Abstract Background The diagnosis of Alzheimer’s disease (AD) is based on the presence of characteristic biomarkers and the presence of a clinical AD phenotype. Since pathological changes typically begin years before a formal diagnosis, early detection is an important objective in AD research. Literature suggests that especially cognitive tests for assessing relational memory and memory tests requiring discrimination between previously learned and similar novel stimuli, are indicative of early AD-related cognitive impairment. Methods 288 memory clinic patients were divided into three Mini-Mental State Examination (MMSE) groups: Group A (MMSE 27–30), Group B (MMSE 23–26), Group C (MMSE 18–22). Logistic regression analyses were conducted to evaluate the ability of seven neuropsychological tests, selected for their clinical relevance in diagnosing AD and distinguishing it from differential diagnoses, to predict whether a patient has AD according to their cerebrospinal fluid profile (AD+) or another neurodegenerative disease/ another dementia syndrome (AD-), for the three MMSE groups separately. Results The model’s classification accuracy decreased from 83.78% in Group A to 72.92% in Group B and 75.81% in Group C. In Group A, significant predictors included Paired-Associate Learning (PAL), with AD+ patients performing worse; Phonemic Fluency (PhonoWF) and Beck’s Depression Inventory (BDI). PhonoWF and BDI are related to impairments of the AD- group: AD- patients showed a poorer test performance and more depressive symptoms. Conclusions Predictive value of neuropsychological tests varies with the stage of cognitive impairment. Integrating relational memory tasks, such as PAL, enhances the utility of neuropsychological assessments in early identification of clinical AD phenotypes.

BackgroundRecent developments in the assessment of Alzheimer's disease (AD) have centered on differential diagnostic questions. Only a few studies have aimed to identify neuropsychological measures that allow the prediction of disease progression. However, this question is central to informing patients about their diagnosis and to decisions regarding the urgency and timing of treatment escalation.ObjectiveWe analyzed which, if any, neuropsychological test results reflect the extent of neurodegenerative progression.MethodsThis retrospective analysis included 290 patients divided into an Aβ-ratio + group (n = 146; AD biomarker profile) and an Aβ-ratio- group (n = 144; non-AD biomarker profile). The Aβ-ratio + group was further divided into four t-tau quartiles. The Aβ-ratio- group was subdivided into patients with normal (n = 94) or elevated t-tau (n = 50).ResultsRegression and variance analyses demonstrated a correlation between Trail Making Test B (TMT-B) performance and t-tau levels in patients with an Aβ-ratio+, driven by differences between low and high tau values, but not in Aβ-ratio- patients. Several additional statistical control analyses endorsed this finding.ConclusionsWe conclude that, for Aβ-ratio + patients, TMT-B performance may serve as a clinically accessible indicator of tau-related disease activity and the extent of neurodegeneration and may help identify patients at risk of faster progression if replicated in longitudinal studies.

Autoimmune limbic encephalitis is an inflammatory condition confined to the limbic system of the brain that is deemed to be due to a dysregulated immune response. However, the exact pathophysiological mechanisms remain elusive. Diagnosis of autoimmune limbic encephalitis currently relies on clinical consensus criteria. However, diagnostic workup can be challenging, potentially delaying treatment initiation associated with poor clinical outcomes. We retrospectively identified 640 patients (81 autoimmune limbic encephalitis, 148 relapsing-remitting multiple sclerosis, 197 Alzheimer's disease, 67 frontotemporal dementia, 37 temporal lobe epilepsy with hippocampal sclerosis and 110 somatic symptom disorder patients). Applying multidimensional flow-cytometry together with novel computational approaches, we analysed the peripheral blood and cerebrospinal fluid immune cell profiles at different disease stages and performed correlations with clinical parameters (i.e. neuropsychological performance, EEG and MRI). We were able to identify a shared immune signature of autoimmune limbic encephalitis showing similarities in adaptive B and T cell response with other inflammatory central nervous system diseases and in T cell patterns with neurodegenerative disorders. Antibody-negative autoimmune limbic encephalitis showed a pronounced T cell response in peripheral blood similar to temporal lobe epilepsy and hippocampal sclerosis and neurodegenerative disorders differentiating from antibody-positive autoimmune limbic encephalitis and classical inflammatory central nervous system diseases with regard to B and plasma cell response. Longitudinal immune cell phenotyping in autoimmune limbic encephalitis revealed dynamic changes over time mainly affecting the innate, B and plasma cell compartment. Correlation analysis indicated associations between the baseline immune cell profile, especially lymphocytes, and neuropsychological performance, as well as EEG and MRI abnormalities. Applying novel computational approaches, we found that multidimensional flow cytometry together with routine CSF parameters could reliably distinguish autoimmune limbic encephalitis from controls and clinical differential diagnoses. Incorporation of multidimensional flow cytometry parameters showed superior discriminatory ability compared with CSF routine parameters alone. Taken together, autoimmune limbic encephalitis is characterized by a B and T cell dominated intrathecal immune-cell signature corresponding to changes reported in the brain parenchyma and showing similarities with classical inflammatory central nervous system diseases and neurodegenerative disorders. Incorporating clinical parameters and applying novel computational approaches, we could show that multidimensional flow cytometry might be a beneficial complement to the established diagnostic workup of autoimmune limbic encephalitis promoting early diagnosis and facilitating outcome prediction to enhance individualized treatment regimes.

IntroductionThe diagnosis of corticobasal syndrome (CBS) is challenging due to its clinical overlap with other neurodegenerative disorders. Ideomotor apraxia is a core feature of CBS and often presents asymmetrically, but is often under-recognized in the clinical setting.MethodsThe “Paper-Toss Test” (PTT) is administered to a video-based case series of four patients with different CBS pathologies (Alzheimer’s disease, progressive supranuclear palsy, and corticobasal degeneration) and involves instructions to throw a paper ball with each hand. A positive test result is indicated by the presence of specific performance deficits of the patient’s affected side such as an absent or delayed release of the paper ball or an interrupted throwing motion.ResultsAll patients exhibited a positive PTT, independent of the underlying cause of CBS.DiscussionThis study proposes the PTT (Paper-Toss Test) as a bedside tool for the detection of unilateral ideomotor apraxia, facilitating the diagnosis of CBS. These deficits correspond to the known impairments in transitive gestures and disturbances of the neuronal apraxia network in CBS patients. These results support further investigation and validation of the PTT in clinical practice.