Dissertations / Theses on the topic 'Progressive supranuclear palsy'

Social cognition has not been studied in PSP, despite its clinical importance with regard to patients’ progressive decline in independence and communication. This thesis focuses on the extent and neural basis of social cognition in PSP. Cognitive function was assessed in multiple domains including social cognition, executive function and perception, at baseline and after one year. At baseline, subjects underwent structural magnetic resonance imaging and saccadometry. Patients were poor at both emotion recognition and theory of mind tasks in visual and auditory modalities, compared with matched controls. Social cognition correlated with global cognitive decline but was not attributable to perceptual disturbance and was independent if executive function. The latency of visually evoked saccades correlated with global and social cognitive performance. Regression analysis revealed latency as the best predictor of cognitive function, above disease duration and motor function. Voxel based morphometry of grey and white matter confirms that areas previously implicated in social cognition were atrophic in PSP. Moreover, this atrophy correlated with social cognition dysfunction, implying a functional association. In summary, social cognition is an integral part of the cognitive syndrome of PSP, and is associated with focal atrophy of regions associated with normal social cognition.

This thesis examines the clinical, pathological and biochemical diversity of progressive supranuclear palsy (PSP). The material and patients used for these studies involved 23 clinically diagnosed living patients and 127 pathologically confirmed cases of PSP, archived at the Queen Square Brain Bank (QSBB). Differences between 'classic' PSP and 'atypical' PSP were identified, and a number of clinical features that separate them from other bradykinetic rigid syndromes were explored. In addition to the clinical phenotype associated with PSP-tau pathology initially described by Richardson in 1963 (Richardson's syndrome, RS) two other distinct clinical syndromes were identified: PSP-Parkinsonism (PSP-P) and pure akinesia with gait freezing (PAGF). The following clinical features, in addition to the operational diagnostic criteria, were supportive of underlying PSP-tau pathology in patients presenting with Parkinsonism: an absence of drug induced dyskinesias, autonomic failure and visual hallucinations the presence of falls within 6 years of disease onset UPSIT scores above the 12th percentile for gender and age and abnormalities in auditory startle response and auditory blink reflex. PSP-tau pathology always involved the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra (SN), but involvement outside these structures was variable and could be sub-divided into at least three different patterns. Severe tau pathology in PSP-P and PAGF was restricted to the GP, STN and SN. Co-existent pathological diagnoses did not differ between RS, PSP-P and PAGF. The ratio of pathological 4-repeat:3-repeat tau in PSP was variable. In RS the mean ratio was higher than in PSP-P (2.84 vs. 1.63 (p<0.003). Mutations of MAPT did not account for the diversity of clinical features The proposed clinical and pathological sub-classification of PSP will be helpful in clinical practice. Pathological and biochemical correlates raise the possibility that PSP-P and PAGF may represent discrete nosological entities. Further research may ultimately lead to their absolute distinction from Richardson's syndrome and related tauopathies.

This thesis characterises the cortical pattern of degeneration in progressive supranuclear palsy (PSP) and its consequences. Global atrophy was first examined using a recently developed staging scheme in pathologically-proven PSP cases compared with other tauopathies: gross atrophy was not observed in PSP. Quantification of regional volume loss throughout the brain was then used to determine the magnitude of more focal tissue atrophy in PSP, cortical dysfunction was investigated by measuring cerebral blood flow (CBF) changes, and several cortical cellular pathologies were analysed. Any changes observed were related to each other and clinical assessments of motor, cognitive and behavioural abnormalities. At mid-stage PSP, frontal and subcortical atrophy related to decreased CBF in the frontal cortex and cognitive decline. Parietocerebellar CBF increases were also identified (related to frontal CBF deficits) and related to motor and non-motor deficits. By end-stage PSP, focal atrophy had advanced from frontal and subcortical structures to include atrophy in the parietal lobe. Parietal lobe atrophy related to behavioural abnormalities. Histopathological analysis at end-stage revealed that the cortical atrophy and cell loss does not relate to tau deposition. The focal cortical cell loss related exclusively to motor deficits whilst the more widespread cortical tau deposition related to cognitive and behavioural impairments. Both the tau deposition and these non-motor impairments increased in severity over time. The results show that frontal atrophy and dysfunction occurs rapidly and early in PSP and relate to increasing cognitive deficits. Such deficits appear to cause compensatory CBF enhancement in parietocerebellar regions which then also undergo rapid and severe neurodegeneration. These later changes occur in concert with the more classic PSP symptoms, such as oculomotor features. Throughout the disease, the progressive increase in frontotemporal tau deposition contributes to cognitive and behavioural deficits which become most marked late in the disease. The findings strongly suggest that progressive clinical dysfunction in PSP is directly related to progressive cortical degeneration. Cortical degeneration appears to occur in two independent functional networks. Increased CBF in PSP may be a useful early indicator for future neurodegeneration, although the cellular mechanism leading to cell death requires further investigation.

