significantly higher than self-reported attention in detecting preclinical AD defined by hippocampal volume (p=.084 and p<.001, respectively). For memory and spatial navigation/visuospatial domains, the AUCs for self-reported and objective measures did not differ in detecting preclinical AD defined by either CSF ptau181/Aß42 ratio or hippocampal volume (ps>.129).

Although the self-reported subsections produced significant AUCs, these were not high enough to indicate clinical utility based on existing recommendations (all AUCs<.60; Mandrekar, 2010). Nonetheless, there was evidence that self-reported cognitive change has promise as a screening tool for preclinical AD but there is a need to develop questionnaires with greater sensitivity to subtle cognitive change associated with preclinical AD.

We examined the use of pupillometry as an early risk marker of Alzheimer's disease (AD). Pupil dilation during a cognitive task has been shown to be an index of cognitive effort and may provide a marker of early change in cognition even before performance begins to decline. Individuals who require more effort to successfully perform a task may be closer to decline. We previously found greater compensatory effort to perform the digit span task in individuals with amnestic mild cognitive impairment (aMCI) who may be at greater risk for AD than individuals with non-amnestic MCI (naMCI). Task evoked pupil dilation is linked to increased norepinephrine output from the locus coeruleus (LC), a structure affected early in the AD pathological process. In this study, we measured pupil dilation during verbal fluency tasks in participants with aMCI or naMCI, and cognitively normal (CN) individuals. Based on our findings using the digit span task, we hypothesized that participants with aMCI would show greater compensatory cognitive effort than the other two groups.

This study included 101 older adults without dementia recruited from the UC San Diego Shiley-Marcos Alzheimer's Disease Research Center and San Diego community (mean [SD] age = 74.7 [5.8]; education = 16.6 [2.5]; N=58 female; N=92 White); 62 CN, 20 aMCI and 19 naMCI participants. Pupillary responses (change relative to baseline at the start of each trial) were recorded at 30 Hz using a Tobii X2-30 (Tobii, Stockholm, Sweden) during semantic (animals, fruits, vegetables) and phonemic (letters F, A, S) fluency tasks. Participants generated as many words as possible in a category (semantic) or starting with a given letter (phonemic) in 60 seconds.

Repeated measures ANOVA (3 groups X 2 fluency conditions) with age, education and sex as covariates showed a significant main effect of group (F(2,95)=3.64, p=.03), but no group X condition interaction (F<1). Pairwise comparisons showed significantly greater fluency task-evoked dilation for aMCI relative to CN (p=.015) and naMCI (p=.019) participants. When controlling for performance (total letter or category words produced), pupil dilation (cognitive effort) remained significantly greater in aMCI relative to the other two groups in both fluency conditions, suggesting pupil dilation informs risk beyond information provided by task performance.

In a previous sample of community-dwelling men who were an average of 13 years younger than the present sample, we found significantly greater pupil dilation during a digit span task in aMCI relative to naMCI and CN groups. In the present study, we replicated those findings in an older sample using a different cognitive task. Significantly greater pupil dilation was found in individuals with aMCI on verbal fluency tasks, indicating greater compensatory cognitive effort to maintain performance. Pupillometry provides a promising biomarker that might be used as an inexpensive and noninvasive additional screening tool for risk of AD.

Definitive diagnosis of Alzheimer’s disease (AD) is often unavailable, so clinical diagnoses with some degree of inaccuracy are often used in research instead. When researchers test methods that may improve clinical accuracy, the error in initial diagnosis can penalize predictions that are more accurate to true diagnoses but differ from clinical diagnoses. To address this challenge, the current study investigated the use of a simple bias adjustment for use in logistic regression that accounts for known inaccuracy in initial diagnoses.

A Bayesian logistic regression model was developed to predict unobserved/true diagnostic status given the sensitivity and specificity of an imperfect reference. This model considers cases as a mixture of true (with rate = sensitivity) and false positives (rate = 1 - specificity) while controls are mixtures of true (rate = specificity) and false negatives (rate = 1 - sensitivity). This bias adjustment was tested using Monte Carlo simulations over four conditions that varied the accuracy of clinical diagnoses. Conditions utilized 1000 iterations each generating a random dataset of n = 1000 based on a true logistic model with an intercept and three arbitrary predictors. Coefficients for parameters were randomly selected in each iteration and used to produce a set of two diagnoses: true diagnoses and observed diagnoses with imperfect accuracy. Sensitivity and specificity of the simulated clinical diagnosis varied with each of the four conditions (C): C1 = (0.77, 0.60), C2 = (0.87, 0.44), C3 = (0.71, 0.71), and C4 = (0.83, 0.55), which are derived from published values for clinical AD diagnoses against autopsy-confirmed pathology. Unadjusted and bias-adjusted logistic regressions were then fit to the simulated data to determine the models’ accuracy in estimating regression parameters and prediction of true diagnosis.

