Excellent Interrater Reliability for Manual Segmentation of the Medial Perirhinal Cortex.

Objective: Evaluation of interrater reliability for manual segmentation of brain structures that are affected first by neurofibrillary tau pathology in Alzheimer's disease. Method: Medial perirhinal cortex, lateral perirhinal cortex, and entorhinal cortex were manually segmented by two raters on structural magnetic resonance images of 44 adults (20 men; mean age = 69.2 ± 10.4 years). Intraclass correlation coefficients (ICC) of cortical thickness and volumes were calculated. Results: Very high ICC values of manual segmentation for the cortical thickness of all regions (0.953-0.986) and consistently lower ICC values for volume estimates of the medial and lateral perirhinal cortex (0.705-0.874). Conclusions: The applied manual segmentation protocol allows different raters to achieve remarkably similar cortical thickness estimates for regions of the parahippocampal gyrus. In addition, the results suggest a preference for cortical thickness over volume as a reliable measure of atrophy, especially for regions affected by collateral sulcus variability (i.e., medial and lateral perirhinal cortex). The results provide a basis for future automated segmentation and collection of normative data.

Conversion between the Montreal Cognitive Assessment and the Mini-Mental Status Examination.

BACKGROUND: Early and accurate detection of cognitive changes using simple tools is essential for an appropriate referral to a more detailed neurocognitive assessment and for the implementation of therapeutic strategies. The Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are two commonly used psychometric tests for cognitive screening. Both tests have different strengths and weaknesses. Preferences regarding test selection may therefore differ among clinicians. The aim of this retrospective observational cohort study was to define corresponding scores for the MMSE and the MoCA. METHODS: We examined the relationship between the cognitive screening tests in 803 German-speaking Memory Clinic outpatients, encompassing a wide range of neurocognitive disorders. We produced a conversion table using the equipercentile equating method with log-linear smoothing. In addition, we conducted a systematic review of existing MMSE-MoCA conversions to create a table allowing for the conversion of MoCA scores into MMSE scores and vice versa using the weighted mean method. RESULTS: The Memory Clinic sample showed that the prediction of MMSE to MoCA was overall less accurate compared to the conversion from MoCA to MMSE. The 19 studies included after thorough literature search showed that MoCA scores were consistently lower than MMSE scores. Eleven of 19 conversion studies had addressed the conversion of the MoCA to the MMSE, while two studies converted MMSE to MoCA scores. Another six studies applied bi-directional conversions. We provide an easy-to-use table covering the entire range of scores and taking into account all currently existing conversion formulas. CONCLUSION: The comprehensive MMSE-MoCA conversion table enables a direct comparison of cognitive test scores at screening examinations and over the course of disease in patients with neurocognitive disorders.

Can you find it? Novel oddity detection task for the early detection of Alzheimer's disease.

OBJECTIVE: We aimed to develop a measure to specifically assess the functioning of the perirhinal cortex (PRC), a brain structure affected very early in Alzheimer's disease (AD) pathology. In this novel task, participants were shown arrays of six complex figures and had to identify the "odd-one." METHOD: The pilot study included 50 normal controls (NCs) and 50 patients in very early stages of AD. Participants completed the task and received MRI scanning. Best differentiating items were determined and applied in a validation study including 25 NCs, 27 early-stage AD patients, and 26 patients with major depression. Logistic regression models investigated if task performance predicted group membership. Task performance was then related to whole-brain gray matter integrity. As proof of concept, cortical thickness values of four regions of interest (ROIs; e.g., medial PRC and entorhinal cortex [ERC]) were compared between the groups. The associations of task performance and cortical thickness of the ROIs were investigated using linear models. RESULTS: Task performance showed good discriminative ability between early-stage AD patients and NCs. Whole-brain analyses revealed four significant clusters (p < .001) with peak voxels in parahippocampal regions including PRC and ERC. ROI analyses showed distinctly reduced cortical thickness in the AD group compared to both other groups in the medial PRC and ERC (p ≤ .001). Task performance modeled by ROI cortical thickness did not achieve significant results. CONCLUSION: Although further validation is needed, especially with age-matched participant groups, these findings indicate that the task detects early cognitive impairment related to AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Moving in Semantic Space in Prodromal and Very Early Alzheimer's Disease: An Item-Level Characterization of the Semantic Fluency Task.

