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.

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.

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.

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.

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).

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load.

OBJECTIVE: To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. METHODS: Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures. RESULTS: LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain. CONCLUSION: Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

A practical guideline for intracranial volume estimation in patients with Alzheimer's disease.

BACKGROUND: Intracranial volume (ICV) is an important normalization measure used in morphometric analyses to correct for head size in studies of Alzheimer Disease (AD). Inaccurate ICV estimation could introduce bias in the outcome. The current study provides a decision aid in defining protocols for ICV estimation in patients with Alzheimer disease in terms of sampling frequencies that can be optimally used on the volumetric MRI data, and the type of software most suitable for use in estimating the ICV measure. METHODS: Two groups of 22 subjects are considered, including adult controls (AC) and patients with Alzheimer Disease (AD). Reference measurements were calculated for each subject by manually tracing intracranial cavity by the means of visual inspection. The reliability of reference measurements were assured through intra- and inter- variation analyses. Three publicly well-known software packages (Freesurfer, FSL, and SPM) were examined in their ability to automatically estimate ICV across the groups. RESULTS: Analysis of the results supported the significant effect of estimation method, gender, cognitive condition of the subject and the interaction among method and cognitive condition factors in the measured ICV. Results on sub-sampling studies with a 95% confidence showed that in order to keep the accuracy of the interleaved slice sampling protocol above 99%, the sampling period cannot exceed 20 millimeters for AC and 15 millimeters for AD. Freesurfer showed promising estimates for both adult groups. However SPM showed more consistency in its ICV estimation over the different phases of the study. CONCLUSIONS: This study emphasized the importance in selecting the appropriate protocol, the choice of the sampling period in the manual estimation of ICV and selection of suitable software for the automated estimation of ICV. The current study serves as an initial framework for establishing an appropriate protocol in both manual and automatic ICV estimations with different subject populations.

Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study.

OBJECTIVE: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. METHODS: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. RESULTS: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. CONCLUSIONS: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology.

Visual rating and volumetric measurement of medial temporal atrophy in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort: baseline diagnosis and the prediction of MCI outcome.

OBJECTIVE: This study aims to determine the clinical utility of visual ratings and volumetric measurements of medial temporal atrophy among subjects from the Alzheimer's Disease Neurorimaging Initiative (ADNI) cohort. METHODS: A sample of 189 subjects from the ADNI, Phase 1 (ADNI-1), was chosen as follows: 49 cognitively normal (CN), 89 with mild cognitive impairment (MCI), and 50 with Alzheimer's disease (AD). Structural MRI images were downloaded from the ADNI website, and a visual rating system (VRS) was used to obtain semi-quantitative ratings of the hippocampus (HPC) and entorhinal cortex (ERC). VRS ratings and FreeSurfer measures of the HPC and ERC were used to predict (i) baseline diagnosis and (ii) progression to AD among subjects with MCI at baseline. RESULTS: VRS and FreeSurfer measures of ERC were equivalent in classifying subjects at baseline, but FreeSurfer measures of HPC were superior to VRS measures for classifying CN versus MCI subjects. VRS and FreeSurfer measures of both HPC and ERC were significant predictors of progression from MCI to AD. However, VRS ratings of ERC were superior to other MRI measures. MCI subjects with minimal ERC atrophy by VRS had a threefold lower progression rate to AD at 3.2 years compared with those with mild, moderate, or severe atrophy (23% vs 63%, 69%, and 87%, respectively). CONCLUSIONS: Visual ratings of HPC and ERC provide useful information to a physician in a clinical setting. Visual ratings of ERC may be especially useful in following patients with MCI.

Significance of normalization on anatomical MRI measures in predicting Alzheimer's disease.