Under all conditions, the bias-adjusted logistic regression model outperformed its unadjusted counterpart. Root mean square error (the variability of estimated coefficients around their true parameter values) ranged from 0.23 to 0.79 for the unadjusted model versus 0.24 to 0.29 for the bias-adjusted model. The empirical coverage rate (the proportion of 95% credible intervals that include their true parameter) ranged from 0.00 to 0.47 for the unadjusted model versus 0.95 to 0.96 for the bias-adjusted model. Finally, the bias-adjusted model produced the best overall diagnostic accuracy with correct classification of true diagnostic values about 78% of the time versus 62-72% without adjustment.

Results of this simulation study, which used published AD sensitivity and specificity statistics, provide evidence that bias-adjustments to logistic regression models are needed when research involves diagnoses from an imperfect standard. Results showed that unadjusted methods rarely identified true effects with credible intervals for coefficients including the true value anywhere from never to less than half of the time. Additional simulations are needed to examine the bias-adjusted model’s performance under additional conditions. Future research is needed to extend the bias adjustment to multinomial logistic regressions and to scenarios where the rate of misdiagnosis is unknown. Such methods may be valuable for improving detection of other neurological disorders with greater diagnostic error as well.

To explore the utility of neuropsychological testing for patients with Primary Progressive Aphasia and compare testing data for a Logopenic and Semantic PPA variants within the medically complex Veteran population.

Both participants were referred by their psychiatrist due to memory concerns. The case studies testing data will be compared to look at the differences on testing between different PPA presentations within the Veteran population. Patient A is a 77 year old, right handed, African American, divorced man with approximately 14 years of formal education. Patient B is a 76 year old, right handed, Caucasian, widowed man with approximately 16 years of formal education.

Patient A displayed problems with single-word retrieval, repetition of nonsense words and sentences, comprehension, reading, spelling, and naming. He also displayed impairments in aspects of working memory, along with learning and memory. His cognitive profile raises concern for a logopenic variant of primary progressive aphasia, which often has Alzheimer's disease pathology. Patient B displayed empty speech, impairments in fluency and reduced semantic knowledge that raises concern for a semantic variant of primary progressive aphasia. However, aspects of his presentation are not consistent with this diagnosis, specifically intact confrontation visual naming. Patient has a history of significant alcohol abuse, although he has mostly remained sober since moving to Texas. This evaluation cannot rule out the contribution of sustained alcohol use on his cognitive functioning; however, this is likely not the primary etiology given his significant language issues.

Patients with medically complex histories and unclear timelines of symptom progressive make it difficult for diagnostic clarity. Diagnoses can be additionally difficult to determine at times when the clinical presentation is not as clearly defined in textbooks. This case study comparison displays the importance of integrating all data to determine the proper diagnosis to optimize patient care and provide recommendations tailored to that individual.

Neuropsychiatric symptoms (NPS) can be observed in mild cognitive impairment (MCI) and dementia. Hallucinations are a core clinical symptom of Dementia with Lewy Bodies (DLB). In this study, we investigated NPS in healthy control and MCI groups who would later be diagnosed with DLB to determine which symptoms would present early.

Participants included those originally diagnosed as healthy controls (n=55), MCI with DLB etiology (n=215), and DLB (n=1059). The control and MCI groups progressed to DLB at later visits in the study. NPS data were collected using the Neuropsychiatric Inventory Questionnaire (NPI-Q) that was obtained from the National Alzheimer's Coordinating Center.

To determine which NPS presented early in the DLB course, we ran ANCOVAs to assess the role of original diagnosis on each NPS, using age as a covariate and applying Bonferroni correction. The control and MCI groups, who were later diagnosed with DLB, had greater severity of delusions, hallucinations, agitation, and apathy than the DLB group. The MCI group that would later be diagnosed with DLB had greater severity of anxiety and motor symptoms than the DLB group. The control group had greater irritability severity than the DLB group, and the controls had greater nighttime behavior severity than the MCI group, who had greater severity than the DLB group.

Overall, we found that NPS present early in those who will be diagnosed with DLB, even when they are diagnosed as healthy controls. These results suggest that examination of NPS is important even in healthy adults, and their presence may be the onset of the DLB process before an official diagnosis of the condition.

Caregiver burden tends to worsen as severity of dementia increases, and elevated burden can lead to negative consequences for dementia caregivers. In contrast, positive aspects of caregiving, such as feelings of being useful, needed, or appreciated as a caregiver, are associated with better outcomes. Caregivers reporting fewer positive experiences robustly demonstrate greater burden, suggesting that a lack of positive aspects of caregiving could be a key component of the relationship between dementia severity and burden. This study investigated whether an indirect effect of positive aspects of caregiving would be observed on the association between dementia severity and burden.