The semantic fluency task is a widely used clinical tool in the diagnostic process of Alzheimer's disease. The task requires efficient mapping of the semantic space to produce as many items as possible within a semantic category. We examined whether healthy volunteers (n = 42) and patients with early Alzheimer's disease (24 diagnosed with amnestic Mild Cognitive Impairment and 18 with early Alzheimer's dementia) take advantage of and travel in the semantic space differently. With focus on the animal fluency task, we sought to emulate the detailed structure of the multidimensional semantic space by utilizing word2vec-method from the natural language processing domain. To render the resulting multidimensional semantic space visually comprehensible, we applied a dimensionality reduction algorithm (t-SNE), which enabled a straightforward division of the semantic space into sub-categories. Moving in semantic space was quantified with the number of items created, sub-categories visited, and switches and returns to these sub-categories. Multinomial logistic regression models were used to predict the diagnostic group with these independent variables. We found that returning to a sub-category provided additional information, besides the number of words produced in the task, to differentiate patients with Alzheimer's dementia from both amnestic Mild Cognitive Impairment patients and healthy controls. The results suggest that the frequency of returning to a sub-category may serve as an additional aid for clinicians in diagnosing early Alzheimer's disease. Moreover, our results imply that the combination of word2vec and subsequent t-SNE-visualization may offer a valuable tool for examining the semantic space and its sub-categories.

Manual Correction of Voxel Misclassifications in Mesiotemporal Structures Does Not Alter Brain-Behavioral Results in an Episodic Memory Task.

Voxel-based morphometry (VBM) is an established method for assessing grey matter volumes across the brain. The quality of magnetic resonance imaging (MRI) and the chosen data preprocessing steps can affect the outcome of VBM analyses. We recognized a lack of publicly available and commonly used protocols, which indicates that standardized and optimized preprocessing protocols are needed. This paper focuses on the time- and resource-consuming manual correction of misclassifications of grey matter voxels in cortical structures important in Alzheimer's dementia. A total of 126 individuals, including 63 patients with very early Alzheimer's disease and 63 cognitively normal participants, received thorough neuropsychological testing and 3-Tesla MRI. Automated preprocessing of T1 MPRAGE images was performed, and misclassifications of grey matter voxels were manually identified and corrected. In a second run, the manual correction step was skipped. Multiple regression analyses using DARTEL in SPM8 were then conducted with the manually corrected and uncorrected sample, respectively. Manual correction of voxel misclassifications did not have a major impact on the correlation between episodic memory performance and structural brain imaging results. We conclude that, although performing all preprocessing steps remains the gold standard, skipping manual correction of voxel misclassifications is permitted when investigating populations on the Alzheimer's disease spectrum.

Cats and Apples: Semantic Fluency Performance for Living Things Identifies Patients with Very Early Alzheimer's Disease.

OBJECTIVE: Reduced semantic memory performance is a known neuropsychological marker of very early Alzheimer's disease (AD), but the task format that best predicts disease status is an open question. The present study aimed to identify the semantic fluency task and measure that best discriminates early-stage AD patients (PATs) from cognitively healthy controls. METHOD: Semantic fluency performance for animals, fruits, tools, and vehicles was assessed in 70 early-stage AD PATs and 67 cognitively healthy participants. Logistic regressions and receiver operating characteristics were calculated for five total score semantic fluency measures. RESULTS: Compared with all other measures, living things (i.e., total correct animals + total correct fruits) achieved highest z-statistics, highest area under the curve and smallest difference between the upper and lower 95% confidence intervals. CONCLUSION: Living things total correct is a powerful tool to detect the earliest signs of incipient AD.

Neural Correlates of Stepping in Healthy Elderly: Parietal and Prefrontal Cortex Activation Reflects Cognitive-Motor Interference Effects.

Gait analysis involving cognitive-motor dual task (DT) is a diagnostic tool in geriatrics. Cognitive-motor interference effects during DT, such as decreased walking speed and increased step-to-step variability, have a high predictive value for fall risk and cognitive decline. Previously we showed the feasibility of DT during functional magnetic resonance imaging (fMRI) using an MRI-compatible stepping device. Here, we improved the DT-fMRI protocol with respect to task difficulty and signal robustness, making it more suitable for individualized analysis to better understand the neuronal substrates of cognitive-motor interference effects. Thirty healthy elderly subjects performed cognitive and motor single tasks (ST; stepping or finger tapping), as well as combined cognitive-motor DT during fMRI. After whole brain group level analysis, a region-of-interest (ROI) analysis and the computation of dual task costs (DTC = activation difference ratio ST/DT) at individual level were performed. Activations in the primary (M1) and secondary motor as well as in parietal and prefrontal cortex were measured at the group level during DT. Motor areas showed decreased activation whereas parietal and prefrontal areas showed increased activation in DT vs. ST. Stepping yielded more distinctive activations in DT vs. ST than finger tapping. At the individual level, the most robust activations (based on occurrence probability and signal strength) were measured in the stepping condition, in M1, supplementary motor area (SMA) and superior parietal lobule/intraparietal sulcus (SPL/IPS). The distribution of individual DTC in SPL/IPS during stepping suggested a separation of subjects in groups with high vs. low DTC. This study proposes an improved cognitive-motor DT-fMRI protocol and a standardized analysis routine of functional neuronal markers for cognitive-motor interference at the individual level.

