Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed ß-amyloid (Aß+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aß+ from Aß-. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aß+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aß+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aß- individuals (HR = 3.11; p = 2.6e-09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aß. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aß status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aß/tau. Plasma NfL predicted longitudinal cognitive decline in both Aß+ and Aß- individuals.

Neighborhood disadvantage reduces cognitive reserve independent of neuropathologic change.

INTRODUCTION: Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia-related neuropathologies is unknown. METHODS: This cross-sectional study included 469 autopsy cases from 2011 to 2023. The relationships between neighborhood disadvantage measured by Area Deprivation Index (ADI) percentiles categorized into tertiles, cognition evaluated by the last Mini-Mental State Examination (MMSE) scores before death, and 10 dementia-associated proteinopathies and cerebrovascular disease were assessed using regression analyses. RESULTS: Higher ADI was significantly associated with lower MMSE score. This was mitigated by increasing years of education. ADI was not associated with an increase in dementia-associated neuropathologic change. Moreover, the significant association between ADI and cognition remained even after controlling for changes in major dementia-associated proteinopathies or cerebrovascular disease. DISCUSSION: Neighborhood disadvantage appears to be associated with decreased cognitive reserve. This association is modified by education but is independent of the major dementia-associated neuropathologies.

The Technology in Caring Questionnaire: Development and Psychometric Properties.

OBJECTIVE: We developed the Technology in Caring Questionnaire (TCQ) to assess the use of technology-based strategies by dementia caregivers. METHODS: One hundred caregivers completed a survey that included TCQ items along with measures of technology proficiency and patient and caregiver-centered outcomes. RESULTS: The final 34-item TCQ scale had adequate to excellent internal consistency (raw Cronbach alpha = 0.75; standardized Cronbach alpha = 0.95; Guttman lambda-6 = 0.97). TCQ scores demonstrated modest convergent associations with scores from measures of smartphone ( r = 0.265, P < 0.01) and computer proficiency ( r = 0.230, P < 0.05) but a strong association with overall technology experience scores ( r = 0.578, P < 0.001). Elevated TCQ scores were associated with reduced informant-reported cognitive symptoms ( B = -0.003, P < 0.05), increased ability of caregivers to find support and information ( B = 0.03, P < 0.001), and increased direct care strain ( B = 0.03, P < 0.05), after controlling for dementia severity and demographics. CONCLUSION: The TCQ has good psychometric properties for the assessment of technology-based care strategies among dementia caregivers. Findings imply that the use of technologies may aid in symptom management and finding support and information but may also increase caregiver strain.

Impact of white matter hyperintensities on structural connectivity and cognition in cognitively intact ADNI participants.

We used indirect brain mapping with virtual lesion tractography to test the hypothesis that the extent of white matter tract disconnection due to white matter hyperintensities (WMH) is associated with corresponding tract-specific cognitive performance decrements. To estimate tract disconnection, WMH masks were extracted from FLAIR MRI data of 481 cognitively intact participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used as regions of avoidance for fiber tracking in diffusion MRI data from 50 healthy young participants from the Human Connectome Project. Estimated tract disconnection in the right inferior fronto-occipital fasciculus, right frontal aslant tract, and right superior longitudinal fasciculus mediated the effects of WMH volume on executive function. Estimated tract disconnection in the left uncinate fasciculus mediated the effects of WMH volume on memory and in the right frontal aslant tract on language. In a subset of ADNI control participants with amyloid data, positive status increased the probability of periventricular WMH and moderated the relationship between WMH burden and tract disconnection in executive function performance.

Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

Cognitive Complaint Types Can Correlate With Cognitive Testing, Perceived Stress, and Symptom Distress in Older Adults With Normal Cognition and Dementia.