Data were extracted from the medical records of 724 patients enrolled for services at an outpatient memory clinic. Caregiver-care recipient dyads were included based on a clinically supported patient diagnosis on the dementia spectrum following a comprehensive geriatric evaluation and having fully completed assessments from an informal caregiver. Caregivers completed the Zarit Burden Interview (ZBI) and the Positive Aspects of Caregiving (PAC) measures. The Montreal Cognitive Assessment and Mini-Mental State Exam were used to estimate dementia severity, standardized to create a single variable. Multiple potential covariates (e.g., age, gender, education, nature of dyadic relationship) were considered for inclusion in the model. A cross-sectional mediation analysis using the Hayes PROCESS macro explored presence of an indirect effect of PAC on the relationship between dementia severity and ZBI using 5000 bootstrap samples.

Of the proposed covariates, only caregiver age was correlated with any of the primary variables; this variable was controlled in subsequent analyses. Significant relationships emerged between dementia severity and ZBI (r=-.12, p<.001), between PAC and ZBI (r=-.23, p<.001), and between dementia severity and PAC (r=-.07, p<.05). An indirect effect of positive aspects of caregiving on the relationship between dementia severity and ZBI was statistically significant (B= .0092, BC 95% CI [.0008, .0185]), accounting for 14.4% of the variance in the model.

A small but significant indirect effect of positive aspects of caregiving was observed on the association between dementia severity and burden. Results suggest that as dementia severity worsens, a caregiver who experiences greater positive aspects of caregiving will sustain less burden. Longitudinal examination of these relationships is needed to fully understand causality. Findings may help healthcare providers tailor treatment to alleviate caregiver burden.

Primary progressive aphasia (PPA) is a dementia syndrome characterized early in its course by gradual dissolution of language and is associated with asymmetric atrophy in the language-dominant hemisphere (usually left). In contrast, behavioral variant frontotemporal dementia (bvFTD) is a dementia syndrome characterized by a progressive early decline in personality and comportment and is associated with relatively symmetric or rightward predominant bifrontal atrophy. This study analyzed the regional and hemispheric distributions of neuronal tau inclusions of the corticobasal degeneration variant of FTLD-tau pathology (FTLD-CBD) in individuals with PPA or bvFTD. The goal was to establish clinicopathologic concordance between FTLD-CBD and behavioral/comportmental vs aphasic dementia syndromes.

Seven participants were clinically diagnosed with PPA and 6 were diagnosed with bvFTD. All had FTLD-CBD as the principal neuropathologic diagnosis at postmortem study. Sections from the following cortical regions were stained immunohistochemically with AT-8 to visualize neuronal tau inclusions: bilateral middle frontal gyrus (MFG), inferior parietal lobule (IPL), superior temporal gyrus (STG); and unilateral occipital cortex (OCC). Bilateral anterior temporal lobes (ATL) were analyzed in PPA cases only. Unbiased stereological analysis was performed to compare regional and hemispheric distributions between and within PPA vs. bvFTD groups.

Overall neocortical (MFG+STG+IPL) tau densities were significantly greater in the PPA group compared to the bvFTD group (p<0.05). Within the bvFTD group, the highest densities of tau inclusions were observed in the right MFG (mean=6,871.17; SD=3,220). In the PPA group, highest densities were observed in the left ATL (mean=9,901.81; SD=6,871). There was leftward hemispheric asymmetry of tau inclusions in IPL, STG and ATL which trended towards significance in the latter (p=0.083). Cortical distributions were symmetric or rightward predominant within the bvFTD group. Occipital cortex was devoid of inclusions.

Preliminary stereological findings of FTLD-CBD tau inclusions suggest that the distributions of pathologic tau are different across two distinct clinical dementia phenotypes. The presence of left-sided neuronal tau inclusions in PPA is concordant with the aphasic phenotype whereas symmetric and frontal-predominant densities in bvFTD are consistent with comportmental dysfunction.

Primary progressive aphasia semantic variant (PPA-SV) is an atypical dementia subtype on the frontotemporal dementia (FTD) spectrum. PPA-SV is clinically defined by naming and semantic deficits, with progressive language decline that generalizes to other domains over time. Typically, it presents as an early-onset dementia with TDP-43 pathology, but 33-46% of PPA-SV cases display initial onset after age 65 with potentially different clinical features. Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE), a more recently discovered neurodegenerative entity, is defined by an older age of onset, hippocampal sclerosis/atrophy, and TDP-43 pathology with a gradually progressive amnestic profile that expands to other cognitive deficits over time. The authors present a case report with overlapping features and suspected TDP-43 neuropathology ante-mortem for two reasons: first, to highlight the need for clinical criteria to formally diagnose LATE, and second, to address a gap in the literature on the possible clinical differences of late-onset PPA-SV.

The authors present a case of a 78-year-old Indian bilingual man (English dominant) with 18 years of education, noncontributory medical history, and gradually progressive cognitive complaints reported over the past few years who was seen for outpatient neuropsychological evaluation. Prior workup was notable for negative amyloid PET scan, negative p-tau 217 blood test, and abnormal brain MRI revealing marked bilateral hippocampal atrophy with ex vacuo ventriculomegaly and minimal cerebrovascular disease. He scored 23/30 on prior MMSE, was diagnosed with amnestic MCI, prescribed Namenda and Exelon, and complained of minor memory and word-finding difficulties with reportedly intact IADLs and no signs of NPH.