The purpose of this thesis is to investigate: whether cross sectional MRI can help to discriminate progressive supranuclear palsy (PSP), multiple system atrophy (Parkinsonian subtype, MSA-P) and Parkinson's disease (PD) whether established methods of serial volumetric MRI analysis can be applied to measure in-vivo rates of brain atrophy in PSP and whether cross sectional MRI and MRI-derived atrophy rates have a clinical correlate. Volumetric and diffusion-weighted MRI (DWI) scans were performed in 24 patients with PSP, 11 with MSA-P, 12 with PD and 18 healthy controls. Detailed clinical and neuropsychological assessments were undertaken, and results at the time of initial assessment and follow-up compared. Whole brain and regional brain volumes were measured on positionally matched (registered) baseline and follow up MR images. The boundary shift integral (BSI), an image analysis technique for assessing volume differences from registered MR scans was applied to whole brain, and hypothesis-driven regions of interest in order to allow quantification of atrophy rates. PSP can be reliably discriminated from MSA-P with quantitative regional volume measurements of the superior cerebellar peduncle, midbrain, pons and cerebellum (p<0.001). DWI may help to identify regional pathological change in-vivo, discriminating MSA-P and PSP using apparent diffusion coefficients in the middle cerebellar peduncle (p0.001). The mean (SD) brain atrophy rate in PSP, 1.2 (1.0) %year_1 was greater than in healthy controls 0.4(0.5)%year"1 (p=0.04) but similar to MSA-P 1.0(l.l)%year'1. In PSP, the mean midbrain atrophy rate was most significantly different from controls (p<0.001). Ponto-cerebellar atrophy rates discriminated MSA-P and PSP (p<0.05). The distinct patterns and rates of atrophy in these diseases have a meaningful clinical correlate and power calculations confirm that in PSP, regional atrophy rates are quantifiable and feasible markers of disease progression that have utility in clinical trials as a marker for evaluating disease-modifying treatments in PSP.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative condition. The aims of this study were to evaluate the association between sleep, the circadian system and autonomic function in a cohort of PSP patients. Methods: Patients with PSP diagnosed according to consensus criteria were recruited prospectively and retrospectively and performed the following tests: body core temperature (BcT), sleep-wake cycle, systolic and diastolic blood pressure (SBP, DBP) continuous monitoring for 48 h under controlled environmental conditions; cardiovascular reflex tests (CRTs). The analysis of circadian rhythmicity was performed with the single cosinor method. For state-dependent analysis, the mean value of variables in each sleep stage was calculated as well as the difference to the value in wake. Results: PSP patients presented a reduced total duration of night sleep, with frequent and prolonged awakenings. During daytime, patients had very short naps, suggesting a state of profound sleep deprivation across the 24-h. REM sleep behaviour disorder was found in 15%, restless legs syndrome in 46%, periodic limb movements in 52% and obstructive sleep apnea in 54%. BcT presented the expected fall during night-time, however, compared to controls, mean values during day and night were higher. However BcT state-dependent modulation was maintained. Increased BcT could be attributed to an inability to properly reduce sympathetic activity favoured by the sleep deprivation. At CRTs, PSP presented mild cardiovascular adrenergic impairment and preserved cardiovagal function. 14% had non-neurogenic orthostatic hypotension. Only 2 PSP presented the expected BP dipping pattern, possibly as a consequence of sleep disruption. State-dependent analysis showed a partial loss of the state-dependent modulation for SBP. Discussion: This study showed that PSP presented abnormalities of sleep, circadian rhythms and cardiovascular autonomic function that are likely to be closely linked one to another.

The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.

Progressive supranuclear palsy (PSP) belongs to a group of neurodegenerative disorders that are characterised by hallmark pathology consisting of intra-neuronal aggregates of the microtubule-associated protein, tau. In PSP, these aggregates are almost exclusively composed of one of the two major tau protein isoform groups normally expressed at similar levels in the healthy brain, indicating a role for altered isoform regulation in PSP aetiology. Although no causal mutations have been identified, common variation within the gene encoding tau, MAPT, has been highly associated with PSP risk. The A-allele of the rs242557 single nucleotide polymorphism has been repeatedly shown to significantly increase the risk of developing PSP. Its location within a distal region of the MAPT promoter region is significant, with independent studies – including this one – demonstrating that the rs242557-A allele alters the function of a transcription regulatory domain. As transcription and alternative splicing processes have been shown to be co-regulated in some genes, it was hypothesised that the rs242557-A allele could directly affect MAPT alternative splicing through its differential effect on transcription. This project describes an investigation into the molecular mechanism linking the MAPT association with the tau isoform dysregulation characteristic of PSP. The design, construction and in vitro investigation of minigenes representing common MAPT variants will be presented in detail and will demonstrate that promoter identity plays an important role in regulating the alternative splicing of MAPT transcripts. The specific role of the rs242557 polymorphism in MAPT transcription and splicing are investigated and the two alleles of the polymorphism are shown to differentially influence these two molecular processes, providing a plausible mechanism linking the two phenomena known to be associated with PSP – a common genetic variant within the MAPT promoter region and detrimental changes to tau isoform production.

Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第11406号
医博第2829号
新制||医||889(附属図書館)
23049
UT51-2005-D156
京都大学大学院医学研究科脳統御医科学系専攻
(主査)教授 金子 武嗣, 教授 林 拓二, 教授 富樫 かおり
学位規則第4条第1項該当

Background Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are atypical Parkinsonian disorders which are rapidly progressive. The impact that Parkinsonian disorders has on quality of life (QoL) is increasingly understood, though less work has been done in MSA and PSP compared to Parkinson’s disease. The role of Palliative Care in enhancing QoL is beginning to be translated into clinical practice though fewer studies have been done in MSA and PSP compared with Parkinson’s disease. Methods A cross-sectional study of 23 MSA patients and 24 PSP patients was carried out, assessing aspects of QoL, depression, palliative symptoms and clinical milestones such as dysarthria. Carers for each disease type were assessed in terms of carer strain and QoL. A range of QoL measures including subjective, disease-specific and general QoL scores were taken with the aim of achieving a holistic impression of QoL and symptom burden. A subset of participants were selected for interviews to obtain personal perspectives of living with these conditions. The interviews were evaluated using thematic analysis, to gain a still fuller, richer picture of the implications of these diseases on QoL for patients and carers. The use of both quantitative and qualitative methods was intended to complement each other, with the recognition that QoL is a complex and subjective concept and cannot be encompassed using a single type of assessment. Results Using multiple linear regression, QoL was predicted for by depression and palliative need in MSA and PSP, with severity having an influence in PSP only. Carer mental well-being and patient depression influenced different aspects of carer QoL. Issues with legs was the highest-rated symptom in both groups and there was no significant difference in palliative need between MSA and PSP. Subjective QoL using the SEIQoL-DW score produced diverse domains which people felt influenced their QoL. The most commonly nominated were ‘family’ and ‘partner’; some domains in common were discussed in interviews. ii The overarching themes in interviews were connection to others, transitions (including adjustment) and seeking support, from peers, palliative care services and sourcing expertise for these rare conditions. Conclusion MSA and PSP have a profound effect on QoL, seen using a range of QoL scores. Depression and symptoms frequently managed in palliative care, predict for patient disease-specific QoL, though severity seems to have a greater impact on QoL in PSP compared with MSA. Carer QoL is impacted by patient depression and by carers’ own mental well-being. This work emphasises that QoL in progressive neurological disorders is heterogeneous and individual. Patients and their carers would likely benefit from an individualised, palliative approach supporting patients through the course of their disease, maximising QoL to enhance the experience of living with a progressive disease.

Background: Idiopathic parkinsonism is a neurodegenerative syndrome of unknown cause and includes Parkinson’s disease (PD) and atypical parkinsonian disorders. The atypical parkinsonian disorders are: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The incidence rates of these diseases in Sweden are largely unknown. The diagnosis of each disease relies mainly on clinical examination although several imaging and laboratory parameters may show changes. A diagnosis based on clinical examination is especially difficult early in the course of each disease; diagnosis is easier later on when disease-charactersistic signs have evolved and become more prominent. However, even in later stages it is not uncommon that patients are misdiagnosed. PD can be divided into subgroups based on the main clinical symptoms, i. e. tremor dominant, postural instability and gait difficulty (PIGD), and indeterminate. The PIGD subtype has worse prognosis including higher risk of dementia. The aims were to study the incidence of idiopathic parkinsonism and the different specific parkinsonian disorders in the Umeåregion and to investigate the patients early in the course of the disease with brainmagnetic resonance tomography (MRI), external anal sphincterelectromyography (EAS-EMG) and oculomotor examination. Can these methods improve the differential diagnostic work-up and/or differentiate between the subtypes of PD? Methods: We examined all patients in our catchment area (142,000 inhabitants) who were referred to us due to a suspected parkinsonian syndrome. Our clinic is the only clinic in the area receiving referrals regarding movement disorders. During the period (January 1, 2004 through April 30,2009) 190 patients fulfilled the inclusion criteria and were included in the study. Healthy volunteers served as controls.  Results: Incidence: We found the highest incidences reported in the literature: PD (22.5/100,000/year), MSA(2.4/100,000/year), and PSP (1.2/100,000/year). No CBD patients were encountered. Brain MRI: Degenerative changes were common both in controls and PD. There were no differences between the PD subtypes. EAS-EMG: Pathological changes in EAS-EMG examination were common in PD, MSA and PSP. It was not possible to separate PD, MSA and PSP by the EAS-EMG examination. Oculomotor examination: Pathological results were common in all diagnosis groups compared to controls. It was not possible to separate PD, MSA and PSP or the PD subtypes with the help of oculomotor examination. Conclusions: The incidences of idiopathic parkinsonism, PD, MSA and PSP were higher than previously reported in the literature. It is not clear weather this is due to a true higher incidence in the Umeå region or a more effective casefinding than in other studies. MRI, EAS-EMG and oculomotor examination could not contribute to the differential diagnostic work-up between PD, MSA and PSP nor differentiate between PD subtypes early in the course of the disease.

