A comparison of magnetic resonance imaging and neuropsychological examination in the diagnostic distinction of Alzheimer’s disease and behavioral variant frontotemporal dementia

The clinical distinction between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) remains challenging and largely dependent on the experience of the clinician. This study investigates whether objective machine learning algorithms using supportive neuroimaging and neuropsychological clinical features can aid the distinction between both diseases. Retrospective neuroimaging and neuropsychological data of 166 participants (54 AD; 55 bvFTD; 57 healthy controls) was analyzed via a Naïve Bayes classification model. A subgroup of patients (n = 22) had pathologically-confirmed diagnoses. Results show that a combination of gray matter atrophy and neuropsychological features allowed a correct classification of 61.47% of cases at clinical presentation. More importantly, there was a clear dissociation between imaging and neuropsychological features, with the latter having the greater diagnostic accuracy (respectively 51.38 vs. 62.39%). These findings indicate that, at presentation, machine learning classification of bvFTD and AD is mostly based on cognitive and not imaging features. This clearly highlights the urgent need to develop better biomarkers for both diseases, but also emphasizes the value of machine learning in determining the predictive diagnostic features in neurodegeneration

Executive function & semantic memory impairments in Alzheimer’s disease — investigating the decline of executive function and semantic memory in Alzheimer’s disease through computer-supported qualitative analysis of semantic verbal fluency and its applications in clinical decision support

