Sex significantly predicts medial temporal volume when controlling for the influence of ApoE4 biomarker and demographic variables: A cross-ethnic comparison.

OBJECTIVE: To explore the relationship between age, education, sex, and ApoE4 (+) status to brain volume among a cohort with amnestic mild cognitive impairment (aMCI). METHOD: One hundred and twenty-three participants were stratified into Hispanic (n = 75) and White non-Hispanic (WNH, N = 48). Multiple linear regression analyses were conducted with age, education, sex, and ApoE4 status as predictor variables and left and right combined MRI volumes of the hippocampus, parahippocampus, and entorhinal cortex as dependent variables. Variations in head sizes were corrected by normalization with a total intracranial volume measurement. RESULTS: Bonferroni-corrected results indicated that when controlling for ApoE4 status, education, and age, sex was a significant predictor of hippocampal volume among the Hispanic group (ß = .000464, R2 = .196, p < .01) and the WNH group (ß = .000455, R2 = .195, p < .05). Education (ß = .000028, R2 = .168, p < .01) and sex (ß = .000261, R2 = .168, p < .01) were significant predictors of parahippocampal volume among the Hispanic MCI group when controlling for the effects of ApoE4 status and age. One-way ANCOVAs comparing hippocampal and parahippocampal volume between males and females within groups revealed that females had significantly larger hippocampal volumes (p < .05). Hispanic females had significantly larger hippocampal (p < .001) and parahippocampal (p < .05) volume compared to males. No sex differences in parahippocampal volume were noted among WNHs. CONCLUSIONS: Biological sex, rather than ApoE4 status, was a greater predictor of hippocampal volume among Hispanic and WNH females. These findings add to the mixed literature on sex differences in dementia research and highlight continued emphasis on ethnic populations to elucidate on neurodegenerative disparities.

Free-water imaging reveals unique brain microstructural deficits in hispanic individuals with Dementia.

Prior evidence suggests that Hispanic and non-Hispanic individuals differ in potential risk factors for the development of dementia. Here we determine whether specific brain regions are associated with cognitive performance for either ethnicity along various stages of Alzheimer's disease. For this cross-sectional study, we examined 108 participants (61 Hispanic vs. 47 Non-Hispanic individuals) from the 1Florida Alzheimer's Disease Research Center (1Florida ADRC), who were evaluated at baseline with diffusion-weighted and T1-weighted imaging, and positron emission tomography (PET) amyloid imaging. We used FreeSurfer to segment 34 cortical regions of interest. Baseline Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used as measures of cognitive performance. Group analyses assessed free-water measures (FW) and volume. Statistically significant FW regions based on ethnicity x group interactions were used in a stepwise regression function to predict total MMSE and MoCA scores. Random forest models were used to identify the most predictive brain-based measures of a dementia diagnosis separately for Hispanic and non-Hispanic groups. Results indicated elevated FW values for the left inferior temporal gyrus, left middle temporal gyrus, left banks of the superior temporal sulcus, left supramarginal gyrus, right amygdala, and right entorhinal cortex in Hispanic AD subjects compared to non-Hispanic AD subjects. These alterations occurred in the absence of different volumes of these regions in the two AD groups. FW may be useful in detecting individual differences potentially reflective of varying etiology that can influence cognitive decline and identify MRI predictors of cognitive performance, particularly among Hispanics.

The association of depression and apathy with Alzheimer's disease biomarkers in a cross-cultural sample.