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Este trabalho consiste de dois estudos: o primeiro estudo avalia o papel da morfometria por ressonÃncia magnÃtica (RM) no diagnÃstico diferencial das sÃndromes parkinsonianas; o segundo avalia as alteraÃÃes do sono nessas sÃndromes e suas relaÃÃes com alteraÃÃes estruturais na RM. Nas fases iniciais da doenÃa o diagnÃstico diferencial entre as sÃndromes parkinsonianas pode ser de difÃcil realizaÃÃo. As medidas por RM podem contribuir para o diagnÃstico diferencial entre a doenÃa Parkinson (DP), paralisia supranuclear progressiva (PSP) e atrofia de mÃltiplos sistemas (AMS). O objetivo do primeiro estudo foi avaliar o valor diagnÃstico das alteraÃÃes anatÃmicas estruturais identificadas pela RM no diagnÃstico diferencial dessas sÃndromes. Foram estudados 21 casos com DP, 11 casos com atrofia de mÃltiplos sistemas forma cerebelar (AMS-c), 8 casos de atrofia de mÃltiplos sistemas forma parkinsoniana (AMS-p) e 20 com PSP. A Ãrea sagital mediana do mesencÃfalo (Ams), Ãrea sagital mediana da ponte (Apn), largura mÃdia do pedÃnculo cerebelar mÃdio (PCM) e pedÃnculo cerebelar superior (PCS) foram medidas pela RM. ComparaÃÃes mÃltiplas foram realizadas entre a PD, AMS-c, AMS-p e PSP. A morfometria da Apn, PCM e PCS apresentaram diferenÃas entre os casos com diferentes diagnÃsticos. A Ams e a morfometria do PCS foram as medidas mais preditivas para o diagnÃstico de PSP, de tal forma que uma Ãrea do mesencÃfalo < 105 mm2 e a medida do PCS < 3 mm mostraram uma grande probabilidade para este diagnÃstico (sensibilidade de 95,0 e 80,0%, respectivamente). Nos casos de AMS-c, a morfometria da Apn < 315mm2 apresentou boa especificidade e valor preditivo positivo para o diagnÃstico (93,8% e 72,7%, respectivamente). Em conclusÃo, demonstramos que dimensÃes e valores de cortes obtidos a partir de exames de RM podem diferenciar entre PD, PSP e AMS-c, com boa sensibilidade, especificidade e precisÃo. Na segunda etapa desse trabalho, foram avaliados e comparados os distÃrbios do sono em pacientes com DP, AMS e PSP e as possÃveis associaÃÃes com a morfometria por RM do encÃfalo em 16 casos de DP, 13 AMS, 14 PSP e 12 controles. Os distÃrbios do sono foram avaliados pela escala de SonolÃncia de Epworth, Ãndice de Qualidade do sono de Pittsburgh (IQSP), escala de pernas inquietas e questionÃrio de Berlim. A Apn e Ams e largura do PCS e do PCM foram medidas pela RM. A mà qualidade do sono, o risco da sÃndrome da apnÃia obstrutiva do sono (SAOS) e sÃndrome das pernas inquietas (SPI) foi detectado em todos os grupos. Pacientes com AMS apresentaram maior risco de SAOS e menor nÃmero de casos com SPI. Nos casos de AMS, uma correlaÃÃo entre os escores do IQSP e o estÃgio do Hoehn & Yahr foi observada (p<0,05). Na PSP, a SPI foi freqÃente (57%) e relacionou-se com a menor duraÃÃo e pior eficiÃncia do sono. Na DP, sonolÃncia diurna excessiva relacionou-se com a atrofia do PCM (p=0,01). Em conclusÃo, o alto risco de SAOS foi comum e proeminente nos casos de AMS. SPI foi mais freqÃente na DP e na PSP. Nos casos com PSP, a SPI associou-se com uma reduÃÃo da eficiÃncia e duraÃÃo do sono; e nos pacientes com DP e sonolÃncia excessiva diurna apresentaram maior atrofia do PCM (DP com sonolÃncia excessiva diurna PCM= 16,08Â0,93; DP sem sonolÃncia excessiva diurna PCM =17,82 0,80 p=0,01), sugerindo degeneraÃÃo de estruturas do tronco cerebral nesses pacientes.
We describe two studies, as follows: one concerns the role of cerebral morphometry as evaluated by magnetic resonance imaging (MRI) in the differential diagnosis of the parkinsonian syndromes; the other is about sleep alterations and the relationship with MRI changes in these syndromes. MRI measures can be useful for differential diagnosis between Parkinson disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). The aim of this study was to evaluate the diagnostic value of structural anatomic changes identified by MRI in the differential diagnosis of these syndromes. We studied 21 cases with PD, 11 with MSA-c, 8 with MSA-p, 20 with PSP and 12 controls. Midbrain area (Ams), Pons area (Apn), middle cerebellar peduncle (MCP) and superior cerebellar peduncle (SCP) width were measured using MRI. Multiple comparisons were made between PD, MSA-p, MSA-c and PSP and we show that Apn, MCP and SCP width morphometry dimensions have clear cut differences in these syndromes. The Ams and SCP were the most predictive measures of PSP. A Midbrain area below 105 mm2 and SCP less than 3 mm showed a major probability for this diagnosis (sensitivity of 95.0 and 80.0%, respectively). For the group of MSA-c patients, an Apn area below 315mm2 showed good specificity and positive predictive value (93.8% and 72.7%, respectively). In conclusion, we demonstrate that dimensions and cut off values obtained from routine MRI can differentiate between PD, PSP and MSA-c with good sensitivity, specificity and accuracy. Despite common reports in PD, in other parkinsonian syndromes, sleep disturbances have been less frequently described. We compare sleep disturbances in patients with PD, MSA and PSP and analyze associations with brain MRI morphometry. This was a cross-sectional study of 16 PD cases, 13 MSA and 14 PSP. Sleep disturbances were evaluated by Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI), Restless Legs Scale and Berlin questionnaire. Apn, Ams, MCP width, and SCP width were measured using MRI. Poor quality sleep, risk of obstructive sleep apnea (OSA) and restless legs syndrome (RLS) were detected in all groups. Patients with MSA showed higher risk of OSA and less frequent RLS. In MSA, a correlation between PSQI scores and Hoehn and Yahr stage was observed (p<0.05). In PSP, RLS was frequent (57%) and related with reduced sleep duration and efficiency. In PD, excessive daytime sleepiness was related to atrophy of the MCP (p= 0.01). High risk of OSA was common and prominent in MSA cases. RLS was more frequent in PD and PSP, and in PSP, was associated with reduced sleep efficiency and sleep duration. In conclusion, the morphometric analysis of PD patients with excessive daytime sleepiness showed more atrophy of MCP (PD with excessive daytime sleepiness MCP= 16.08Â0.93; PD without excessive daytime sleepiness MCP=17.82Â0.80 p= 0.01) suggesting widespread degeneration of brainstem sleep structures on the basis of sleep abnormalities in these patients.