Alzheimer’s Disease (AD) has a huge impact on an ever-aging society in highly developed industrialized countries such as the EU member states: according to the World Alzheimer’s Association the number one risk factor for AD is age. AD patients suffer from neurodegenerative processes driving cognitive decline which eventually results in the loss of patients’ ability of independent living. Episodic memory impairment is the most prominent cognitive symptom of AD in its clinical stage. In addition, also executive function and semantic memory impairments significantly affect activities of daily living and are discussed as important cognitive symptoms during prodromal as well as acute clinical stages of AD. Most of the research on semantic memory impairments in AD draws evidence from the Semantic Verbal Fluency (SVF) task which evidentially also places high demands on the executive function level. At the same time, the SVF is one of the most-applied routine assessments in clinical neuropsychology especially in the diagnosis of AD. Therefore, the SVF is a prime task to study semantic memory and executive function impairment side-by-side and draw conclusions about their parallel or successive impairments across the clinical trajectory of AD. To effectively investigate semantic memory and executive function processes in the SVF, novel computational measures have been proposed that tap into data-driven semantic as well as temporal metrics scoring an SVF performance on the item-level. With a better and more differentiated understanding of AD-related executive function and semantic memory impairments in the SVF, the SVF can grow from a well-established screening into a more precise diagnostic tool for early AD. As the SVF is one of the most-applied easy-to-use and low-burden neurocognitive assessments in AD, such advancements have a direct impact on clinical practice as well. For the last decades huge efforts have been put on the discovery of disease-modifying compounds responding to specific AD biomarker-related cognitive decline characteristics. However, as most pharmaceutical trials failed, the focus has shifted towards population-wide early screening with cost-effective and scalable cognitive tests representing an effective mid-term strategy. Computer-supported SVF analysis responds to this demand. This thesis pursues a two-fold objective: (1) improve our understanding of the progressive executive function and semantic memory impairments and their interplay in clinical AD as measured by the SVF and (2) harness those insights for applied early and specific AD screening. To achieve both objectives, this thesis comprises work on subjects from different clinical stages of AD (Healthy Aging, amnestic Mild Cognitive Impairment—aMCI, and AD dementia) and in different languages (German & French). All results are based on SVF speech data generated either as a one-time assessment or a repeated within-participant testing. From these SVF speech samples, qualitative markers are extracted with different amount of computational support (ranging from manual processing of speech to fully automated evaluation). The results indicate, that semantic memory is structurally affected from an early clinical—amnestic Mild Cognitive Impairment (aMCI)—stage on and is even more affected in the later acute dementia stage. The semantic memory impairment in AD is particularly worsened through the patients’ inability to compensate by engaging executive functions. Hence, over the course of the disease, hampered executive functioning and therefore the inability to compensate for corrupt semantic memory structures might be the main driver of later-stage AD patients’ notably poor cognitive performance. These insights generated on the SVF alone are only made possible through computer-supported qualitative analysis on an item-per-item level which leads the way towards potential applications in clinical decision support. The more fine-grained qualitative analysis of the SVF is clinically valuable for AD diagnosis and screening but very time-consuming if performed manually. This thesis shows though that automatic analysis pipelines can reliably and validly generate this diagnostic information from the SVF. Automatic transcription of speech plus automatic extraction of the novel qualitative SVF features result in clinical interpretation comparable to manual transcripts and improved diagnostic decision support simulated through machine learning classification experiments. This indicates that the computer-supported SVF could ultimately be used for cost-effective fully automated early clinical AD screening. This thesis advances current AD research in a two-fold manner. First it improves the understanding of the decline of executive function and semantic memory in AD as measured through computational qualitative analysis of the SVF. Secondly, this thesis embeds these theoretical advances into practical clinical decision support concepts that help screen population-wide and cost-effective for early-stage AD.Die Alzheimer-Krankheit (AD) stellt eine enorme Herausforderung für die immer älter werdende Gesellschaft in hochentwickelten Industrieländern wie den EU-Mitgliedsstaaten dar. Nach Angaben der World Alzheimer's Association ist der größte Risikofaktor für AD das Alter. Alzheimer-Patienten leiden unter neurodegenerativen Prozessen, die kognitiven Abbau verursachen und schließlich dazu führen, dass Patienten nicht länger selbstbestimmt leben können. Die