Neurologic conditions presenting as psychiatric disorders.

Journal ArticleUnderstanding underlying neuroanatomic function helps physicians to localize defects and search for treatable neurologic conditions. Neurologic conditions such as Huntington's chorea, Wilson's disease, Gille de la Tourette syndrome, brain tumors, encephalitis and meningitis, neurodegenerative conditions and metabolic or toxic conditions can have psychiatric manifestations

Tau pathology in Alzheimer's disease and other dementias : translational approach from in vitro autoradiography to in vivo PET imaging

Tauopathies, including Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are complex neurodegenerative disorders characterized by the pathological accumulation of tau proteins in the brain. These often overlapping disorders, with intricate pathologies and growing prevalence, lack definitive treatments, highlighting the necessity for advanced research. Positron emission tomography (PET) imaging aids in the diagnosis and monitoring of diseases, by providing in vivo insights into pathological features. This thesis focused on deciphering the binding properties and brain regional distribution of PET tracers for accurate disease differentiation. Spanning four studies, we aimed to bridge in vitro and in vivo PET data to investigate tau pathology and its association with dementia-related markers such as reactive astrogliosis, peripheral inflammation, and dopaminergic dysfunction. The 2nd generation tau PET tracers, 3H-MK6240 and 3H-PI2620, demonstrated high affinity and specificity in AD post-mortem brain tissues, especially in early-onset AD, compared to controls. 3H-PI2620, 3H-MK6240, and 3HRO948 displayed similar binding patterns in AD tissue, with multiple binding sites and equivalent high affinities (Papers I and II). 3H-PI2620 showed specificity in CBD and PSP tissues, in contrast to 3H-MK6240. However, differentiating CBD from PSP brains with 3H-PI2620 remained challenging in multiple brain regions, potentially due to complex tracer-target interactions (Papers II and III). Reactive astrogliosis PET tracers 3H-Deprenyl and 3H-BU99008 bound primarily to stable distinct high-affinity binding sites in AD, CBD and PSP, but also to transient binding sites, differing by brain region and condition. This pattern implied that these tracers may interact with similar or diverse subtypes or populations of astrocytes, expressing varying ratios of transient sites, which may vary depending on the brain location and the disease (Paper III). Using 3H-FEPE2I, we delineated a reduction in dopamine transporter (DAT) levels within the putamen across CBD, PSP and Parkinson's Disease (PD) brains. Concomitantly, elevated 3H-Raclopride binding reflected higher dopamine D2 receptor (D2R) levels in PSP and PD. Nonetheless, our observations underscored the heterogeneity inherent to these neurodegenerative pathologies, emphasizing the criticality of individual variability in neuropathological manifestations (Paper III). Lastly, we investigated late middle-aged cognitively unimpaired Hispanic individuals, in dichotomous groups of in vivo amyloid-β (Aβ) PET (18F-Florbetaben) and plasma neurofilament light (NfL) biomarkers. Our findings suggest that elevated plasma inflammation and tau burden as measured by 18FMK6240, can be detected at early preclinical stages of AD, offering potential for early diagnosis (Paper IV). This thesis underscored the importance of PET imaging in advancing our understanding of tauopathies. The innovative use of multiple PET tracers provided crucial insights into their potential use in clinics to distinguish pathological features of AD, CBD and PSP. The findings emphasized the need for more studies applying a multifaceted approach to studying and managing these complex neurodegenerative disorders, combining advanced imaging techniques with a broad spectrum of biological markers