The dementias are persistent or progressive disorders affecting more than one cognitive domain that interfere with an individual’s ability to function at work or home, and represent a decline from a previous level of function. In this thesis I consider the neurophysiology of dementia at a number of levels. I investigate the ways in which the connectivity and function of the brain predisposes to the specific focal patterns of neurodegeneration seen in the various dementias. I aim to identify the mesoscopic changes that occur in individuals with neurodegeneration and how these relate to their cognitive difficulties. I show how, by assessing patients in whom there is focal disruption of brain networks and observing the outcomes in comparison to controls, I can gain insight into the mechanisms by which the normal brain makes predictions and processes language. In Chapter 1, I set the scene for the focussed experimental investigations of model diseases by beginning with an introductory, clinically-focussed review that sets out the features, aetiology, management, epidemiology and prognosis of the dementias. This places these model diseases in the context of the broader clinical challenge posed by the dementias. In Chapter 2, I turn to ‘prototypical’ model diseases that represent neurodegenerative tauopathies with predominantly cortical (Alzheimer’s disease, AD) and subcortical (Progressive Supranuclear Palsy, PSP) disease burdens. I investigate the neurophysiological causes and consequences of Tau accumulation by combining graph theoretical analyses of resting state functional MR imaging and in vivo ‘Tau’ PET imaging using the ligand AV-1451. By relating Tau distribution to the functional connectome I provide in vivo evidence consistent with ‘prion-like’ trans-neuronal spread of Tau in AD but not PSP. This provides important validation of disease modification strategies that aim to halt or slow down the progression of AD by sequestration of pathological Tau in the synapse. In contrast, I demonstrate associations consistent with regional vulnerability to Tau accumulation due to metabolic demand and a lack of trophic support in PSP but not AD. With a cross-sectional approach, using Tau burden as a surrogate marker of disease severity, I then go on to show how the changes in functional connectivity that occur as disease progresses account for the contrasting cognitive phenotypes in AD and PSP. In advancing AD, functional connectivity across the whole brain becomes increasingly random and disorganised, accounting for symptomatology across multiple cognitive domains. In advancing PSP, by contrast, disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer passed through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Together, this resulted in increasingly modular processing with inter-network communication taking less direct paths, accounting for the bradyphrenia characteristic of the ‘subcortical dementias’. From chapter 3 onwards, I turn to the in-depth study of a model disease called non-fluent variant Primary Progressive Aphasia (nfvPPA). This disease has a clear clinical phenotype of speech apraxia and agrammatism, associated with a focal pattern of mild atrophy in frontal lobes. Importantly, general cognition is usually well preserved until late disease. In chapter 3 itself, I relate an experiment in which patients with nfvPPA and matched controls performed a receptive language task while having their brain activity recorded with magnetoencephalography. I manipulated expectations and sensory detail to explore the role of top-down frontal contributions to predictive processes in speech perception. I demonstrate that frontal neurodegeneration led to inflexible and excessively precise predictions, and that fronto-temporal interactions play a causal role in reconciling prior predictions with degraded sensory signals. The discussion here concentrates on the insights provided by neurodegenerative disease into the normal function of the brain in processing language. Overall, I demonstrate that higher level frontal mechanisms for cognitive and behavioural flexibility make a critical functional contribution to the hierarchical generative models underlying speech perception In chapter 4, I precisely define the sequence processing and statistical learning abilities of patients with nfvPPA in comparison to patients with non-fluent aphasia due to stroke and neurological controls. I do this by exposing participants to a novel, mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships, and then assessing the degree of implicit rule learning. I demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently in health and disease. In chapter 5, I summarise the synergies between the experimental chapters, and explain how I have applied a systems identification framework to a diverse set of experimental methods, with the common goal of defining the physiology of dementia. I then return to the results of chapter 3 with a clinical focus to explain how inflexible predictions can account for subjective speech comprehension difficulties, auditory processing abnormalities and (in synthesis with chapter 4) receptive agrammatism in nfvPPA. Overall, this body of work has contributed to knowledge in several ways. It has achieved its tripartite aims by: 1) Providing in vivo evidence consistent with theoretical models of trans-neuronal Tau spread (chapter 2), and a comprehensive clinical account of the previously poorly-understood receptive symptomatology of nfvPPA (chapter 5), thus demonstrating that systems neuroscience can provide a translational bridge between the molecular biology of dementia and clinical trials of therapies and medications. In this way, I begin to disentangle the network-level causes of neurodegeneration from its consequences. 2) Providing evidence for a causal role for fronto-temporal interactions in language processing (chapter 3), and demonstrating domain separation of statistical learning between linguistic and non-linguistic sequences (chapter 4), thus demonstrating that studies of patients with neurodegenerative disease can further our understanding of normative brain function. 3) Successfully integrating neuropsychology, behavioural psychophysics, functional MRI, structural MRI, magnetoencephalography and computational modelling to provide comprehensive research training, as the platform for a future research programme in the physiology of dementia.

