Primary progressive aphasia : neuropsychological analysis and evolution

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2015Frontotemporal lobar degeneration (FTLD) is the second leading cause of early-onset ( 2) revealed some clusters composed mostly by nonfluent or by semantic PPA cases. However, we could not evidence any group chiefly composed of logopenic PPA cases. Hence, findings obtained with the application of unsupervised data mining approaches do not clearly support a logopenic PPA. However further, supervised learning studies may indicate distinct results. Behaviour changes may occur early in PPA but the frequency of these symptoms across the three variants is still controversial. In the third study, 94 consecutive PPA patients (26 nonfluent, 36 semantic, 32 logopenic) underwent language and neuropsychological assessments. The presence of behavioural changes was ascertained by semi-structured informant-based interviews using the Blessed Dementia Rating Scale. Eighty-two percent of the cases endorsed at least one behaviour change. Nonfluent patients presented significantly more behaviour changes and scored more often (46.2%) the item “hobbies relinquished” when compared to logopenic patients. These differences in behaviour symptoms probably reflect distinct underlying neurodegenerative diseases. PPA is a neurodegenerative disorder with no effective pharmacological treatment. Cognition-based interventions are adequate alternatives, but their benefit has not been thoroughly explored. The aim of this last investigation was to study the effect of speech and language therapy (SLT) on naming ability in PPA. An open parallel prospective longitudinal study involving two centers was designed to compare patients with PPA submitted to SLT (1 h/week for 11 months, on average) with patients receiving no therapy. Twenty patients were enrolled and undertook baseline language and neuropsychological assessments; among them, 10 received SLT and 10 constituted an age- and education-matched historical control group. The primary outcome measure was the change in group mean performance on the Snodgrass and Vanderwart Naming Test between baseline and follow-up assessments. Intervention and control groups did not significantly differ on demographic and clinical variables at baseline. A mixed repeated measures ANOVA revealed a significant main effect of therapy (F(1,18) = 10.763; p = 0.005) on the performance on the Snodgrass and Vanderwart Naming Test. Although limited by a non-randomized open study design with a historical control group, the present study suggests that SLT may have a benefit in PPA, and it should prompt a randomized, controlled, rater-blind clinical trial. Conclusion: Despite the recent harmonization efforts, the delineation of certain PPA variants is still controversial. The present results show that neuropsychology is a key instrument not only for the clear definition of PPA subtypes but also for the study of the abnormal mechanisms and features underlying the main forms of PPA. Moreover, a neuropsychological approach to disease management seems to be feasible. Specifically, SLT emerges as an alternative and adequate approach to tackle the increasing language deficits experienced in all PPA phenotypes for some time. The emergence of promising disease-modifying therapies in the context of FTLD, in association with these cognitive-based interventions, will certainly be the future of PPA disease management

Comparison of longitudinal changes in resting state functional magnetic resonance imaging between alzheimer’s and healthy controls

Resting State Functional Magnetic Resonance Imaging (rs-fMRI) is a technique that is widely used for analyzing brain function using different approaches and methods. This study involves rs-fMRI analysis of Blood Oxygenation Level Dependent (BOLD) signals acquired from Alzheimer’s disease (AD) Patients and Healthy Controls (HC). Each subject in the study had both functional and anatomical images with at least one rs-fMRI scan with their Anatomical (T1) scans. Previous rs-fMRI studies have demonstrated that AD shows differences in Amplitude of Low Frequency (\u3c0.1 Hz) Fluctuations (ALFF), and Regional Homogeneity (ReHo) measures according to HCs. The aim of the study is to investigate individual and group level differences using ReHo and mALFF related measures in a longitudinal analysis. The hypothesis is that with the age and group (AD or HC) of the subject, it is possible to separate AD and HC subjects from each other using 3 different ROIs (DMN – MT – MV), These regions are known to show abnormalities in AD patients but clinical wise never been identified as neuroimaging biomarkers. This study tries to check these ROIs to see if there are significant differences between the AD patients and HCs using 3 different features

Identifying patterns in signs and symptoms preceding the clinical diagnosis of Alzheimer’s disease