Neuropsychological testing revealed a profound dysnomia (RBANS Naming raw score = 1/10), and he provided 0 words on two semantic fluency tasks but 15 words on letter fluency. Receptive vocabulary score was also impaired (PPVT-4, <1st %). Memory performance also demonstrated rapid forgetting of information (RBANS List Recall raw = 0/10, Story Recall raw = 0/12) with no benefit to recognition cues (RBANS List Recognition raw = 12/20), but slightly better visual memory recall, albeit still impaired (RBANS Figure Recall raw = 4/20). Grooved pegboard scores were significantly worse with right-hand than left-hand. Irregular word reading (NAART = 16th %ile) was significantly below expectations and thought to reflect more of a surface dyslexia rather than a cultural confounder given that he has lived in the US for over 50 years and his occupational and educational history was completed in English.

Results support the clinical utility of neuropsychological evaluation in the differential diagnosis to support a predominant clinical syndrome of PPA-SV despite overlapping features with LATE and suspected TDP-43 pathology. This case report highlights the diagnostic issue with the lack of literature describing the typical clinical progression or suggested diagnostic criteria of LATE. These findings also indicate that late-onset PPA-SV may include greater memory deficits earlier in the course, but this may also be a clinical masquerade that is more reflective of the extent of language deficits. Further research on late-onset manifestations of PPA-SV and LATE consensus clinical guidelines is advised.

Abnormalities in social and emotional behavior are the major diagnostic criteria for behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed their behavioral disturbances to disease in mesial prefrontal and related networks, such as the salience network. This study examined the main neural correlates of informant-reported socioemotional dysfunction among patients with bvFTD compared to those with early-onset (before age 65) Alzheimer's Disease (EOAD).

Participants included 13 patients with bvFTD and their caregivers and 18 patients with EOAD and their caregivers. The caregivers consisted of a spouse, family member, or other informant who resided with the patient. They completed the informant-based Socioemotional Dysfunction Scale (SDS), a 40-item scale which rates common disturbances in social and emotional behavior on a five-point Likert scale (1-5). The patients underwent magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) analysis of the 3D T1-weighted MRI scans. Computations of mean Jacobian values within select regions of interest (ROIs) in frontal and temporal lobes generated numerical summaries of regional volumes, and voxel-wise regressions created 3D statistical maps of the association between tissue volume and SDS total scores. Statistical analyses included independent samples t-tests group differences in ROIs and SDS scores, Pearson correlations between SDS scores and brain volumes, and multiple regression of ROIs with SDS scores and group as predictor variables.

Compared to the EOAD group, the bvFTD group had significantly higher SDS scores (p < .001; d = 2.24), smaller frontal lobe volumes (specifically dorsolateral-prefrontal cortex, p = .003; d = 1.24), and larger temporal lobe volumes (specifically hippocampus, p = .014; d = 0.979). Within the bvFTD group, higher SDS scores were associated with a smaller right anterior temporal lobe (ATL; p = .005; r = -.729), especially the lateral ATLs (p = .002; r = -.776), and a smaller bilateral orbitofrontal cortex (OFC; p = .016; r = -.650). In contrast, within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex (p = .030; r = .542). In the entire sample (both bvFTD and EOAD), higher SDS scores was associated with a smaller lateral ATL volumes (p = .019; r = -.431). Regression analyses confirmed that SDS score predicted lateral ATL volume (p = .041; b = -.262) after controlling for diagnosis (p < .001; b = -.692).

These findings are consistent with greater socioemotional dysfunction, smaller frontal, and larger mesial temporal regions in bvFTD, when compared to EOAD. The findings, however, suggest that positively disturbed socioemotional behavior in bvFTD, as reported by caregivers, results from involvement of the right temporal lobe and the lateral temporal region, with further contribution from disease in OFC. The association of SDS scores and ATL volume across diagnostic groups suggests that this region is instrumental in socioemotional functioning and that the SDS may have diagnostic value in distinguishing the "right-temporal variant" of bvFTD.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that can only be diagnosed at post-mortem. Revised criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES), include impairments in episodic memory and/or executive function as core clinical features. These criteria were informed by retrospective interviews with next-of-kin and the presence and rates of objective impairments in memory and executive functions in CTE are unknown. Here, we characterized antemortem neuropsychological test performance in episodic memory and executive functions among deceased contact sport athletes neuropathologically diagnosed with CTE.