Beeinträchtigung des episodischen Gedächtnisses ist das prominenteste kognitive Symptom von AD im klinischen Stadium. Darüber hinaus führen auch Störungen der Exekutivfunktionen sowie der semantischen Gedächtnisleistung zu erheblichen Einschränkungen bei Aktivitäten des täglichen Lebens und werden als wichtige kognitive Symptome sowohl im Prodromal- als auch im akuten klinischen Stadium von AD diskutiert. Der Großteil der Forschung zu semantischen Gedächtnisbeeinträchtigungen bei AD stützt sich auf Ergebnisse aus dem Semantic Verbal Fluency Tests (SVF), der auch die Exekutivfunktionen stark fordert. In der Praxis ist die SVF eines der am häufigsten eingesetzten Routine- Assessments in der klinischen Neuropsychologie, insbesondere bei der Diagnose von AD. Daher ist die SVF eine erstklassige Aufgabe, um die Beeinträchtigung des semantischen Gedächtnisses und der exekutiven Funktionen Seite an Seite zu untersuchen und Rückschlüsse auf ihre parallelen oder sukzessiven Beeinträchtigungen im klinischen Verlauf von AD zu ziehen. Um semantische Gedächtnis- und Exekutivfunktionsprozesse in der SVF effektiv zu untersuchen, wurden jüngst neuartige computergestützte Verfahren vorgeschlagen, die sowohl datengetriebene semantische als auch temporäre Maße nutzen, die eine SVF-Leistung auf Item-Ebene bewerten. Mit einem besseren und differenzierteren Verständnis von ADbedingten Beeinträchtigungen der Exekutivfunktionen und des semantischen Gedächtnisses in der SVF kann sich die SVF von einem gut etablierten Screening zu einem präziseren Diagnoseinstrument für frühe AD entwickeln. Da die SVF eines der am häufigsten angewandten, einfach zu handhabenden und wenig belastenden neurokognitiven Assessments bei AD ist, haben solche Fortschritte auch einen direkten Einfluss auf die klinische Praxis. In den letzten Jahrzehnten wurden enorme Anstrengungen unternommen, um krankheitsmodifizierende Substanzen zu finden, die auf spezifische, mit AD-Biomarkern verbundene Merkmale des kognitiven Abbaus reagieren. Da jedoch die meisten pharmazeutischen Studien in jüngster Vergangenheit fehlgeschlagen sind, wird heute als mittelfristige Strategie bevölkerungsweite Früherkennung mit kostengünstigen und skalierbaren kognitiven Tests gefordert. Die computergestützte SVF-Analyse ist eine Antwort auf diese Forderung. Diese Arbeit verfolgt deshalb zwei Ziele: (1) Verbesserung des Verständnisses der fortschreitenden Beeinträchtigungen der Exekutivfunktionen und des semantischen Gedächtnisses und ihres Zusammenspiels bei klinischer AD, gemessen durch die SVF, und (2) Nutzung dieser Erkenntnisse für angewandte AD-Früherkennung. Um beide Ziele zu erreichen, umfasst diese Thesis Forschung mit Probanden aus verschiedenen klinischen AD Stadien (gesundes Altern, amnestisches Mild Cognitive Impairment-aMCI, und AD-Demenz) und in verschiedenen Sprachen (Deutsch & Französisch). Alle Ergebnisse basieren auf SVF Sprachdaten, erhoben im Querschnittdesign oder als wiederholte Testung in einem Längsschnittdesign. Aus diesen SVF-Sprachproben werden mit unterschiedlicher rechnerischer Unterstützung qualitative Marker extrahiert (von manueller Verarbeitung der Sprache bis hin zu vollautomatischer Auswertung). Die Ergebnisse zeigen, dass das semantische Gedächtnis bereits im frühen aMCI Stadium strukturell beeinträchtigt ist und im späteren akuten Demenzstadium noch stärker betroffen ist. Die strukturelle Beeinträchtigung des semantischen Gedächtnisses bei Alzheimer wird insbesondere dadurch verschlimmert, dass die Patienten nicht in der Lage sind, dies durch den Einsatz exekutiver Funktionen zu kompensieren. Daher könnten im Verlauf der Erkrankung eingeschränkte Exekutivfunktionen und damit die Unfähigkeit, degenerierte semantische Gedächtnisstrukturen zu kompensieren, die Hauptursache für die auffallend schlechten kognitiven Leistungen von AD-Patienten im Akutstadium sein. Diese Erkenntnisse basierend auf der SVF alleine werden erst durch die computergestützte qualitative Analyse auf Item-per-Item-Ebene möglich und weisen den Weg zu möglichen Anwendungen in der klinischen Entscheidungsunterstützung. Die feinkörnigere qualitative Analyse der SVF ist klinisch wertvoll für die AD-Diagnose und das Screening, aber sehr zeitaufwändig, wenn sie manuell durchgeführt wird. Diese Arbeit zeigt jedoch, dass automatische Analysepipelines diese diagnostischen Informationen zuverlässig und valide aus der SVF generieren können. Die automatische Transkription von Sprache plus die automatische Extraktion der neuartigen qualitativen SVF-Merkmale führen zu einer klinischen Interpretation, die mit manuellen Analysen vergleichbar ist. Diese Verarbeitung führt auch zu einer verbesserten diagnostischen Entscheidungsunterstützung, die durch Klassifikationsexperimente mit maschinellem Lernen simuliert wurde. Dies deutet darauf hin, dass die computergestützte SVF letztendlich für ein kostengünstiges vollautomatisches klinisches AD-Frühscreening eingesetzt werden könnte. Diese Arbeit bringt die aktuelle AD-Forschung auf zweifache Weise voran. Erstens verbessert sie unser Verständnis der kognitiven Einschränkungen im Bereich der Exekutivfunktionen und des semantischen Gedächtnisses bei AD, gemessen durch die computergestützte qualitative Analyse der SVF. Zweitens bettet diese Arbeit diese theoretischen Fortschritte in ein praktisches Konzept zur klinischen Entscheidungsunterstützung ein, das zukünftig ein bevölkerungsweites und kosteneffektives Screening für AD im Frühstadium ermöglichen könnte

