Neuropathology, Neuroimaging, and Fluid Biomarkers in Alzheimer's Disease.

An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-ß plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aß peptides, especially Aß42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.

Diffusion MRI relates to plasma Aß42/40 in PET negative participants without dementia.

INTRODUCTION: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-ß (Aß42/40) positivity in Aß positron emission tomography (PET) negative individuals. METHODS: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aß plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aß42/40 and p-tau181. DISCUSSION: FW imaging changes distinguish plasma Aß42/40 positive and negative groups, independent of group differences in cognitive status, Aß PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). HIGHLIGHTS: Plasma Aß42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aß42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

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.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

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.

Cross-cultural Diagnostic Validity of the Multilingual Naming Test (MINT) in a Sample of Older Adults.

OBJECTIVE: We aimed to evaluate the psychometric properties and diagnostic accuracy of the 32-item version of the Multilingual Naming Test (MINT) in participants from 2 ethnic groups (European Americans [EA; n = 106] and Hispanic Americans [HA; n = 175]) with 3 diagnostic groups (cognitively normal [CN], n = 94, mild cognitive impairment [MCI], n = 148, and dementia, n = 39). METHOD: An Item Response Theory model was used to evaluate items across ethnicity and language groups (Spanish and English), resulting in a 24-item version. We analyzed the MINT discriminant and predictive validity across diagnostic groups. RESULTS: A total of 8 items were differentially difficult between languages in the 32-item version of the MINT. EA scored significantly higher than HA, but the difference was not significant when removing those 8 items (controlling for Education). The Receiver Operating Characteristics showed that the MINT had poor accuracy when identifying CN participants and was acceptable in identifying dementia participants but unacceptable in classifying MCI participants. Finally, we tested the association between MINT scores and magnetic resonance imaging volumetric measures of language-related areas in the temporal and frontal lobes. The 32-item MINT in English and Spanish and the 24-item MINT in Spanish were significantly correlated with the bilateral middle temporal gyrus. The left fusiform gyrus correlated with MINT scores regardless of language and MINT version. We also found differential correlations depending on the language of administration. CONCLUSIONS: Our results highlight the importance of analyzing cross-cultural samples when implementing clinical neuropsychological tests such as the MINT.

Semantic intrusion errors are associated with plasma Ptau-181 among persons with amnestic mild cognitive impairment who are amyloid positive.

Introduction: Semantic intrusion errors (SI) have distinguished between those with amnestic Mild Cognitive Impairment (aMCI) who are amyloid positive (A+) versus negative (A-) on positron emission tomography (PET). Method: This study examines the association between SI and plasma - based biomarkers. One hundred and twenty-eight participants received SiMoA derived measures of plasma pTau-181, ratio of two amyloid-ß peptide fragments (Aß42/Aß40), Neurofilament Light protein (NfL), Glial Fibrillary Acidic Protein (GFAP), ApoE genotyping, and amyloid PET imaging. Results: The aMCI A+ (n = 42) group had a higher percentage of ApoE ɛ4 carriers, and greater levels of pTau-181 and SI, than Cognitively Unimpaired (CU) A- participants (n = 25). CU controls did not differ from aMCI A- (n = 61) on plasma biomarkers or ApoE genotype. Logistic regression indicated that ApoE ɛ4 positivity, pTau-181, and SI were independent differentiating predictors (Correct classification = 82.0%; Sensitivity = 71.4%; Specificity = 90.2%) in identifying A+ from A- aMCI cases. Discussion: A combination of plasma biomarkers, ApoE positivity and SI had high specificity in identifying A+ from A- aMCI cases.

Stability in cognitive classification as a function of severity of impairment and ethnicity: A longitudinal analysis.