OBJECTIVE: We examined how cognitive complaint types (CCTs) correlate with cognitive testing, perceived stress, and symptom distress in older adults with normal cognition and dementia. METHODS: Older adults (n = 259) with normal cognition, mild cognitive impairment, or mild-stage Alzheimer disease completed cognitive testing and self-report measures (Cognitive Difficulties Scale, Global Distress Index, Perceived Stress Scale). Cross-sectional analyses examined: (1) CCT composition by classification method,( 2) CCTs by diagnostic group, (3) correlations of CCTs with cognitive testing scores, and (4) correlations of CCTs with perceived stress and symptom distress. RESULTS: CCTs derived from 2 classification approaches loaded onto 4 factors: memory, attention-concentration (AC), temporal orientation, and praxis. Memory contained complaints about both memory and executive functioning. AC contained both classifications of AC complaints. Complaints about AC (AC1 and AC2) differed by diagnostic group (all P < 0.05). One of 2 classifications of AC (AC1) complaints discerned between impaired and unimpaired long-delay memory scores (both P < 0.05). In multivariable analyses, that same classification of AC (AC1) complaints correlated with higher perceived stress (both P < 0.001) but not symptom distress (both P > 0.05). CONCLUSION: CCTs showed a factor structure that was mostly robust between classification methods; however, some content-divergent CCTs shared factors, suggesting construct overlap. Relatively slight variations in content altered how CCTs correlated with diagnostic groups, perceived stress, and symptom distress. Most CCTs did not discern between impaired and unimpaired cognitive test scores. Research is needed to better understand CCTs as clinical markers and targets of clinical interventions.

Discrepancies in Patient and Caregiver Ratings of Personality Change in Alzheimer's Disease and Related Dementias.

OBJECTIVE: Personality change in Alzheimer's disease and related dementias (ADRD) is complicated by the patient and informant factors that confound accurate reporting of personality traits. We assessed the impact of caregiver burden on informant report of Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness) and investigated the regional cortical volumes associated with larger discrepancies in the patient and informant report of the Big Five personality traits. METHOD: Sixty-four ADRD participants with heterogeneous neurodegenerative clinical phenotypes and their informants completed the Big Five Inventory (BFI). Caregiver burden was measured using the Zarit Burden Interview. Discrepancy scores were computed as the difference between patient and informant ratings for the BFI. Regional gray matter volumes from T1-weighted 3T MRI were normalized to intracranial volume and related to global Big Five discrepancy scores using linear regression. RESULTS: Higher levels of caregiver burden were associated with higher informant ratings of patient neuroticism (ß = 0.08, p = .012) and with lower informant ratings of patient agreeableness (ß = 0.11, p = .021) and conscientiousness (ß = 0.04, p = .034) independent of disease severity. Patients with greater Big Five discrepancy scores showed smaller cortical volumes in the right medial prefrontal cortex (ß = -5.24, p = .045) and right superior temporal gyrus (ß = -7.91, p = .028). CONCLUSIONS: Informant ratings of personality traits in ADRD can be confounded by the caregiver burden, highlighting the need for more objective measures of personality and behavior in dementia samples. Discrepancies between informant and patient ratings of personality may additionally reflect loss of insight secondary to cortical atrophy in the frontal and temporal structures.

Normative Data for the 12-Item Sniffin' Sticks Odor Identification Test in Older Adults.

OBJECTIVE: Quantitative olfactory assessment has demonstrated clinical utility for the evaluation of a range of neurologic, psychiatric, and sinonasal conditions. Here, we provide age, sex, race, and education-specific normative data for the 12-item Sniffin Sticks Odor Identification Test (SSOIT-12) in older Black and White U.S. adults without preclinical or clinical dementia or sinonasal disease. METHOD: A sample of 2,224 Atherosclerosis Risk in Communities study participants aged 66-89 years were included. A normative regression equation was developed using a linear model for the association of age, sex, race, and education with odor identification score. Regression-based normative mean scores and percentiles were generated by age, sex, race, and education groups. RESULTS: Participants (mean age = 74 years, 59% women, 20% Black, 48% > high school education) had a mean SSOIT-12 score of 9.8. Age, sex, race, and education were all associated with odor identification performance (all ps < .05). A linear regression model for the predicted SSOIT-12 score was developed for use with an individual's actual SSOIT-12 score in order to calculate the Z-score and corresponding percentile for a specific age, sex, race, and education group. Data are also reported in tabular format. CONCLUSIONS: Our study provides SSOIT-12 normative data obtained from a large population of White and Black older adults without preclinical or clinical dementia or sinonasal disease living in the USA. These findings can aid clinicians in assessing the degree of olfactory loss, establishing concordance with a person's perception of olfactory difficulties and quantitatively monitoring changes in olfactory performance over time.