A thesis submitted to the University of Bedfordshire in partial fulfilment of the requirements for the degree of Doctor of PhilosophyPrevious research indicates that there is a major challenge caused by the late diagnosis of Alzheimer’s disease (AD), with no suitable diagnostic tool available for use in primary care. Aim: This research is aimed at identifying patterns in the early signs and symptoms of AD to suggest the development of a predictive model for the early detection of AD. Objectives: To; a) map, synthesise and appraise the quality of existing literature on the signs and symptoms preceding the diagnosis of AD via the systematic scoping review of the literature; b) identify patterns in signs and symptoms preceding the clinical diagnosis of AD in general practices via a retrospective medical record review study (RMRRS); c) explore the clinicians perspectives regarding the early signs and symptoms, issues surrounding the late diagnosis and collect recommendations for overcoming barriers to timely detection of AD via a semi-structured interview. Methods: This was a mixed method research comprising a systematic scoping review of literature from 1937-2016, undertaken using the descriptive analysis on the sequence and the timing of signs and symptoms preceding the diagnosis of AD. Methodological quality of studies was assessed with the QUADAS-2 tool as well as PRISMA guidelines and descriptive analysis followed. A RMRRS followed using the logistic regression analysis and a semi-structured interview of general practitioners (GPs) in Milton Keynes (MK) and Luton, using the framework analysis. Results: The findings from the review suggest that neurological and depressive behaviours are an early occurrence in early-onset AD with depressive and cognitive symptoms in the measure of semantic memory and conceptual formation in late-onset AD. It appears that there is a big variation in the patterns of signs and symptoms with cases of misdiagnosis. However, there was limited evidence due to the limited number of studies of this kind. The nested case control design of 109 samples indicates that auditory disturbances could have diagnostic value, with a range of signs and symptoms that appears at different time. While the interviews highlight and confirm areas for consideration in the primary care and NHS. Additionally, the study reports practices in relation to the early diagnosis of AD. However, the result is not an overall representation of the views of GPs. Conclusion: Findings suggest that individuals with auditory disturbances have increased odds of AD. This was more striking in the white female population, with borderline significance due to limited data that is too small to detect such an uncommon symptom(s)

Social Signal Decoding in Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is associated with progressive social cognitive impairment. Currently a comprehensive pathophysiological model allowing disease effects to be understood and anticipated at the level of the whole brain is lacking. In this thesis I explored candidate cognitive operations underpinning complex behaviours in patients with the canonical syndromes of FTLD; behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD). I correlated behavioural deficits with brain network disintegration using the structural magnetic resonance imaging (MRI) technique, voxel based morphometry (VBM). I created synthetic scenes to manipulate congruity across semantic and emotional domains (Chapter 3) and showed deficits across both patient groups. The deficits have grey matter correlates in prefronto-parieto-temporo-insular network and a temporo-insulo-striatal network. I used music as a non-verbal syntactic probe to investigate reward anticipation and valuation (Chapter 4) and demonstrated dissociable deficits across dementias. Performance was associated with grey matter in a distributed network including anterior temporal cortex and orbitofrontal cortex (OFC), previously implicated in computing diverse rewards. I created a novel neuropsychological test of humorous intent (Chapter 5) to model incongruity processing. bvFTD demonstrates a particular difficulty decoding novel humorous situations while SD produces a more general deficit of humour detection. Humour detection accuracy was associated with temporoparietal junction (TPJ) and anterior superior temporal cortical volume which are hubs for processing incongruity and semantic associations. To assess the relevance of these findings (Chapter 5) to daily life behaviour I explored humour preferences across dementias (Chapter 6). Altered sense of humour is particularly salient in bvFTD and SD, but also frequent in AD and may predate more typical symptoms. In conclusion, impairment in incongruity processing and reward allocation was shown across paradigms. The neuroanatomical networks underpinning these processes overlapped with areas known to be targeted by FTLD. These processes have implications for our understanding of the social dysfunction that defines bvFTD

Cognitive impairment in Parkinson’s disease: Impact and identification of comorbid disease mechanisms

Cognitive impairment is a common and debilitating feature of Parkinson's disease (PD). While it is primarily caused by cerebral propagation of α-synuclein protein, evidence of comorbid diseases is frequently found in autopsy samples. This includes tau and amyloid-β pathologies – the hallmarks of Alzheimer's disease (AD) – and cerebrovascular damage. Comorbid diseases may influence cognition in PD over and above the effects of α-synuclein alone, and this influence may interfere with the results of clinical trials of next-generation medical treatments that target α-synuclein. The primary aims of this thesis were to define the extent and the effects of comorbid disease mechanisms in PD, and to identify viable clinical strategies for detecting coexistent disorders in vivo. Methods included a systematic review of autopsy studies; a factor analysis of the Montreal Cognitive Assessment (MoCA); a regression analysis of two genes; and a cross-sectional neuropsychological study of 45 patients. The systematic review found significant tau pathology in around one-third of PD patients at death. Significant amyloid-β pathology affected over half, and conferred a worse prognosis. Other pathologies (e.g. cerebrovascular disease) were less common, and did not contribute to dementia in PD. The factor analysis showed that the MoCA has limited value for distinguishing cognitive profiles in PD, suggesting that it should be used only for screening. The genetic project found that variation in the APOE gene influenced cognitive decline in early PD; the effect varied between men and women. Variation in MAPT did not affect cognitive decline. Finally, the neuropsychological study found that over half of cognitively impaired PD patients could be clinically diagnosed with a coexistent cognitive disorder, with AD being the most common. Collectively, the results of this thesis show that comorbid diseases, particularly AD, are common in PD, and these contribute to the cognitive phenotype. Consequently, a clinical assessment incorporating selected neuropsychological tests can be used to identify comorbid diseases in PD patients. It is important to consider the potentially confounding impact of multimorbidity in the design and analysis of clinical trials that aim to modulate neurodegeneration in PD by targeting α-synuclein