OBJECTIVE: The interaction of ethnicity, progression of cognitive impairment, and neuroimaging biomarkers of Alzheimer's Disease remains unclear. We investigated the stability in cognitive status classification (cognitively normal [CN] and mild cognitive impairment [MCI]) of 209 participants (124 Hispanics/Latinos and 85 European Americans). METHODS: Biomarkers (structural MRI and amyloid PET scans) were compared between Hispanic/Latino and European American individuals who presented a change in cognitive diagnosis during the second or third follow-up and those who remained stable over time. RESULTS: There were no significant differences in biomarkers between ethnic groups in any of the diagnostic categories. The frequency of CN and MCI participants who were progressors (progressed to a more severe cognitive diagnosis at follow-up) and non-progressors (either stable through follow-ups or unstable [progressed but later reverted to a diagnosis of CN]) did not significantly differ across ethnic groups. Progressors had greater atrophy in the hippocampus (HP) and entorhinal cortex (ERC) at baseline compared to unstable non-progressors (reverters) for both ethnic groups, and more significant ERC atrophy was observed among progressors of the Hispanic/Latino group. For European Americans diagnosed with MCI, there were 60% more progressors than reverters (reverted from MCI to CN), while among Hispanics/Latinos with MCI, there were 7% more reverters than progressors. Binomial logistic regressions predicting progression, including brain biomarkers, MMSE, and ethnicity, demonstrated that only MMSE was a predictor for CN participants at baseline. However, for MCI participants at baseline, HP atrophy, ERC atrophy, and MMSE predicted progression.

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.

Heterogeneity in Alzheimer's Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials.

The clinical presentation and the pathological processes underlying Alzheimer's disease (AD) can be very heterogeneous in severity, location, and composition including the amount and distribution of AB deposition and spread of neurofibrillary tangles in different brain regions resulting in atypical clinical patterns and the existence of distinct AD variants. Heterogeneity in AD may be related to demographic factors (such as age, sex, educational and socioeconomic level) and genetic factors, which influence underlying pathology, the cognitive and behavioral phenotype, rate of progression, the occurrence of neuropsychiatric features, and the presence of comorbidities (e.g., vascular disease, neuroinflammation). Heterogeneity is also manifest in the individual resilience to the development of neuropathology (brain reserve) and the ability to compensate for its cognitive and functional impact (cognitive and functional reserve). The variability in specific cognitive profiles and types of functional impairment may be associated with different progression rates, and standard measures assessing progression may not be equivalent for individual cognitive and functional profiles. Other factors, which may govern the presence, rate, and type of progression of AD, include the individuals' general medical health, the presence of specific systemic conditions, and lifestyle factors, including physical exercise, cognitive and social stimulation, amount of leisure activities, environmental stressors, such as toxins and pollution, and the effects of medications used to treat medical and behavioral conditions. These factors that affect progression are important to consider while designing a clinical trial to ensure, as far as possible, well-balanced treatment and control groups.

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.

Patient values in healthcare decision making among diverse older adults.

OBJECTIVE: To provide high-quality healthcare, it is essential to understand values that guide the healthcare decisions of older adults. We investigated the types of values that culturally diverse older adults incorporate in medical decision making. METHODS: Focus groups were held with older adults who varied in cognitive status (mildly impaired versus those with normal cognition) and ethnicity (Hispanic and non-Hispanic). Investigators used a qualitative descriptive approach to analyze transcripts and identify themes. RESULTS: Forty-nine individuals (49% with cognitive impairment; 51% Hispanic) participated. Participants expressed a wide range of values relating to individual factors, familial/cultural beliefs and expectations, balancing risks and benefits, receiving decisional support, and considering values other than their own. Participants emphasized that values are individual-specific, influenced by aging, and change throughout life course. Participants described barriers and facilitators that interfere with or promote value solicitation and incorporation during medical encounters. CONCLUSION: Study findings highlight that in older adults with various health experiences, cognitive and physical health status, and sociocultural backgrounds, medical decisions are influenced by a variety of values. PRACTICAL IMPLICATIONS: Clinicians should take time to elicit, understand, and reassess the different types of values of older adults.

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.

Intrusion Errors and Progression of Cognitive Deficits in Older Adults with Mild Cognitive Impairment and PreMCI States.