Turning apathy into action in neurodegenerative disease: Development and pilot testing of a goal-directed behaviour app.

This study aims to design and pilot an empirically based mobile application (ActiviDaily) to increase daily activity in persons with apathy and ADRD and test its feasibility and preliminary efficacy. ActiviDaily was developed to address impairments in goal-directed behaviour, including difficulty with initiation, planning, and motivation that contribute to apathy. Participants included patients with apathy and MCI, mild bvFTD, or mild AD and their caregivers. In Phase I, 6 patient-caregiver dyads participated in 1-week pilot testing and focus groups. In Phase II, 24 dyads completed 4 weeks of at-home ActiviDaily use. Baseline and follow-up visits included assessments of app usability, goal attainment, global cognition and functioning, apathy, and psychological symptoms. App use did not differ across diagnostic groups and was not associated with age, sex, education, global functioning or neuropsychiatric symptoms. Patients and care-partners reported high levels of satisfaction and usability, and care-partner usability rating predicted app use. At follow-up, participants showed significant improvement in goal achievement for all goal types combined. Participant goal-directed behaviour increased after 4 weeks of ActiviDaily use. Patients and caregivers reported good usability and user satisfaction. Our findings support the feasibility and efficacy of mobile-health applications to increase goal-directed behaviour in ADRD.

Discrepancies in patient and caregiver ratings of personality change in Alzheimer's disease and related dementias.

Background: Assessment of personality change in Alzheimer's disease and related dementias (ADRD) is clinically meaningful but complicated by patient (i.e., reduced insight) and informant (i.e., caregiver burden) factors that confound accurate reporting of personality traits. This study assessed the impact of caregiver burden on informant report of Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness) and investigated regional cortical volumes associated with larger discrepancies in patient and informant report of Big Five personality traits. Methods: Sixty-four ADRD participants with heterogeneous neurodegenerative clinical phenotypes and their informants completed the Big Five Inventory (BFI). Caregiver burden was measured using the Zarit Burden Interview (ZBI). Discrepancy scores were computed as the absolute value of the difference between patient and informant ratings for all BFI trait scores and summed to create a global score. Regional grey matter volumes from T1-weighted 3T MRI were normalized to intracranial volume and related to global Big Five discrepancy scores using linear regression. Results: Higher levels of caregiver burden were associated with higher informant ratings of patient Neuroticism (ß =0.27, p =.016) and lower informant ratings of patient Agreeableness (ß =-0.32, p =.002), Conscientiousness (ß =-0.3, p =.002), and Openness (ß =-0.34, p =.003) independent of disease severity. Patients with greater Big Five discrepancy scores showed smaller cortical volumes in right medial PFC (ß = -0.00015, p = .002), right superior temporal gyrus (ß = -0.00028, p = .025), and left inferior frontal gyrus (ß = -0.00006 p = .013). Conclusions: Informant ratings of personality traits in ADRD can be confounded by caregiver burden, highlighting the need for more objective measures of personality and behavior in dementia samples. Discrepancies between informant and patient ratings of personality may additionally reflect loss of insight secondary to cortical atrophy in frontal and temporal structures.

TREM2 risk variants are associated with atypical Alzheimer's disease.

Alzheimer's disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes.

Self- and Partner-Reported Subjective Memory Complaints: Association with Objective Cognitive Impairment and Risk of Decline.

Background: Episodic memory decline is a hallmark of Alzheimer's disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer's Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.

Regional distribution and maturation of tau pathology among phenotypic variants of Alzheimer's disease.

