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.

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.

Abstract. 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,

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- MentalStatus 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 bidirectional conversions. We provide an easy-to-use table covering the entire range of scores and taking into account all currently existing conversion formulas.Jael S. Fasnacht and Alexandra S. Wueest contributed equally to this study.

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.

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.

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.

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.