Background: Single photon emission computed tomography (SPECT) with dopamine transporter (DAT) and dopamine D2 receptor (D2R) ligands can visualise the integrity of the nigrostriatal dopamine system. Parkinson’s disease (PD) and the atypical parkinsonian diseases (APD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), have similar symptoms and dopamine depletion, but differ in pharmacological response and prognosis. Clinical differentiation between PD and APD is often difficult in the early stages. The aims of the thesis were to evaluate the differential diagnostic and prognostic value of SPECT in early PD, MSA and PSP, to map the pattern of progression with dopamine SPECT, and map the pattern of dopamine SPECT in non-affected elderly volunteers with a prospective approach. Also, we evaluated the methodological aspects of dopamine SPECT with respect to image evaluation tools, reconstruction parameters and gamma cameras. Methods: 172 patients, included in an on-going clinical prospective study on idiopathic parkinsonism, participated in the SPECT study. Also, 31 age-matched healthy controls (HC) were followed within this study. SPECT was done with 123I-FP-Cit (DAT SPECT) and 123I-IBZM (D2R SPECT). Regions of interest (ROI) were used as a standard method for semi-quantitative image analysis. Results: SPECT uptake ratios from different gamma cameras could be equalised through correction equations derived from images of a brain-like phantom, provided that attenuation correction was applied. The ROI method had high reproducibility. SPECT uptake  in HC, measured with the ROI method and a volume based (VOI) method rendered similar trends, but gender and age differences in SPECT uptake were more marked with the VOI method, and less pronounced in DAT SPECT compared to D2R SPECT with both methods. The DAT SPECT uptake was significantly reduced in very early disease stage of PD and APD compared to HC. DATSPECT uptake was more reduced in PD with postural and gait disturbance (PIGD) compared to tremor-dominant PD. Decline in DAT SPECT uptake during the first year was more pronounced in PD and PSP compared to HC. D2R SPECT uptake overlapped between untreated PD and APD. After initiated treatment, the D2R SPECT uptake was significantly higher in MSA patients compared to PD, PSP and HC. Decline in D2R SPECT uptake during the first year was not significantly different between patients or compared to HC. Conclusions: 123I-FP-Cit SPECT is a valuable and sensitive method to detect early stage idiopathic parkinsonism. A different level of uptake between PIGD-PD compared to TD-PD indicates a prognostic potential. It is not possible to differ between PD, MSA and PSP in early stage with 123I-FP-Cit SPECT and no differential diagnostic value was found using 123I-IBZM SPECT in the early, untreated stage of PD, MSA and PSP. A different pattern of uptake of this ligand in MSA compared to PD and PSP during the first years of L-dopa treatment may, however, indicate a diagnostic value during the follow-up period.