This study establishes a new approach for combining neuroimaging and neuropsychological measures for an optimal decisional space to classify subjects with Alzheimer's disease (AD). This approach relies on a multivariate feature selection method with different MRI normalization techniques. Subcortical volume, cortical thickness, and surface area measures are obtained using MRIs from 189 participants (129 normal controls and 60 AD patients). Statistically significant variables were selected for each combination model to construct a multidimensional space for classification. Different normalization approaches were explored to gauge the effect on classification performance using a support vector machine classifier. Results indicate that the Mini-mental state examination (MMSE) measure is most discriminative among single-measure models, while subcortical volume combined with MMSE is the most effective multivariate model for AD classification. The study demonstrates that subcortical volumes need not be normalized, whereas cortical thickness should be normalized either by intracranial volume or mean thickness, and surface area is a weak indicator of AD with and without normalization. On the significant brain regions, a nearly perfect symmetry is observed for subcortical volumes and cortical thickness, and a significant reduction in thickness is particularly seen in the temporal lobe, which is associated with brain deficits characterizing AD.

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.

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.

Amyloid positron emission tomography with (18)F-flutemetamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: To evaluate the contributions of amyloid-positive (Am+) and medial temporal atrophy-positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimer's disease (AD). METHODS: (18)F-flutemetamol-labeled amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to classify 10 young normal, 15 elderly normal, 20 amnestic mild cognitive impairment (aMCI), and 27 AD subjects. MTA+ status was determined using a cut point derived from a previous study, and Am+ status was determined using a conservative and liberal cut point. RESULTS: The rates of MRI scans with positive results among young normal, elderly normal, aMCI, and AD subjects were 0%, 20%, 75%, and 82%, respectively. Using conservative cut points, the rates of Am+ scans for these same groups of subjects were 0%, 7%, 50%, and 93%, respectively, with the aMCI group showing the largest discrepancy between Am+ and MTA+ scans. Among aMCI cases, 80% of Am+ subjects were also MTA+, and 70% of amyloid-negative (Am-) subjects were MTA+. The combination of amyloid PET and MTA data was additive, with an overall correct classification rate for aMCI of 86%, when a liberal cut point (standard uptake value ratio = 1.4) was used for amyloid positivity. INTERPRETATION: (18)F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample.

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.

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.

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.

Comparing new templates and atlas-based segmentations in the volumetric analysis of brain magnetic resonance images for diagnosing Alzheimer's disease.

BACKGROUND: The segmentation of brain structures on magnetic resonance imaging scans for calculating regional brain volumes, using automated anatomic labeling, requires the use of both brain atlases and templates (template sets). This study aims to improve the accuracy of volumetric analysis of hippocampus (HP) and amygdala (AMG) in the assessment of early Alzheimer's disease (AD) by developing template sets that correspond more closely to the brains of elderly individuals. METHODS: Total intracranial volume and HP and AMG volumes were calculated for elderly subjects with no cognitive impairment (n = 103), with amnestic mild cognitive impairment (n = 68), or with probable AD (n = 46) using the following: (1) a template set consisting of a standard atlas (atlas S), drawn on a young adult male brain, and the widely used Montreal Neurological Institute template (MNI template set); (2) a template set (template S set) in which the template is based on smoothing the image from which atlas S is derived; and (3) a new template set (template E set) in which the template is based on an atlas (atlas E) created from the brain of an elderly individual. RESULTS: Correspondence to HP and AMG volumes derived from manual segmentation was highest with automated segmentation by template E set, intermediate with template S set, and lowest with the MNI template set. The areas under the receiver operating curve for distinguishing elderly subjects with no cognitive impairment from elderly subjects with amnestic mild cognitive impairment or probable AD and the correlations between HP and AMG volumes and cognitive and functional scores were highest for template E set, intermediate for template S set, and lowest for the MNI template set. CONCLUSIONS: The accuracy of automated anatomic labeling and the diagnostic value of the derived volumes are improved with template sets based on brain atlases closely resembling the anatomy of the to-be-segmented brain magnetic resonance imaging scans.

An investigation of PreMCI: subtypes and longitudinal outcomes.

BACKGROUND/AIMS: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). METHODS: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. RESULTS: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. CONCLUSION: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.

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.