The sample included 80 deceased male contact sport athletes from the UNITE brain bank who had autopsy-confirmed CTE (and no other neurodegenerative diseases). Published criteria were used for the autopsy diagnosis of CTE. Neuropsychological test reports (raw scores) were acquired through medical record requests. Raw scores were converted to z-scores using the same age, sex, and education-adjusted normative data. Tests of memory included long delay trials from the Rey Complex Figure, CVLT-II, HVLT-R, RBANS, and BVMT-R. Tests of executive functions included Trail Making Test-B (TMT-B), Controlled Oral Word Association Test, WAIS-III Picture Arrangement, and various WAIS-IV subtests. Not all brain donors had the same tests, and the sample sizes vary across tests, with 33 donors having tests from both domains. Twenty-eight had 1 test in memory and 3 had 2+. Eight had 1 test of executive function and 46 had 2+. A z-score of 1.5 standard deviations below the normative mean was impaired. Interpretation of test performance followed the American Academy of Clinical Neuropsychology guidelines (Guilmette et al., 2020). Bivariate correlations assessed cumulative p-tau burden (summary semiquantitative ratings of p-tau severity across 11 brain regions) and TMT-B (n=34) and CVLT-II (n=14), the most common tests available.

Of the 80 (mean age= 59.9, SD=18.0 years; 13, 16.3% were Black), 72 played football, 4 played ice hockey, and 4 played other contact sports. Most played at the professional level (57, 71.3%). Mean time between neuropsychological testing and death was 3.9 (SD= 4.5) years. The most common reason for testing was dementia-related (43, 53.8%). Mean z-scores fell in the average psychometric range(mean z= -0.52, SD=1.5, range= -6.0 to 3.0) for executive function and the low average range for memory (mean z= -1.3, SD=1.1, range= -4.0 to 2.0). Eleven (20.4%) had impairment on 1 test and 3 (5.6%) on 2+ tests of executive functions. The most common impairment was on TMT-B (mean z= -1.77, 13 [38.2%] impaired). For memory, 13 (41.9%) had impairment on 1 test. Of the 14 who had CVLT-II, 7 were impaired (mean z= -1.33). Greater p-tau burden was associated with worse performance on CVLT-II (r= -.653, p= .02), but not TMT-B (r= .187, p>.05).

This study provides the first evidence for objectively-measured impairments in executive functions and memory in a sample with known, autopsy-confirmed CTE. Furthermore, p-tau burden corresponded to worse memory test performance. Examination of neuropsychological tests from medical records has limitations but can overcome shortcomings of retrospective informant reports to provide insight into the cognitive profiles associated with CTE.

Although performance validity is critical in determining the quality and accuracy of test data, research suggests not all neuropsychologists incorporate performance validity tests (PVTs) in dementia evaluations (McGuire et al., 2019). Furthermore, well-validated embedded measures, such as Reliable Digit Span (RDS) from the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV), have evidenced an unusually high number of failures in a dementia population when utilizing typical clinical cut-offs (Zenisek et al., 2016). The objective of this study is to explore performance on embedded PVTs among older adults who have a major neurocognitive disorder (MND), specifically among Alzheimer disease (AD) and non-AD patients.

Archival data from outpatient neuropsychological evaluations were analyzed. All participants were at least 65 years of age, diagnosed with a MND, and completed Digit Span from the WAIS-IV, Brief Visuospatial Memory Test- Revised (BVMT-R), and Hopkins Verbal Learning Test-Revised (HVLT-R). In total, 84 participants, aged 67-96 (M=78.44, SD=6.11) with 6-20 years of education (M=13.47, SD=3.30), were included. The sample predominantly identified as female (n=60) and White (n=61). More individuals were diagnosed with AD (n=50) than non-AD dementia (n=34). Common non-AD diagnoses included Vascular (n=44), Lewy bodies (n=8), and Parkinson’s (n=2) dementias. Fisher’s Exact Test of Independence was used to account for the smaller sample to determine if there was a nonrandom association between diagnosis (AD vs non-AD) and embedded PVT performance: RDS< 7, BVMT-R Hits<4, BVMT-R Recognition Discrimination (RD) < 4, and HVLT-R RD < 5 (Bailey et al., 2018).

The Fisher’s Exact Test of Independence revealed a statistically significant association between neurocognitive diagnosis and RDS (p= .008), BVMT-R RD (p<.001), and HVLT-R RD (p<.001). BVMT-R Hits were not significantly associated with diagnosis (p = 0.10). These measures evidenced opposite patterns with RDS demonstrating a higher percentage of fails for the non-AD (63%) versus AD (20%) group. The AD group had a higher percentage of fails for BVMT-R RD (58% for AD and 13% for non-AD groups) and HLVT-R RD (66% for AD and 29% for non-AD group).

The current study suggests performance on embedded PVTs vary across MND diagnoses. Individuals with a non-AD diagnosis were more likely to fail RDS than those with AD. This is likely secondary to attention and working memory demands that are mediated by the frontal-subcortical networks, which are less impacted by AD pathology (Bonelli & Cummings, 2022; Loring et al., 2016). In contrast, AD patients were more likely to fail embedded PVTs within memory measures, which are largely mediated by the mesial temporal cortex associated with AD (Pluta, 2022). These results suggest embedded measures operate differently based on diagnosis and neuroanatomical systems affected. The clinical relevance of these findings includes potentially using alternative PVTs or different cut-offs based on diagnosis. Future research should attempt to better delineate more appropriate, as well as time efficient, PVTs among the dementia population.