INTRODUCTION: Among persons with amnestic mild cognitive impairment (aMCI), intrusion errors on subscales that measure proactive semantic interference (PSI) may be among the earliest behavioral markers of elevated Alzheimer's disease brain pathology. While there has been considerable cross-sectional work in the area, it is presently unknown whether semantic intrusion errors are predictive of progression of cognitive impairment in aMCI or PreMCI (not cognitively normal but not meeting full criteria for MCI). METHODS: This study examined the extent to which the percentage of semantic intrusion errors (PIE) based on total responses on a novel cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), could predict clinical/cognitive outcomes over an average 26-month period in older adults initially diagnosed with aMCI, PreMCI, and normal cognition. RESULTS: On the LASSI-L subscale sensitive to PSI, a PIE cut point of 44% intrusion errors distinguished between those at-risk individuals with PreMCI who progressed to MCI over time compared to individuals with PreMCI who reverted to normal on longitudinal follow-up. Importantly, PIE was able to accurately predict 83.3% of aMCI individuals who later progressed to dementia. DISCUSSION: These preliminary findings indicate that PIE on LASSI-L subscales that measure PSI may be a useful predictor of clinical progression overtime in at-risk older adults.

Depression and the Diagnosis of MCI in a Culturally Diverse Sample in the United States.

OBJECTIVE: To analyze (1) whether there are ethnic differences in the severity of depressive symptoms between groups of elders classified as cognitively normal (CN) or amnestic mild cognitive impairment (aMCI) and (2) the influence of depressive symptoms on specific cognitive performance by ethnicity across diagnoses, controlling for covariates. METHODS: 164 Hispanics residing in the United States (HAs) and European Americans (EAs) (100 women; Mage = 72.1, SD = 8.0) were diagnosed as either CN or aMCI. Depressive symptoms were measured with the Geriatric Depression Scale (GDS-15). Cognition was assessed using the Loewenstein-Acevedo Scales for Semantic Interference and Learning (semantic memory), Multilingual Naming Test (confrontation naming), and the Stroop Test (Color-Word condition; executive function). A 2 × 2 univariate ANCOVA as well as linear and logistic regressions explored differences in depressive symptoms among diagnostic and ethnic groups. RESULTS: Higher depression was seen in aMCI compared to the CN group for both ethnicities, after controlling for age, education, gender, and Mini-Mental State Examination score. Greater levels of depression also predicted lower scores in confrontation naming and semantic memory for only the EA group and marginally in scores of executive function for HA participants. GDS-15 scores of ≤ 4 also predicted less likelihood of aMCI diagnosis. CONCLUSIONS: Severity of depressive symptoms was associated with greater cognitive impairment, independent of ethnicity. Significant results suggest detrimental effects of depression on clinical diagnoses most evidently for subjects from the EA group.

The Association Between Functional Assessment and Structural Brain Biomarkers in an Ethnically Diverse Sample With Normal Cognition, Mild Cognitive Impairment, or Dementia.

OBJECTIVE: To investigate the association between the functional activities questionnaire (FAQ) and brain biomarkers (bilateral hippocampal volume [HV], bilateral entorhinal volume [ERV], and entorhinal cortical thickness [ERT]) in cognitively normal (CN) individuals, mild cognitive impairment (MCI), or dementia. METHOD: In total, 226 participants (137 females; mean age = 71.76, SD = 7.93; Hispanic Americans = 137; European Americans = 89) were assessed with a comprehensive clinical examination, a neuropsychological battery, a structural magnetic resonance imaging, and were classified as CN or diagnosed with MCI or dementia. Linear regression analyses examined the association between functional activities as measured by the FAQ on brain biomarkers, including HV, ERV, and ERT, controlling for age, education, global cognition, gender, and ethnicity. RESULTS: The FAQ significantly predicted HV, ERV, and ERT for the entire sample. However, this association was not significant for ERV and ERT when excluding the dementia group. The FAQ score remained a significant predictor of HV for the non-dementia group. Age, education, gender, ethnicity, Montreal Cognitive Assessment score, and FAQ were also significant predictors of HV for the overall sample, suggesting that younger Hispanic females with fewer years of education, higher global mental status, and better functioning, were more likely to have larger HV. CONCLUSION: FAQ scores were related to HV in older adults across clinical groups (CN, MCI, and dementia), but its association with the entorhinal cortex was driven by individuals with dementia. Demographic variables, including ethnicity, additionally influenced these associations.