Alzheimer's disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic variants of Alzheimer's disease (AD). In this study, autopsy-confirmed patients with ADNC, were classified into amnestic (aAD, N = 40) and non-amnestic (naAD, N = 39) groups based on clinical criteria. We performed digital assessment of tissue sections immunostained for phosphorylated-tau (AT8 detects pretangles and mature tangles), D421-truncated tau (TauC3, a marker for mature tangles and ghost tangles), and E391-truncated tau (MN423, a marker that primarily detects ghost tangles), in hippocampal subfields and three cortical regions. Linear mixed-effect models were used to test regional and group differences while adjusting for demographics. Both groups showed AT8-reactivity across hippocampal subfields that mirrored traditional Braak staging with higher burden of phosphorylated-tau in subregions implicated as affected early in Braak staging. The burden of phosphorylated-tau and TauC3-immunoreactive tau in the hippocampus was largely similar between the aAD and naAD groups. In contrast, the naAD group had lower relative distribution of MN423-reactive tangles in CA1 (ß = - 0.2, SE = 0.09, p = 0.001) and CA2 (ß = - 0.25, SE = 0.09, p = 0.005) compared to the aAD. While the two groups had similar levels of phosphorylated-tau pathology in cortical regions, there was higher burden of TauC3 reactivity in sup/mid temporal cortex (ß = 0.16, SE = 0.07, p = 0.02) and MN423 reactivity in all cortical regions (ß = 0.4-0.43, SE = 0.09, p < 0.001) in the naAD compared to aAD. In conclusion, AD clinical variants may have a signature distribution of overall phosphorylated-tau pathology within the hippocampus reflecting traditional Braak staging; however, non-amnestic AD has greater relative mature tangle pathology in the neocortex compared to patients with clinical amnestic AD, where the hippocampus had greatest relative burden of C-terminally cleaved tau reactivity. Thus, varying neuronal susceptibility to tau-mediated neurodegeneration may influence the clinical expression of ADNC.

Development of a Comprehensive Battery to Collect Social and Structural Determinants of Health (SSDOH) in Cognitively Normal or Very Mildly Impaired Persons.

INTRODUCTION: Research addressing Alzheimer disease and related dementias must examine nonbiological factors influencing the risk for and expression of Alzheimer disease and related dementias. These factors address the interplay of cognition with lived experiences and social and structural determinants of health (SSDOH). However, coordinated measures of SSDOH are limited. METHODS: The Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis developed and piloted a comprehensive battery to measure SSDOH. One hundred and twelve participants, very mildly cognitively impaired or unimpaired, enrolled in memory studies completed the electronic SSDOH battery. The Clinical Dementia Rating (CDR) determined the presence or absence of cognitive impairment. RESULTS: Four domains demonstrated above acceptable intraclass correlation scores for test-retest reliability (≥0.70), including adverse childhood events, discrimination, social status, and early education. Twenty very mildly impaired participants completed the electronic pilot study. CONCLUSION: Our findings indicate that participants with early-stage symptomatic Alzheimer disease are able to participate in electronic SSDOH data collection. In collaboration with the University of Pennsylvania ADRC, we replaced/modified certain assessments to increase intraclass correlation. The resulting battery, Social and Structural Life-courses Influencing Aging and Dementia (SS-DIAD), can serve as a SSDOH collection tool and is currently utilized in cognitively impaired and unimpaired research participants at both ADRCs.

Establishing a Framework for Gathering Structural and Social Determinants of Health in Alzheimer's Disease Research Centers.

Structural and social determinants of health (SSDoH) are environmental conditions in which individuals are born, live, learn, work, play, worship, and age that affect health, functioning, and quality-of-life outcomes across the life course. Growing evidence suggests that SSDoH can help to explain heterogeneity in outcomes in Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) research and clinical practice. The National Institute on Aging has prioritized collecting SSDoH data to elucidate disease mechanisms and aid discovery of disease-modifying treatments. However, a major nexus of AD/ADRD research, the national network of Alzheimer's Disease Research Centers (ADRCs), collects few SSDoH data. We describe a framework for feasibly gathering and modeling SSDoH data across ADRCs. We lay out key constructs, their measures, and empirical evidence for their importance in elucidating disease and prevention mechanisms. Toward a goal of translation, the framework proposes a modular structure with a core set of measures and options for adjunctive modules. We describe considerations for measuring SSDoH in existing geographically and culturally diverse research cohorts. We also outline a rationale for universal implementation of a set of SSDoH measures and juxtapose the approach with alternatives aimed at collecting SSDoH data.

Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods.

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

OBJECTIVE: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology. METHODS: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF ß-amyloid1-42 (Aß42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aß42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. RESULTS: Patients with LBD + AD performed worse on BNT than patients with LBD - AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, p < 0.05) and p-tau (ρ = -0.26, p = 0.05) but not Aß42 (p > 0.1). CONCLUSION: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Neural and behavioral correlates of episodic memory are associated with temporal discounting in older adults.

When facing decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. One neurocognitive system that may underlie these individual differences is episodic memory, given the overlap in the neural circuitry involved in imagining the future and remembering the past. Here we tested this hypothesis in older adults, including both those that were cognitively normal and those with amnestic mild cognitive impairment (MCI). We found that performance on neuropsychological measures of episodic memory retrieval was associated with temporal discounting, such that people with better memory discounted delayed rewards less. This relationship was specific to episodic memory and temporal discounting, since executive function (another cognitive ability) was unrelated to temporal discounting, and episodic memory was unrelated to risk tolerance (another decision-making preference). We also examined cortical thickness and volume in medial temporal lobe regions critical for episodic memory. Entorhinal cortical thickness was associated with reduced temporal discounting, with episodic memory performance partially mediating this association. The inclusion of MCI participants was critical to revealing these associations between episodic memory and entorhinal cortical thickness and temporal discounting. These effects were larger in the MCI group, reduced after controlling for MCI status, and statistically significant only when including MCI participants in analyses. Overall, these findings suggest that individual differences in temporal discounting are driven by episodic memory function, and that a decline in medial temporal lobe structural integrity may impact temporal discounting.

A Quantitative Meta-analysis of Olfactory Dysfunction in Epilepsy.

Olfactory dysfunction in epilepsy is well-documented in several olfactory domains. However, the clinical specificity of these deficits remains unknown. The aim of this systematic meta-analysis was to determine which domains of olfactory ability were most impaired in individuals with epilepsy, and to assess moderating factors affecting olfactory ability. Extant peer-reviewed literature on olfaction in epilepsy were identified via a computerized literature search using PubMed, MEDLINE, PsycInfo, and Google Scholar databases. Twenty-one articles met inclusion criteria. These studies included a total of 912 patients with epilepsy and 794 healthy comparison subjects. Included studies measured olfaction using tests of odor identification, discrimination, memory, and detection threshold in patients with different types of epilepsy, including temporal lobe epilepsy (TLE), mixed frontal epilepsy (M-F), and mixed epilepsy (MIX). Olfactory deficits were robust in patients with epilepsy when compared to healthy individuals, with effect sizes in the moderate to large range for several olfactory domains, including odor identification (d = -1.59), memory (d = -1.10), discrimination (d = -1.04), and detection threshold (d = -0.58). Olfactory deficits were most prominent in patients with TLE and M-F epilepsy. Amongst patients with epilepsy, sex, age, smoking status, education, handedness, and age of illness onset were significantly related to olfactory performance. Overall, these meta-analytic findings indicate that the olfactory system is compromised in epilepsy and suggest that detailed neurobiological investigations of the olfactory system may provide further insight into this disorder.

Older Adult Normative Data for the Sniffin' Sticks Odor Identification Test.

OBJECTIVE: The current study establishes normative Sniffin' Sticks Odor Identification Test (SS-OIT) scores for cognitively intact older adults. METHOD: Two hundred and twenty-six cognitively normal older adults were identified as eligible for the current study (Mean Age = 70.49 years; 71.7% female). Important demographic covariates were identified using step-wise regression, and a normative regression equation was developed. RESULTS: Analyses of the effects of demographic variables (including age, education, and sex) on SS-OIT performance revealed that age was the only significant predictor, b = -0.07, SEb = .01, p < .01. A final regression equation was determined and normative data are reported in 5-year increments for a number of percentile ranks. CONCLUSIONS: Normative performance on the SS-OIT for adults over the age of 50 was established in a large and demographically diverse sample. These data are needed in order for clinicians to be able to include olfactory testing, a sensitive marker of neurodegeneration, in their assessment armamentarium.