Language impairment in frontotemporal lobar degeneration

The term frontotemporal lobar degeneration (FTLD) describes a heterogeneous group of neurodegenerative disorders associated with frontal and temporal lobe atrophy. Within this spectrum, two progressive aphasia syndromes, progressive nonfluent aphasia (PNFA) and semantic dementia (SD), are well described. FTLD is commonly a genetic disorder and mutations in two genes, microtubule-associated protein tau (MAPT) and progranulin (GRN) account for a large proportion of familial cases. A retrospective imaging study using cortical thickness measures shows involvement of the anteroinferior temporal lobes in SD and the left inferior frontal lobe/insula in PNFA. Studies of disease severity and of longitudinal imaging reveal spread through the left hemisphere and into the right hemisphere in both groups. A genetics and heritability study shows that PNFA can be familial, although much less than the behavioural variant of FTLD, and that this is often due to mutations in GRN. Differing patterns of atrophy are shown between different genetic mutations and also between different pathologies with the same clinical syndrome. Evidence from the neurological, neuropsychological, neuroanatomical, genetic and pathological features of the nonfluent aphasias suggests that there are at least three nonfluent aphasia syndromes: a disorder with motor speech impairment with or without agrammatism, a disorder with agrammatism but no apraxia of speech (found in patients with progranulin mutations) and a disorder without agrammatism or apraxia of speech but with word-finding pauses (consistent with descriptions of logopenic/phonological aphasia and pathologically associated with Alzheimer’s disease). Studies of specific deficits (single word processing, prosody, neologistic jargon, apraxia and behavioural symptoms) in the progressive aphasias provide further insight into the disease. This thesis therefore provides neurological, neuropsychological and imaging data with related genetic and pathological information that can provide greater insights into the natural history and classification, and therefore pathophysiological basis of the neurodegenerative disorders that cause primary progressive language impairment

A cross-linguistic perspective to classification of healthiness of speech in Parkinson's disease

People with Parkinson's disease often experience communication problems. The current cross-linguistic study investigates how listeners' perceptual judgements of speech healthiness are related to the acoustic changes appearing in the speech of people with Parkinson's disease. Accordingly, we report on an online experiment targeting perceived healthiness of speech. We studied the relations between healthiness perceptual judgements and a set of acoustic characteristics of speech in a cross-sectional design. We recruited 169 participants, who performed a classification task judging speech recordings of Dutch speakers with Parkinson's disease and of Dutch control speakers as ‘healthy’ or ‘unhealthy’. The groups of listeners differed in their training and expertise in speech language therapy as well as in their native languages. Such group separation allowed us to investigate the acoustic correlates of speech healthiness without influence of the content of the recordings. We used a Random Forest method to predict listeners' responses. Our findings demonstrate that, independently of expertise and language background, when classifying speech as healthy or unhealthy listeners are more sensitive to speech rate, presence of phonation deficiency reflected by maximum phonation time measurement, and centralization of the vowels. The results indicate that both specifics of the expertise and language background may lead to listeners relying more on the features from either prosody or phonation domains. Our findings demonstrate that more global perceptual judgements of different listeners classifying speech of people with Parkinson's disease may be predicted with sufficient reliability from conventional acoustic features. This suggests universality of acoustic change in speech of people with Parkinson's disease. Therefore, we concluded that certain aspects of phonation and prosody serve as prominent markers of speech healthiness for listeners independent of their first language or expertise. Our findings have outcomes for the clinical practice and real-life implications for subjective perception of speech of people with Parkinson's disease, while information about particular acoustic changes that trigger listeners to classify speech as ‘unhealthy’ can provide specific therapeutic targets in addition to the existing dysarthria treatment in people with Parkinson's disease

Clinical aspects of acquired aphasia and dysarthria in childhood

For the last decade, it has been a common clinical belief that the prognosis of acquired childhood aphasia is good. However, our own clinical experiences were rather conflicting on this point. As a consequence, we re-examined all the children (15) with an acquired aphasia who in a period from 1969-1972 were hospitalized in the University Hospital Rotterdam-Dijkzigt. On re-examination 7 children failed to show complete recovery (VanDongen and Loonen, 1977). One year later Woods and Teuber published an outstanding study entitled "Changing patterns of childhood aphasia", in which they also contradicted the expectation of a good recovery of acquired childhood aphasia. In addition, they criticized the view supported by the earlier literature that "childhood aphasias differ in kind from adult aphasia being predominantly motor or non-fluent". The research carried out after 1977 on the classification and the recovery of the different speech disturbances is subject of this thesis