Cognitive reserve (CR) refers to how flexibly and efficiently the individual makes use of available brain resources. Early-life education, midlife social and occupational activities, and later-life cognitive and social interactions are associated with greater CR. Years of education, premorbid intellectual (IQ) functioning, linguistic ability, and occupational complexity are often used as proxies of CR. CR theory seeks to explain discrepancies between the extent of disease pathology and clinical presentation amongst individuals with dementia. In the presence of Alzheimer’s Disease (AD) pathology, higher CR is associated with slower declines in executive functioning (EF). The current study examined the correlation between CR and EF performance across various stages of dementia severity as measured by the total score on the Clinical Dementia Rating Scale (CDRS).

The study cohort consisted of 269 individuals who had completed measures of EF and the CDRS from phase 1 of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Individuals who scored less than 2 on the CDRS were included in the MCI group (n=197), while individuals that scored 2 or higher on the CDRS were included in the dementia group (n=73). A simple linear regression was utilized to compare the MCI group to dementia group across CR and EF performance.

There was significant correlation between CR and EF performance in the MCI group as quantified on total CDRS score (F (200) = .353, p = .0, p < .05). CR was not observed to be predictive of EF in the dementia group (F (200) = .031, p = .666, p > .05).

Findings are consistent with prior research suggesting CR is protective during early stages of dementia, but not in the later disease stages. As prior research has shown the expression of dementia is based on a complex interaction between genetic and lifestyle factors that are unique to each person, future research exploring the potentially protective role of CR amongst pre-symptomatic adults with a genetic predisposition for developing dementia may expand our understanding of the potential role of CR on dementia prevention and progression.

Persons with behavioral variant frontotemporal dementia (bvFTD) have been shown to exhibit altered morality, manifested as atypical utilitarian tendencies towards sacrificial moral dilemmas. This takes the form of endorsing harmful actions towards single individuals, including vulnerable or relationally close individuals (e.g. children, loved ones), in order to promote the greater good for the community or society as a whole. The dual process model of moral cognition interprets such tendencies as deriving from a lack of emotional engagement, whereas moral emotion theory views them as selective impairment in prosocial sentiments. We hypothesized that both the widespread neuropsychological practice of using sacrificial moral dilemmas to evaluate moral reasoning, and these tests' overreliance on quantitative results, inadequately represent how persons with bvFTD reason and feel while responding to moral dilemmas. To evaluate this hypothesis, we applied a mixed-methods approach to identify the reasoning, motivations, and emotional experiences of bvFTD persons during their deliberation about moral scenarios.

We conducted semi-structured interviews with 14 participants: 7 persons with bvFTD & 7 older healthy controls. Transcripts were coded in Atlas 5.0 to characterize the underlying reasoning, emotions, response processes, and values that emerged when responding to a structured set of moral dilemmas. Our dilemmas measured utilitarian reasoning holistically by incorporating both sacrificial and impartial/altruistic components, as suggested by the 2-dimensional model of utilitarianism.

Unexpectedly, bvFTD persons articulated a prosocial compass when asked about their values, stating they were organizing their choices predominantly around kindness and altruism, even when they were making choices to harm loved ones or vulnerable individuals to promote the greater good. During moral deliberation, persons with bvFTD showed significantly less metacognition (bvFTD = 10%, HC = 90%) but reported more positive emotions (joy; bvFTD = 83%, HC = 17%) than negative (frustration; bvFTD = 30 %, HC = 70 %) compared to controls. Qualitatively, this observed emotional outlook was typically coupled with a more rigid, simplistic viewpoint (e.g., "I felt great, it was a no brainer"), suggesting a moral understanding lacking emotional nuance and complexity.

Our data showed that bvFTD persons' utilitarian responses to moral dilemmas did not arise from an emotionally flat or antisocial cognitive perspective, but instead were guided by positive emotionality, simplistic reasoning, and prosocial values. These findings challenge the current understanding of the reasoning processes and experiences of persons with bvFTD and highlight the importance of incorporating mixed method approaches in dementia research that take into consideration the viewpoint of the cognitively compromised individual.

Decline in everyday function is a hallmark of dementia and is associated with increased caregiver burden, medical spending, and poorer quality of life. Neuropsychiatric symptoms (e.g., apathy, hallucinations) can also occur in those with dementia and have been associated with worse everyday functioning cross-sectionally. However, research on which neuropsychiatric symptoms are most associated with everyday functioning in those with dementia longitudinally has been more limited. Further, it is unknown which neuropsychiatric symptoms may add incremental validity beyond cognition in predicting everyday function longitudinally. The current study aimed to address both of these gaps in the literature by identifying which neuropsychiatric symptoms are most associated with everyday function over time and if symptoms add incremental validity in predicting everyday function beyond cognition in those with dementia.