Use of nonintrusive sensor-based information and communication technology for real-world evidence for clinical trials in dementia

Cognitive function is an important end point of treatments in dementia clinical trials. Measuring cognitive function by standardized tests, however, is biased toward highly constrained environments (such as hospitals) in selected samples. Patient-powered real-world evidence using information and communication technology devices, including environmental and wearable sensors, may help to overcome these limitations. This position paper describes current and novel information and communication technology devices and algorithms to monitor behavior and function in people with prodromal and manifest stages of dementia continuously, and discusses clinical, technological, ethical, regulatory, and user-centered requirements for collecting real-world evidence in future randomized controlled trials. Challenges of data safety, quality, and privacy and regulatory requirements need to be addressed by future smart sensor technologies. When these requirements are satisfied, these technologies will provide access to truly user relevant outcomes and broader cohorts of participants than currently sampled in clinical trials

Neuropsychological Testing and Machine Learning Distinguish Alzheimer’s Disease from Other Causes for Cognitive Impairment

With promising results in recent treatment trials for Alzheimer’s disease (AD), it becomes increasingly important to distinguish AD at early stages from other causes for cognitive impairment. However, existing diagnostic methods are either invasive (lumbar punctures, PET) or inaccurate Magnetic Resonance Imaging (MRI). This study investigates the potential of neuropsychological testing (NPT) to specifically identify those patients with possible AD among a sample of 158 patients with Mild Cognitive Impairment (MCI) or dementia for various causes. Patients were divided into an early stage and a late stage group according to their Mini Mental State Examination (MMSE) score and labeled as AD or non-AD patients based on a post-mortem validated threshold of the ratio between total tau and beta amyloid in the cerebrospinal fluid (CSF; Total tau/Aβ(1–42) ratio, TB ratio). All patients completed the established Consortium to Establish a Registry for Alzheimer’s Disease—Neuropsychological Assessment Battery (CERAD-NAB) test battery and two additional newly-developed neuropsychological tests (recollection and verbal comprehension) that aimed at carving out specific Alzheimer-typical deficits. Based on these test results, an underlying AD (pathologically increased TB ratio) was predicted with a machine learning algorithm. To this end, the algorithm was trained in each case on all patients except the one to predict (leave-one-out validation). In the total group, 82% of the patients could be correctly identified as AD or non-AD. In the early group with small general cognitive impairment, classification accuracy was increased to 89%. NPT thus seems to be capable of discriminating between AD patients and patients with cognitive impairment due to other neurodegenerative or vascular causes with a high accuracy, and may be used for screening in clinical routine and drug studies, especially in the early course of this disease

AI and Non AI Assessments for Dementia

Current progress in the artificial intelligence domain has led to the development of various types of AI-powered dementia assessments, which can be employed to identify patients at the early stage of dementia. It can revolutionize the dementia care settings. It is essential that the medical community be aware of various AI assessments and choose them considering their degrees of validity, efficiency, practicality, reliability, and accuracy concerning the early identification of patients with dementia (PwD). On the other hand, AI developers should be informed about various non-AI assessments as well as recently developed AI assessments. Thus, this paper, which can be readable by both clinicians and AI engineers, fills the gap in the literature in explaining the existing solutions for the recognition of dementia to clinicians, as well as the techniques used and the most widespread dementia datasets to AI engineers. It follows a review of papers on AI and non-AI assessments for dementia to provide valuable information about various dementia assessments for both the AI and medical communities. The discussion and conclusion highlight the most prominent research directions and the maturity of existing solutions.Comment: 49 page

Speech- and Language-Based Classification of Alzheimer’s Disease: A Systematic Review

Background: Alzheimer’s disease (AD) has paramount importance due to its rising prevalence, the impact on the patient and society, and the related healthcare costs. However, current diagnostic techniques are not designed for frequent mass screening, delaying therapeutic intervention and worsening prognoses. To be able to detect AD at an early stage, ideally at a pre-clinical stage, speech analysis emerges as a simple low-cost non-invasive procedure. Objectives: In this work it is our objective to do a systematic review about speech-based detection and classification of Alzheimer’s Disease with the purpose of identifying the most effective algorithms and best practices. Methods: A systematic literature search was performed from Jan 2015 up to May 2020 using ScienceDirect, PubMed and DBLP. Articles were screened by title, abstract and full text as needed. A manual complementary search among the references of the included papers was also performed. Inclusion criteria and search strategies were defined a priori. Results: We were able: to identify the main resources that can support the development of decision support systems for AD, to list speech features that are correlated with the linguistic and acoustic footprint of the disease, to recognize the data models that can provide robust results and to observe the performance indicators that were reported. Discussion: A computational system with the adequate elements combination, based on the identified best-practices, can point to a whole new diagnostic approach, leading to better insights about AD symptoms and its disease patterns, creating conditions to promote a longer life span as well as an improvement in patient quality of life. The clinically relevant results that were identified can be used to establish a reference system and help to define research guidelines for future developments.This work was partially supported by FCT- UIDB/04730/2020 project.info:eu-repo/semantics/publishedVersio

Exploring the Diagnosis of Frontotemporal Dementia by Analyzing Neuropsychological Data With K-Means Clustering