In der Differentialdiagnose von Parkinson-Syndromen wurden in frühen und in fortgeschrittenen Stadien insgesamt 138 Patienten mit der Verdachtsdiagnose eines Morbus Parkinson und mit der Verdachtsdiagnose einer progressiven supranukleären Blickparese untersucht. Es wurden klinische Verlaufsbeobachtungen sowie die dopaminerge Stimulation mit Apomorphin, die Kernspintomographie und die single photon emission computed tomography (SPECT) mit dem Liganden Jodobenzamid für die Untersuchungen eingesetzt. Die Ergebnisse der zu untersuchenden Hypothesen können wie folgt zusammengefaßt werden: Bei bis dato unbehandelten Patienten mit akinetisch-rigiden Syndromen kann mittels einer Testinjektion von 3 -5 mg Apomorphin mit einer Sensitivität und Spezifität von etwa 90 % das Ansprechen auf eine L-Dopa-Langzeittherapie korrekt vorhergesagt werden. Das IBZM-SPECT ist in der Lage, mit einem positiven Vorhersagewert von 72 % und einem negativen Vorhersagewert von 89 % das Ansprechen auf eine spätere orale L-Dopa-Therapie korrekt vorherzusagen. In der Langzeitbeobachtung entwickeln sich aus den 10 Patienten im Frühstadium, die nach den klinischen Kriterien nicht eindeutig zuzuordnen waren, die eine verminderte Ligandenaufnahme haben, und die nicht auf Apomorphin reagieren, 7 ein "atypisches" Parkinson-Syndrom im Sinne einer MSA (n = 5), einer PSP (n = 1) oder einer CBGD (n = 1) Von diesen 7 Patienten hatten 5 bereits in der Erstdiagnostik eine verminderte IBZM-Bindung im SPECT. Vaskuläre Syndrome entwickeln nicht nur das klinische Bild des "lower body parkinsonism", sondern auch Zeichen einer vertikalen Blickparese mit Demenz bei akinetisch-rigidem Syndrom. Bei gut 30 % der untersuchten Patienten mit der klinischen Diagnose der PSP wurden vaskulär gedeutete Läsionen im MRT in der weißen Substanz und in den Basalganglien gefunden; diese hatten signifikant häufiger eine normale Bindung im IBZM-SPECT und unterschieden sich von degenerativen PSP-Patienten mit erniedrigter IBZM-Bindung. Wir deuten diese Patienten als eine andere nosologische Entität. Außerdem konnte erstmals gezeigt werden, daß bei Patienten, die klinisch wahrscheinlich oder möglicherweise eine PSP hatten, der antero-posteriore Durchmesser des Mittelhirns nach kernspintomographischer Messung mit der Ligandenaufnahme im IBZM-SPECT korreliert. Dies gilt für die Gesamtgruppe der untersuchten Patienten, aber auch für die Untergruppe, die keine hyperintensen T2-Läsionen haben. Diese Ergebnisse bedeuten für den klinische Alltag, daß nach einer sorgfältigen klinischen Untersuchung von Patienten mit Parkinson-Syndromen, die die gültigen Kriterien für die klinische Diagnose des Morbus Parkinson, der progressiven supranukleären Blickparese und auch der Multi-System-Atrophie beachtet, das Kernspintomogramm und das IBZM-SPECT notwendige Untersuchungen in der korrekten ätiologischen Zuordnung von Parkinson-Syndromen, insbesondere auch der progressiven supranukleären Blickparese sind. Dies ist für die weitere Planung insbesondere von neuroprotektiven Strategien bei diesen Krankheitsbildern von essentieller Bedeutung.
One hundred thirty eight patients, in whom the diagnoses of Parkinson's disease or progressive supranuclear palsy (PSP) was suspected, were examined in order to improve the differential diagnosis of these syndromes. We observed the clinical course, tested for the dopaminergic response to the dopamine receptor agonist apomorphine, and used the technical measures of MRI and single photon emission computed tomography (SPECT) with the ligand 123[I] Iodobenzamide (IBZM) in all patients. Apomorphine correctly predicts the response to long term levodopa therapy with a sensitivity and specificity of approximately 90 % in previously untreated parkinsonian patients. The positive predictive value and negative predictive value of IBZM SPECT are 72 % and 89 % respectively. Ten early stage patients, who could not explicitly be assigned according to the clinical criteria, who had reduced IBZM SPECT binding and who did not respond to apomorphine, developed atypical parkinsonian syndromes in the sense of multiple system atrophy (MSA, n = 5), PSP (n = 1) or corticobasal degeneration (n = 1). Five of these 7 patients had a reduced IBZM binding in SPECT already during the early stage. Vascular syndromes depict not only the clinical picture of lower body parkinsonism, but also of supranuclear palsy, dementia and akinetic-rigid syndrome. We found MRI lesions within the white matter and the basal ganglia in about 30 % of our patients with the clinical diagnosis of PSP; we interpreted these lesions as vascular. In contrast to patients without these MRI lesions, who had decreased IBZM binding in SPECT, these patients with vascular disorders had significantly more frequently a normal binding. We interpret our results in that way that these patients represent another nosological entity. In addition, we showed for the first time that the anteroposterior diameter (measured in midbrain MRI scans) correlates to ligand binding measured by IBZM SPECT. This applies as well to all PSP patients as well to the sub-group without hyperintense MRI lesions. The in vivo diagnosis of bradykinetic syndromes relies on clinical examination; after careful observation of valid criteria for Parkinson's disease, PSP and MSA, MRI and IBZM SPECT are mandatory for the correct differential diagnosis, especially for PSP. This applies in particular, if neuroprotective therapies are to be investigated.