Parietal lobe critically supports successful paired immediate and single-item delayed memory for targets.

The parietal lobe is important for successful recognition memory, but its role is not yet fully understood. We investigated the parietal lobes' contribution to immediate paired-associate memory and delayed item-recognition memory separately for hits (targets) and correct rejections (distractors). We compared the behavioral performance of 56 patients with known parietal and medial temporal lobe dysfunction (i.e. early Alzheimer's Disease) to 56 healthy control participants in an immediate paired and delayed single item object memory task. Additionally, we performed voxel-based morphometry analyses to investigate the functional-neuroanatomic relationships between performance and voxel-based estimates of atrophy in whole-brain analyses. Behaviorally, all participants performed better identifying targets than rejecting distractors. The voxel-based morphometry analyses associated atrophy in the right ventral parietal cortex with fewer correct responses to familiar items (i.e. hits) in the immediate and delayed conditions. Additionally, medial temporal lobe integrity correlated with better performance in rejecting distractors, but not in identifying targets, in the immediate paired-associate task. Our findings suggest that the parietal lobe critically supports successful immediate and delayed target recognition memory, and that the ventral aspect of the parietal cortex and the medial temporal lobe may have complementary preferences for identifying targets and rejecting distractors, respectively, during recognition memory.

Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia.

Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

Cortical thinning of parahippocampal subregions in very early Alzheimer's disease.

The stereotypical pattern of neurofibrillary tangle spreading in the earliest stages of typical Alzheimer's dementia (AD) predicts that medial perirhinal cortex (mPRC) atrophy precedes entorhinal cortex (ERC) atrophy, whereas the status of the parahippocampal cortex (PHC) remains unclear. Atrophy studies have focused on more advanced rather than early AD patients, and usually segment the entire PRC as opposed to the mPRC versus lateral PRC (lPRC). The present study therefore determined the extent of ERC, mPRC, lPRC, and PHC atrophy in very early AD (mean Mini-Mental State Examination score = 26) patients and its presumed prodrome amnestic mild cognitive impairment (mean Mini-Mental State Examination score = 28) compared to demographically matched controls. PHG structures were manually segmented (blinded rater) and cortical thicknesses extracted. ERC and mPRC were similarly atrophied in both patient groups. The lPRC was atrophied in the AD group only. Thus, atrophic changes in very early AD broadly map onto the pattern of neurofibrillary tangle spreading and suggest that mPRC, ERC, and lPRC, but not PHC-associated functional impairments, characterize very early-stage AD.

The 12 Years Preceding Mild Cognitive Impairment Due to Alzheimer's Disease: The Temporal Emergence of Cognitive Decline.

BACKGROUND: The identification of the type and sequence of cognitive decline in preclinical mild cognitive impairment (MCI) prior to Alzheimer's disease (AD) is crucial for understanding AD pathogenesis and implementing therapeutic interventions. OBJECTIVE: To model the longitudinal courses of different neuropsychological functions in MCI due to AD. METHODS: We investigated the prodromal phase of MCI over a 12-year period in 27 initially healthy participants with subsequent MCI preceding AD (NC-MCI) and 60 demographically matched healthy individuals (NC-NC). The longitudinal courses of cognitive performance (verbal and visual episodic memory, semantic memory, executive functioning, constructional praxis, psychomotor speed, language, and informant-based reports) were analyzed with linear mixed effects models. RESULTS: The sequence with which different cognitive functions declined in the NC-MCI relative to the NC-NC group began with verbal memory and savings performance approximately eight years, and verbal episodic learning, visual memory, and semantic memory (animal fluency) circa four years prior to the MCI diagnosis. Executive functioning, psychomotor speed, and informant-based reports of the NC-MCI group declined approximately two years preceding the MCI diagnosis. CONCLUSIONS: Measurable neuropsychological deterioration occurs up to approximately eight years preceding MCI due to AD.