Cross-cultural differences in the association between neuropsychiatric symptoms and Alzheimer's disease (AD) biomarkers are not well understood. This study aimed to (1) compare depressive symptoms and frequency of reported apathy across diagnostic groups of participants with normal cognition (CN), mild cognitive impairment (MCI), and dementia, as well as ethnic groups of Hispanic Americans (HA) and European Americans (EA); (2) evaluate the relationship between depression and apathy with Aß deposition and brain atrophy. Statistical analyses included ANCOVAs, chi-squared, nonparametric tests, correlations, and logistic regressions. Higher scores on the Geriatric Depression Scale (GDS-15) were reported in the MCI and dementia cohorts, while older age corresponded with lower GDS-15 scores. The frequency of apathy differed across diagnoses within each ethnicity, but not when comparing ethnic groups. Reduced volume in the rostral anterior cingulate cortex (ACC) significantly correlated with and predicted apathy for the total sample after applying false discovery rate corrections (FDR), controlling for covariates. The EA group separately demonstrated a significant negative relationship between apathy and superior frontal volume, while for HA, there was a relationship between rostral ACC volume and apathy. Apathy corresponded with higher Aß levels for the total sample and for the CN and HA groups.

Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans.

BACKGROUND: African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. METHOD: Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. FINDINGS: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. INTERPRETATION: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. FUNDING: This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].

The effect of acculturation on cognitive performance among older Hispanics in the United States.

The effect of acculturation on cognition was examined among 142 older Hispanics: cognitively normal [CN; n = 70], Mild Cognitive Impairment, amnestic [aMCI; n = 27], and Dementia [D; n = 45]. Acculturation levels (high vs. low) were determined using the Short Acculturation Scale for Hispanics (SASH). ANCOVAs used a wide variety of neuropsychological tests as independent variables controlling for age and education. Among CN subjects, the highly acculturated group performed better on Logical Memory delayed recall (LM-II) [F(1, 56) = 9.26, p < .001, ηp2 = 0.14], Digit Span Forward [F(1, 56) = 4.37, p < .05, ηp2 = 0.07], Trail Making Test A [F(1, 56) = 7.74, p < .05, ηp2 = 0.12], and Trail Making Test B [F(1, 56) = 4.66, p = .03, ηp2 = 0.08], indicating that high acculturation was associated with a better performance on tests of episodic memory, auditory attention, working memory, cognitive flexibility, and processing speed among CN Hispanics. ANCOVA analyses were not significant among the other groups. In the absence of acculturation scales in clinical practice, caution should be exerted when interpreting neurocognitive results.

Changes in LASSI-L performance over time among older adults with amnestic MCI and amyloid positivity: A preliminary study.

There is a pressing need to develop measures that are sensitive to the earliest subtle cognitive changes of Alzheimer's disease (AD) to improve early detection and track disease progression. The Loewenstein-Acevedo Scales of Semantic Interference (LASSI-L) has been shown to successfully discriminate between cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (MCI) and to correlate with total and regional brain amyloid load. The present study investigated how the LASSI-L scores change over time among three distinct diagnostic groups. Eighty-six community-dwelling older adults underwent a baseline evaluation including: a clinical interview, a neuropsychological evaluation, Magnetic Resonance Imaging (MRI), and amyloid Positron Emission Tomography (PET). A follow up evaluation was conducted 12 months later. Initial mean values were calculated using one-way ANOVAs and chi-square analyses. Post-hoc comparisons were conducted using Tukey's Honestly Significant Difference (HSD). A 3 × 2 repeated measures analysis was utilized to examine differences in LASSI-L performance over time. The MCI amyloid positive group demonstrated a significantly greater decline in LASSI-L performance than the MCI amyloid negative and CU groups respectively. The scales that best differentiated the three groups included the Cued A2, which taps into maximum learning capacity, and Cued B2, which assesses the failure to recover from proactive semantic interference. Our findings further support the LASSI-L's discriminative validity.

The relationship of semantic intrusions to different etiological subtypes of MCI and cognitively healthy older adults.

INTRODUCTION: There is increasing evidence that susceptibility to proactive semantic interference (PSI) and the failure to recover from PSI (frPSI) as evidenced by intrusion errors may be early cognitive markers of both preclinical and prodromal Alzheimer's disease (AD). METHODS: One hundred forty-five participants were administered extensive clinical and neuropsychological evaluations including the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive stress test measuring PSI and frPSI. Participants also underwent structural magnetic resonance imaging (MRI) and amyloid positron emission tomography/computed tomography (PET/CT) imaging. RESULTS: PSI and frPSI errors were much more prevalent in the mild cognitive impairment (MCI)-AD (amyloid positive) group than the other diagnostic groups. The number of intrusion errors observed across the other MCI groups without amyloid pathology and those with normal cognition were comparable. DISCUSSION: Semantic intrusion errors on the LASSI-L occur much less frequently in persons who have different types of non-AD-related MCI and may be used as an early cognitive marker of prodromal AD.