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

An investigation of sign dysarthria

This study explores the nature of sign production in individuals with neurogenic movement disorders. The research goals are to broadly define the phenomenon of dysarthria in signed language; to determine whether anything other than the set of articulators involved differentiates it from dysarthria in spoken language; and to delineate the differences between sign dysarthria and apraxia, and between sign dysarthria and disruption of simple limb movements. In the same way that hearing people may exhibit speech dysarthria in the absence of oral apraxia, deaf signers may, in some cases, exhibit sign dysarthria in the absence of higher level ideomotor impairments. Conversely, just as many movement disorders are more apparent in speech than in simple limb movements, sign dysarthria may also arise in the absence of severe impairment of simple movements, such as reaching or pointing. An ancillary question that this research addresses is the establishment of articulatory measures of sign dysarthria, and of normal signing. Findings from this study indicate that dysarthria, as distinct from apraxia, aphasia, and loss of simple movement, does manifest itself in sign language, which suggests that speech motor control research should eschew models of dysarthria framed around specific articulators, in favour of those that emphasize patterns of movement. However, just as dysarthria is not articulator-specific, it is also not fundamentally linguistic in nature. The reason that dysarthria can occur in either a vocal or a manual language modality is because both use very rapid, complex, co-ordinated movements. The movement speed and complexity facilitate the rapid information transfer that is necessary for any linguistic system, but that does not make disruptions to it inherently linguistic. One would predict that subjects with dysarthria would also be impaired at any task with similar motor demands, but since few normal activities require such a high level of movement precision, deficits manifest themselves primarily in speech or sign

Handbook on clinical neurology and neurosurgery

HANDBOOKNEUROLOGYNEUROSURGERYКЛИНИЧЕСКАЯ НЕВРОЛОГИЯНЕВРОЛОГИЯНЕЙРОХИРУРГИЯThis handbook includes main parts of clinical neurology and neurosurgery

Claudius at the river: aspects of biography

Tiberius Claudius Germanicus was acclaimed emperor in AD41 after the murder of Gaius by members of the Praetorian Guard. Despite manifest handicaps that worried the imperial family enough to result in a career of education, scholarship and minor offices, Ti. Claudius Caesar emerged as princeps, a position which he held until his untimely death in AD54.Scholars have assessed the impact of Claudius' disabilities in a negative light, or, in a spirit of revisionism without producing evidence that would authentically refute the original allegations. This is a contradictory result; one is asked to accept as fact the brutality of the negative and satirical portrait of Claudius, but then be obliged by the sources to assume that he was in fact still capable - this is not a tenable position.Past scholarship has given a cursory assessment of Claudius' illness, and promoted infantile paralysis (polio) or cerebral palsy as being consistent with his apparent eccentricities in the sources. This study carries out a risk assessment of Claudius' birth and early childhood, a pathological examination based on the evidence; the result of the study shows that any long-term illness is stable and then progresses to a degenerative state. After a survey of neurological diseases, the conclusion drawn is that Claudius' ill health is Post Polio Syndrome (PPS).An important conclusion is that PPS is not connected to the reported stutter, although the voice quality may have been affected by progressive muscle wasting. A detailed and critical examination of the source's descriptions of the events of AD41 demonstrates that selecting Claudius was a realistic choice, one borne out by the medical pathology of PPS

Study and characterisation of the prodromal motor phase of Parkinson’s Disease

There is sufficient evidence that a neurodegenerative process in Parkinson’s Disease (PD) starts many years before the clinical diagnosis. The progression of PD is generally slow and, because it is diagnosed based on established motor features, it is probable that subtle motor manifestations appear in the pre-diagnostic phase of PD. Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a condition known to be part of the prodromal phase of PD. The PREDICT-PD study is a population-based cohort which aims to identify individuals at risk of PD based on the presence and absence of risk factors. The first project of this thesis investigated the association between first presentation of motor symptoms (tremor, rigidity and balance difficulties) and subsequent PD in a large primary care dataset in East London, including almost 3 decades of clinical information from over a million individuals. People who went on to develop PD reported motor symptoms up to 10 years before PD diagnosis. Tremor had the highest association with future PD followed by balance difficulties and rigidity. The second project aimed to identify the range of motor features in the elderly population participating in the PREDICT-PD cohort study and document their rate of progression over time. People classified as having a higher risk of future PD (using the PREDICT-PD algorithm) were more likely to have early parkinsonian signs than the lower risk group. Six years later, they also showed a bigger motor decline compared with people in the lower risk group. The third project was focused on developing two new objective motor tools, the Distal Finger Tapping test and the Slow-Motion Analysis of Repetitive Tapping. Both tests were able to detect abnormal patterns of movement amongst people with early PD. Finally, a motor battery was created and implemented in a group of patients with iRBD. A higher proportion of patients with iRBD had early parkinsonian signs compared with controls. The motor battery was able to detect early patterns of motor dysfunction not captured by standardised clinical scales. The work presented in this thesis demonstrates that motor features start in the pre-diagnostic phase of PD and describes new motor signatures in the prodromal phase of PD