Older adult participants (N = 4525), classified as having dementia at baseline by the National Alzheimer's Coordinating Center, were examined. Severity of neuropsychiatric symptoms were measured via the Neuropsychiatric Symptoms Questionnaire-Informant. Everyday function was assessed via the Functional Activities Questionnaire-Informant. Memory (Logical Memory immediate and delayed) and executive function (Digit Symbol Test, TMT-A and TMT-B) composites were created to assess cognition. Severity of neuropsychiatric symptoms at baseline were analyzed as predictors of everyday functioning beyond demographic factors and cognition at baseline and over the course of five years using multilevel modeling.

At baseline, severity of the majority of symptoms, excluding irritability, manic symptoms, and changes in appetite, were associated with everyday function (all p < .05). When examining everyday functioning longitudinally, only severity of hallucinations, apathy, motor dysfunction, and sleep dysfunction were associated with differences in everyday function over time (all p < .01).

There is heterogeneity in the degree to which neuropsychiatric symptoms are associated with everyday functioning over time in those with dementia. Additionally, our results show that some neuropsychiatric symptoms are associated with longitudinal changes in everyday function beyond domains of cognition show to be associated with function. Clinicians should pay particular attention to which neuropsychiatric symptoms individuals with dementia and their families are reporting to aid with treatment planning and clinical decision making related to autonomy. Future research would benefit from examining pathways through which neuropsychiatric symptoms are associated with everyday functioning over time in this population, and if treatments of neuropsychiatric symptoms may improve everyday function in this population.

In the field of neurocognitive disorders, the perspective offered by new disease-modifying therapy increases the importance of etiological diagnosis. The prescription of cerebrospinal fluid analysis (CSF) and imaging biomarkers is a common practice in the clinic but is often driven more by personal expertise and local availability of diagnostic tools than by evidence of efficacy and cost-effectiveness analysis. This leads to a widely heterogeneous dementia care across Europe. Therefore, a European initiative is currently being conducted to establish a consensus for biomarker-based diagnosis of patients with mild cognitive impairment (MCI) and mild dementia.

Since November 2020, a European multidisciplinary task force of 22 experts from 11 scientific societies have been defining a diagnostic workflow for the efficient use of biomarkers. The Delphi consensus procedure was used to bridge the gaps of incomplete scientific evidence on biomarker prioritization. The project has been in two phases. During Phase 1, we conducted a literature review on the accuracy of imaging, CSF, neurophysiological and blood biomarkers in predicting the clinical progression or in defining the underpinning aetiology of main neurocognitive disorders. Evidence was provided to support the panelists’ decisions. In phase 2, a modified Delphi procedure was implemented, and consensus was reached at a threshold of 70% agreement, or 50%+1 when a question required rediscussion.

In phase 1, 167 out of 2,200 screened papers provided validated measures of biomarker diagnostic accuracy compared with a gold standard or in predicting progression or conversion of MCI to the dementia stage (i.e., MRI, CSF, FDG-PET, DaT-imaging, amyloid-PET, tau-PET, and myocardial MIBG-scintigraphy and EEG). During phase 2, panelists agreed on the clinical workspace of the workflow, the stage of application, and the patient age window. The workflow is patient-centered and features three levels of assessment (W): W1 defines eleven clinical profiles based on integrated results of neuropsychology, MRI atrophy patterns, and blood tests; W2 describes the first-line biomarkers according to W1 versus clinical suspicion; and W3 suggests the second-line biomarkers when the results of first-line biomarkers are inconsistent with the diagnostic hypothesis, uninformative or inconclusive. CSF biomarkers are first-line in the suspect of Alzheimer’s disease (AD) and when inconsistent neuropsychological and MRI findings hinder a clear diagnostic hypothesis; dopamine SPECT/PET for those leading to suspect Lewy body spectrum. FDG-PET is first-line for the clinical profiles leading to suspect frontotemporal lobar degeneration and motor tauopathies and is followed by CSF biomarkers in the case of atypical metabolic patterns, when an underlying AD etiology is conceivable.

The workflow will promote consistency in diagnosing neurocognitive disorders across countries and rational use of resources. The initiative has some limitations, mainly linked to the Delphi procedure (e.g., kickoff questions were driven by the moderators, answers are driven by the Delphi panel composition, a subtle phrasing of the questions may drive answers, and 70% threshold for convergence is conventional). However, the diagnostic workflow will be able to help clinicians achieve an early and sustainable etiological diagnosis and enable the use of disease-modifying drugs as soon as they become available.

Assessment of learning potential in patients with cognitive disorders in individuals with alcohol-related cognitive disorders (including Korsakoff’s syndrome; KS) is highly relevant, as this may help to tailor interventions, guide treatment planning and help to optimize care. However, studies on assessing learning potential or learning ability using neuropsychological assessment in relation to changes in everyday activities during the course of treatment are scarce. In this study we examined whether verbal and visuospatial learning curves could be used as an index of learning ability in relation to everyday activities before and after a treatment program.