A cognitive stress test for prodromal Alzheimer's disease: Multiethnic generalizability.

INTRODUCTION: Culturally fair cognitive assessments sensitive to detecting changes associated with prodromal Alzheimer's disease are needed. METHODS: Performance of Hispanic and non-Hispanic older adults on the Loewenstein-Acevedo Scale of Semantic Interference and Learning (LASSI-L) was examined in persons with amnestic mild cognitive impairment (aMCI) or normal cognition. The association between a novel cognitive marker, the failure to recover from proactive semantic interference (frPSI), and cortical thinning was explored. RESULTS: English-speaking aMCI participants scored lower than cognitively normal participants on all LASSI-L indices, while Spanish-speaking aMCI participants scored lower in learning, frPSI, and delayed recall. Healthy controls obtained equivalent scores on all indices except retroactive semantic interference. English-speaking and Spanish-speaking aMCI participants had equivalent scores except English speaker's greater vulnerability to frPSI. Across aMCI groups, frPSI was associated with cortical thinning of the entorhinal cortex and precuneus (r = -0.45 to r = 0.52; P < .005). DISCUSSION: In diverse populations, LASSI-L performance differentiated patients with aMCI from cognitively normal older adults and was associated with thinning in Alzheimer's disease-prone regions, suggesting its clinical utility.

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort.

INTRODUCTION: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases. METHODS: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539). RESULTS: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups. DISCUSSION: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment.

OBJECTIVE: Semantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition. METHODS: Eighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy-), or other neurological/psychiatric diagnosis (Amy-). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning). RESULTS: SIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP. CONCLUSIONS: SIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy- participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.

Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness.

BACKGROUND: Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory. OBJECTIVES: We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI). METHODS: Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions. RESULTS: SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models. CONCLUSION: Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.

Relationship between Cognitive Performance and Measures of Neurodegeneration among Hispanic and White Non-Hispanic Individuals with Normal Cognition, Mild Cognitive Impairment, and Dementia.

OBJECTIVES: The aim of this study was to determine the presence and severity of potential cultural and language bias in widely used cognitive and other assessment instruments, using structural MRI measures of neurodegeneration as biomarkers of disease stage and severity. METHODS: Hispanic (n=75) and White non-Hispanic (WNH) (n=90) subjects were classified as cognitively normal (CN), amnestic mild cognitive impairment (aMCI) and mild dementia. Performance on the culture-fair and educationally fair Fuld Object Memory Evaluation (FOME) and Clinical Dementia Rating Scale (CDR) between Hispanics and WNHs was equivalent, in each diagnostic group. Volumetric and visually rated measures of the hippocampus entorhinal cortex, and inferior lateral ventricles (ILV) were measured on structural MRI scans for all subjects. A series of analyses of covariance, controlling for age, depression, and education, were conducted to compare the level of neurodegeneration on these MRI measures between Hispanics and WNHs in each diagnostic group. RESULTS: Among both Hispanics and WNH groups there was a progressive decrease in volume of the hippocampus and entorhinal cortex, and an increase in volume of the ILV (indicating increasing atrophy in the regions surrounding the ILV) from CN to aMCI to mild dementia. For equivalent levels of performance on the FOME and CDR, WNHs had greater levels of neurodegeneration than did Hispanic subjects. CONCLUSIONS: Atrophy in medial temporal regions was found to be greater among WNH than Hispanic diagnostic groups, despite the lack of statistical differences in cognitive performance between these two ethnic groups. Presumably, unmeasured factors result in better cognitive performance among WNH than Hispanics for a given level of neurodegeneration. (JINS, 2018, 24, 176-187).