Predictive cognition in dementia: the case of music

The clinical complexity and pathological diversity of neurodegenerative diseases impose immense challenges for diagnosis and the design of rational interventions. To address these challenges, there is a need to identify new paradigms and biomarkers that capture shared pathophysiological processes and can be applied across a range of diseases. One core paradigm of brain function is predictive coding: the processes by which the brain establishes predictions and uses them to minimise prediction errors represented as the difference between predictions and actual sensory inputs. The processes involved in processing unexpected events and responding appropriately are vulnerable in common dementias but difficult to characterise. In my PhD work, I have exploited key properties of music – its universality, ecological relevance and structural regularity – to model and assess predictive cognition in patients representing major syndromes of frontotemporal dementia – non-fluent variant PPA (nfvPPA), semantic-variant PPA (svPPA) and behavioural-variant FTD (bvFTD) - and Alzheimer’s disease relative to healthy older individuals. In my first experiment, I presented patients with well-known melodies containing no deviants or one of three types of deviant - acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). I assessed accuracy detecting melodic deviants and simultaneously-recorded pupillary responses to these deviants. I used voxel-based morphometry to define neuroanatomical substrates for the behavioural and autonomic processing of these different types of deviants, and identified a posterior temporo-parietal network for detection of basic acoustic deviants and a more anterior fronto-temporo-striatal network for detection of syntactic pitch deviants. In my second chapter, I investigated the ability of patients to track the statistical structure of the same musical stimuli, using a computational model of the information dynamics of music to calculate the information-content of deviants (unexpectedness) and entropy of melodies (uncertainty). I related these information-theoretic metrics to performance for detection of deviants and to ‘evoked’ and ‘integrative’ pupil reactivity to deviants and melodies respectively and found neuroanatomical correlates in bilateral dorsal and ventral striatum, hippocampus, superior temporal gyri, right temporal pole and left inferior frontal gyrus. Together, chapters 3 and 4 revealed new hypotheses about the way FTD and AD pathologies disrupt the integration of predictive errors with predictions: a retained ability of AD patients to detect deviants at all levels of the hierarchy with a preserved autonomic sensitivity to information-theoretic properties of musical stimuli; a generalized impairment of surprise detection and statistical tracking of musical information at both a cognitive and autonomic levels for svPPA patients underlying a diminished precision of predictions; the exact mirror profile of svPPA patients in nfvPPA patients with an abnormally high rate of false-alarms with up-regulated pupillary reactivity to deviants, interpreted as over-precise or inflexible predictions accompanied with normal cognitive and autonomic probabilistic tracking of information; an impaired behavioural and autonomic reactivity to unexpected events with a retained reactivity to environmental uncertainty in bvFTD patients. Chapters 5 and 6 assessed the status of reward prediction error processing and updating via actions in bvFTD. I created pleasant and aversive musical stimuli by manipulating chord progressions and used a classic reinforcement-learning paradigm which asked participants to choose the visual cue with the highest probability of obtaining a musical ‘reward’. bvFTD patients showed reduced sensitivity to the consequence of an action and lower learning rate in response to aversive stimuli compared to reward. These results correlated with neuroanatomical substrates in ventral and dorsal attention networks, dorsal striatum, parahippocampal gyrus and temporo-parietal junction. Deficits were governed by the level of environmental uncertainty with normal learning dynamics in a structured and binarized environment but exacerbated deficits in noisier environments. Impaired choice accuracy in noisy environments correlated with measures of ritualistic and compulsive behavioural changes and abnormally reduced learning dynamics correlated with behavioural changes related to empathy and theory-of-mind. Together, these experiments represent the most comprehensive attempt to date to define the way neurodegenerative pathologies disrupts the perceptual, behavioural and physiological encoding of unexpected events in predictive coding terms