Utility of Plasma Neurofilament Light in the 1Florida Alzheimer's Disease Research Center (ADRC).

BACKGROUND: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. OBJECTIVE: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. METHODS: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. RESULTS: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. CONCLUSION: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

A novel method of evaluating semantic intrusion errors to distinguish between amyloid positive and negative groups on the Alzheimer's disease continuum.

BACKGROUND: The development and validation of clinical outcome measures to detect early cognitive decline associated with Alzheimer's disease (AD) biomarkers is imperative. Semantic intrusions on the Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) has outperformed widely used cognitive measures as an early correlate of elevated brain amyloid in prodromal AD and has distinguished those with amnestic mild cognitive impairment (aMCI) and high amyloid load from aMCI attributable to other non-AD conditions. METHODS: Since intrusion errors on memory tasks vary widely, we employed a novel method that accounts for the percentage of intrusion errors (PIE) in relation to total responses. Individuals with either high or low amyloid load across the spectrum of aMCI and dementia and amyloid negative cognitively normal older adults (CN) were studied. RESULTS: Mean PIE on indices sensitive to proactive semantic interference (PSI) and failure to recover from proactive semantic interference (frPSI) could distinguish amyloid positive from amyloid negative aMCI and dementia groups. Number of correct responses alone, while able to differentiate the different diagnostic groups, did not differentiate amyloid positive aMCI from their counterparts without amyloid pathology. CONCLUSIONS: PIE, a novel and sensitive index of early memory dysfunction, demonstrated high levels of sensitivity and specificity in differentiating CN from amyloid positive persons with preclinical AD. Mean levels of PIE are higher for amyloid positive aMCI and dementia participants relative to their amyloid negative counterparts.

Greater Regional Cortical Thickness is Associated with Selective Vulnerability to Atrophy in Alzheimer's Disease, Independent of Amyloid Load and APOE Genotype.

BACKGROUND: Regional cortical thickness (rCTh) among cognitively normal (CN) adults (rCThCN) varies greatly between brain regions, as does the vulnerability to neurodegeneration. OBJECTIVE: The goal of this study was to: 1) rank order rCThCN for various brain regions, and 2) explore their vulnerability to neurodegeneration in Alzheimer's disease (AD) within these brain regions. METHODS: The relationship between rCTh among the CN group (rCThCN) and the percent difference in CTh (% CThDiff) in each region between the CN group and AD patients was examined. Pearson correlation analysis was performed accounting for amyloid-ß (Aß) protein and APOE genotype using 210 age, gender, and APOE matched CN (n = 105, age range: 56-90) and AD (n = 105, age range: 56-90) ADNI participants. RESULTS: Strong positive correlations were observed between rCThCN and % CThDiff accounting for Aß deposition and APOE status. Regions, such as the entorhinal cortex, which had the greatest CTh in the CN state, were also the regions which had the greatest % CThDiff. CONCLUSIONS: Regions with the greatest CTh at the CN stage are found to aggregate in disease prone regions of AD, namely in the medial temporal lobe, including the temporal pole, ERC, parahippocampal gyrus, fusiform and the middle and inferior temporal gyrus. Although rCTh has been found to vary considerably across the different regions of the brain, our results indicate that regions with the greatest CTh at the CN stage are actually regions which have been found to be most vulnerable to neurodegeneration in AD.

Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints.

BACKGROUND: The impact of amyloid positron emission tomography (Aß-PET) in a "real-world" memory disorders clinic remains poorly studied. OBJECTIVE: We studied the impact of Aß-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aß-PET scans. RESULTS: Following Aß-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aß-PET versus post-Aß-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001). CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aß-PET scans.