We examined the episodic learning ability of patients with KS (N=137), other alcohol-related cognitive impairments (ARCI; N=164), and uncomplicated alcohol use disorder (AUD; N=49). For this, we calculated the learning curves for the California Verbal Learning Test (CVLT) and the Location Learning Test - Revised (LLT-R) and examined their association with ratings of everyday activities by the patient and his/her professional caregiver using the Patient Competency Rating Scale (PCRS) before and after a 10-12 week treatment program following admission to the Korsakoff Centre.

For both verbal and visuospatial memory, the AUD group had a steeper learning curve than the ARCI patients, who in turn had a steeper learning curve than the KS group (p<.01). While the VLGT total score was related to the PCRS in all patient groups (Pearson r>.38, p<.01), this was only the case for the KS group for the LLT-R total score (r>-.29, p<.01). However, the learning curve estimates of both tests were neither related to the PCRS absolute scores (for patients and caregivers, before and after treatment) nor to the APCRS scores during the course of the treatment program.

Episodic learning ability, as measured with the learning curves of the CVLT and LLT-R, were unrelated to the patients everyday activity level as measures by the patients themselves or their professional caregiver. The results will be discussed in relation to other tools for assessing the learning potential of cognitively impaired patients, such as dynamic testing.

There is limited and inconsistent research exploring diagnosis, treatment, and prevention of dementias amongst Black Indigenous People of Color (BIPOC). By 2050, it is suspected that the White population will significantly decrease and BIPOC groups will comprise the majority of the US population yet BIPOC are historically underrepresented in dementia research. Prior research indicates apolipoprotein 4 allele (APOE-4) status is associated with a greater risk of developing Alzheimer’s disease in Black individuals when compared to non-Hispanic Whites. Investigating the racial disparities in dementia will expand our knowledgebase of risk for dementia types in the Black community to better meet the evergrowing population needs. The current study explored the impact of racial identity on global cognitive functioning, independent of age, education, and APOE e4 status.

Participants were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study and consisted of five pairs of Black and White individuals (n = 10) matched based on age, education, and APOE status. Global cognitive performance was measured by the total Mini Mental Status Examination (MMSE) score. Notably, only five Black individuals in phase 1 of ADNI met inclusion criteria. It was hypothesized Black individuals would be more cognitively impaired than their White counterparts. A matched pairs t-test was utilized to examine the relationship between global cognitive performance and race.

Black and White individuals’ MMSE scores did not significantly differ (p > .05). The mean MMSE performance of White participants (26.40) was less robust than Black participants (27.80). Findings are inconsistent with current research, indicating that BIPOC individuals are disproportionately impacted by AD, with increased severity of cognitive impairment. There is a profound need for more research in preventative interventions and recruitment of BIPOC individuals who have been historically marginalized in cognitive research trials to help better understand diagnosis, treatment, and prevention of AD in BIPOC.

The observed commensurate global cognitive functioning performance between matched Black and White individuals is not consistent with prior research findings demonstrating increased risk of developing dementia amongst BIPOC. This study’s small sample size reflects a significant barrier to detecting clinically meaningful differences. Efforts to address the recruitment crisis, underreporting, cultural influences, and overall mistrust of research among BIPOC is warranted. Inclusive research is critical to dismantling health disparities.

Prospective memory (PM) is the ability to execute a planned action in the future (e.g., remembering to take medication before going to bed). Prior work has suggested that PM failure can account for 50-80% of reported memory problems. Research has also shown that PM becomes increasingly impaired in the Alzheimer's disease (AD) process. To our knowledge, most PM studies use PM accuracy as a measure of PM performance. However, examining the speed of the response as it relates to the AD process remains relatively unexplored. In this study, we examined both PM accuracy and speed in healthy aging, mild cognitive impairment (MCI), and AD.

Participants included healthy older controls (N=65), persons with MCI (N=70), and persons with AD (N=11). The PM task was embedded within a working memory task as PM demands often occur during an ongoing activity in everyday life. For the working memory component of the PM task, participants were shown a series of words and asked to continuously monitor the words while maintaining the last 3 in memory. All words were displayed within 1 of 6 background patterns. For the PM component, participants were asked to press "1" on the keyboard whenever they were shown a particular background pattern on the screen. PM abilities were measured using the median response time and total accuracy.

Age was correlated with PM accuracy. An ANCOVA, controlling for age, and examining the impact of diagnosis on PM accuracy, was significant. Post-hoc tests revealed a trend toward the AD and MCI groups being less accurate than healthy controls. In contrast to accuracy, age was not related to PM speed. An ANOVA examining the impact of diagnosis on PM accuracy found that the AD group responded faster than healthy controls. The MCI group did not show differences in speed from the healthy control and AD groups.

Overall, the pattern of results differed in accuracy and speed of PM performance. There was a trend for the MCI and AD groups being less accurate than the controls, with no difference in performance between the MCI and AD groups. However, the AD group responded more quickly than the controls, which may have impacted their accuracy. These findings indicate that PM performance differences among groups can be detected by examining speed and not just accuracy. As speed appears to be an essential aspect involved in PM performance, future research should consider incorporating speed as a measure of PM performance when examining PM differences in populations.