Background: Differential diagnosis of dementia syndromes is difficult. Treatments are available for Alzheimer’s dementia (AD), but effects do not translate to other dementia syndromes. Therefore, early differential diagnosis is necessary to administer appropriate interventions and to boost drug development and research of therapeutic strategies that may lower patient and care-giver burden. The focus of the current study is to disentangle the clinical picture of frontotemporal dementia (FTD) from AD spectrum disorders. Findings could support an early, cheap, and more accurate diagnosis. Methods: K-means clustering, an unsupervised machine learning algorithm, was used on neuropsychological data from neurologic patients of the FTLD consortium databank. The analysis was performed twice, once including only neuropsychological test scores and a second time combining the neuropsychological variables with questionnaire scores assessing behavioral changes. In total n = 484 and n = 469 participants were included in the analysis with and without questionnaires, respectively. Participants included were either healthy controls with no family relation to patients in the dataset, or patients diagnosed with one of the following dementia disorders: AD, a behavioral variant of FTD (bvFTD), or one of three possible primary progressive aphasia (PPA) syndromes - a semantic variant (svPPA), a non-fluent variant (nfvPPA) or a logopenic variant (lvPPA). Results: Agreement of results from the various analyses performed was relatively high. Homogeneous clusters of diagnostic groups emerged. Homogeneity seemed higher for bvFTD and svPPA than for the other patient groups. NfvPPA and lvPPA patients were particularly likely to cluster together. Exploring neuropsychological patterns of cluster results demonstrated high variability between patients of the same diagnostic groups which could partly be explained by differences in disease severity. Tests that might prove particularly relevant to distinguish diagnostic subgroups are the FTLD-CDR sub-scores, the repeat and point task as well as questionnaires assessing apathy. Conclusion: K-means clustering proved to be a useful technique to explore various diagnostic syndromes that show overlapping clinical pictures. This study helped to formulate specific hypotheses based on the observation of patterns in multidimensional data. Disease severity showed to impact k-means clustering results considerably and should therefore be accounted for in future studies. Future studies will need to test the formulated hypotheses and inspect the meaning of impure clusters. Keywords: k-means clustering, frontotemporal dementia, primary progressive aphasia, Alzheimer’s dementia, differential diagnosis, neuropsychological testsBackground: Differential diagnosis of dementia syndromes is difficult. Treatments are available for Alzheimer’s dementia (AD), but effects do not translate to other dementia syndromes. Therefore, early differential diagnosis is necessary to administer appropriate interventions and to boost drug development and research of therapeutic strategies that may lower patient and care-giver burden. The focus of the current study is to disentangle the clinical picture of frontotemporal dementia (FTD) from AD spectrum disorders. Findings could support an early, cheap, and more accurate diagnosis. Methods: K-means clustering, an unsupervised machine learning algorithm, was used on neuropsychological data from neurologic patients of the FTLD consortium databank. The analysis was performed twice, once including only neuropsychological test scores and a second time combining the neuropsychological variables with questionnaire scores assessing behavioral changes. In total n = 484 and n = 469 participants were included in the analysis with and without questionnaires, respectively. Participants included were either healthy controls with no family relation to patients in the dataset, or patients diagnosed with one of the following dementia disorders: AD, a behavioral variant of FTD (bvFTD), or one of three possible primary progressive aphasia (PPA) syndromes - a semantic variant (svPPA), a non-fluent variant (nfvPPA) or a logopenic variant (lvPPA). Results: Agreement of results from the various analyses performed was relatively high. Homogeneous clusters of diagnostic groups emerged. Homogeneity seemed higher for bvFTD and svPPA than for the other patient groups. NfvPPA and lvPPA patients were particularly likely to cluster together. Exploring neuropsychological patterns of cluster results demonstrated high variability between patients of the same diagnostic groups which could partly be explained by differences in disease severity. Tests that might prove particularly relevant to distinguish diagnostic subgroups are the FTLD-CDR sub-scores, the repeat and point task as well as questionnaires assessing apathy. Conclusion: K-means clustering proved to be a useful technique to explore various diagnostic syndromes that show overlapping clinical pictures. This study helped to formulate specific hypotheses based on the observation of patterns in multidimensional data. Disease severity showed to impact k-means clustering results considerably and should therefore be accounted for in future studies. Future studies will need to test the formulated hypotheses and inspect the meaning of impure clusters. Keywords: k-means clustering, frontotemporal dementia, primary progressive aphasia, Alzheimer’s dementia, differential diagnosis, neuropsychological test