African American exome sequencing identifies potential risk variants at Alzheimer disease loci.

OBJECTIVE: In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes. METHODS: We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants. RESULTS: Two ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant gene-based association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes. CONCLUSIONS: Our findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.

The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida.

Mutations in the gene encoding the presenilin-1 protein (PSEN1) were first discovered to cause Alzheimer's disease (AD) 20 years ago. Since then more than 200 different pathogenic mutations have been reported, including a p.Gly206Ala founder mutation in the Hispanic population. Here we report mutation analysis of known AD genes in a cohort of 27 early-onset (age of onset ≤65, age of death ≤70) Hispanic patients ascertained in Florida. The PSEN1 p.Gly206Ala mutation was identified in 13 out of 27 patients (48.1%), emphasizing the importance of this specific mutation in the etiology of early-onset AD in this population. One other patient carried the known PSEN1 p.Gly378Val mutation. Genotyping of the PSEN1 p.Gly206Ala and p.Gly378Val mutations in 63 late-onset Hispanic AD patients did not identify additional mutation carriers. All p.Gly206Ala mutation carriers shared rare alleles at two microsatellite markers flanking PSEN1 supporting a common founder. This study confirms the p.Gly206Ala variant as a frequent cause of early onset AD in the Hispanic population and for the first time reports the high frequency of this mutation in Hispanics in Florida.

Cognitive and structural magnetic resonance imaging features of Lewy body dementia and Alzheimer's disease.

OBJECTIVE: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer's disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures. METHODS: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson's Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed. RESULTS: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson's Disease Rating Scale scores and Peri-IIIVent atrophy measures. CONCLUSIONS: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD.

Diagnosis and staging of mild cognitive impairment, using a modification of the clinical dementia rating scale: the mCDR.

OBJECTIVE: To examine the reliability and validity of the mCDR, a modified version of the clinical dementia rating (CDR) scale. METHODS: The mCDR is an informant-based, technician-administered, structured interview with multiple choice responses, which does not include objective cognitive testing. Subjects (n = 556) with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), and dementia were assessed with mCDR, CDR, and neuropsychological evaluation, while medial temporal atrophy (MTA) was measured on MRI scans. The mCDR and CDR were compared with respect to inter-rater reliability, validity, and ability to predict progression in cognitive diagnosis at 12 month follow-up. RESULTS: The mCDR can be administered in less than one third of the time required to administer the CDR (30 min). Inter-rater reliability (Cohen's weighted kappa) was 0.86 for the mCDR and 0.56 for the CDR. Ability to distinguish between NCI, aMCI, and Dementia subjects, and correlations to memory and non-memory measures were marginally better for the CDR, in comparison to the mCDR. Correlations of mCDR and CDR scores to MTA scores did not differ. Baseline mCDR scores predicted transition from NCI to aMCI, whereas baseline CDR scores predicted transition from aMCI to Dementia. CONCLUSIONS: The mCDR, as compared to the CDR, is briefer and more reliable, and is a valid measure of functional ability among subjects with normal cognition, mild cognitive impairment, and mild dementia. The mCDR should be particularly useful as a reliable and economical instrument for assessing change in functional abilities, especially in multi-center clinical trials and population studies of MCI and mild dementia.

A clinical perspective of mild cognitive impairment: what radiologists should know.

Mild cognitive impairment (MCI), a major risk factor for dementia, has an amnestic subtype that has a high probability of progressing to Alzheimer's disease. The rate of progression may be predicted by the severity of memory impairment at baseline, the severity of hippocampal atrophy, and, possibly, the presence of an epsilon4 allele of the apolipoprotein E gene. MCI can be diagnosed using purely clinical or a combination of clinical and neuropsychologic criteria. Treatment trials show no disease-modifying effect. The radiologists' role is to determine whether or not the hallmarks of degenerative and vascular disease of the brain are present, aiding in the diagnosis of the cause of MCI.