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.

Hyperfosforylering av biomarkörproteinet Tau förekommer i flera neurodegenerativa sjukdomar som kallas Taupathies. Proteinets huvudfunktion i människokroppen är att modulera flexibilitet och stabilitet för axonal-mikrotubulin. I Taupathies utlöser hyperfosforyleringen av Tau instabilitet och neurodegenerationen. I dagens läge kan hyperfosforylering av treonin 217 (P217) endast mätas i hjärnan. I den här studien undersöks hyperfosforyleringen av treonin 217 (P217). I syfte att se om nivåerna av P217 är mätbara i cerebrospinalvätska (CSV) och i blodet. Samt för att evaluera hur nivåer av P217 förändras i olika Taupathies, genom att testa hjärnprover från friska kontroller och olika Taupathies. Studien görs för att öka kunskapen om effekten av hyperfosforylering av treonin 217 i Taupathies och för att bidra med en ny provtagningsmetod för P217. Simoa HD-1 Analyzer var instrumentet som användes för analyserna av P217. Det är ett instrument som kan upptäcka onormala nivåer av biomarkörer genom kvantifiering, med hjälp av antikroppar och ett enzym. Enzymet kallas Streptavidin β-galaktosidas och omvandlar en befintlig P217-molekyl i proven till en fluorescerande produkt. Genom Simoa HD-1 Analyzer utvecklades en ultrasensitiv analys med antikropparna P217 och Tau 12, som kunde upptäcka mycket låga nivåer av P217 i hjärnan, CSF och i blod. Förändring av P217-nivåer hittades även i olika Taupathies. De Taupathies med de högsta nivåerna av P217 var Progressiv supranukleär pares, Corticobasal degeneration och Globular glial Taupathies.
Hyperphosphorylation of the biomarker protein Tau occurs in many neurodegenerative diseases called Taupathies. The proteins main function in the human body is to modulate flexibility and stability for axonal microtubules. In Taupathies the hyperphosphorylation of the Tau triggers instability and neurodegeneration. Nowdays hyperphoshorylation on threonine 217 (P217) can only be measured in the brain. In this study the hyperphoshorylation on the phosphorylation site of threonine 217 (P217) is examined. In aim to see if levels of P217 is measurable in cerebrospinal fluid (CSF) and in blood. As well to evaluate how P217 variate in different Taupathies, through the use of brain samples from healthy controls and different Taupathies. The study is made for the purpose of enhancing the pure knowledge about the effect of hyperphosphorylation on threonine 217 in Taupathies and to contribute with a new sampling method for P217. Simoa HD-1 Analyzer was the key instrument of the analyses of P217. It’s an instrument which can detect abnormal levels of biomarkers through quantification, with help of antibodies and an enzyme. The enzyme is called Streptavidin β-galactosidase and converts an existing P217 molecule in the samples to a fluoresce product. Through the use of Simoa HD-1 Analyzer an ultrasensitive assay with antibodies P217 and Tau 12 was developed which could detect very low levels of P217 in brain, CSF and in blood. Variation of P217 levels was also found in different Taupathies. The Taupathies with the highest levels of P217 was Progressive supranuclear palsy, Corticobasal Degeneration and Globular glial Taupathies.

The present thesis comprises three main parts: one theoretical and two experimental. The first part, composed of two chapters, will introduce the clinical and neuropathological features underlying parkinsonian disorders, namely in Parkinson’s disease (PD) as well as in atypical parkinsonisms — multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) (Chapter 1). In this regard, PD and MSA are defined as synucleinopathies due to the presence of synuclein aggregates; while PSP that is characterized by tau protein accumulations, is part of tauopathies. Further, Chapter 2 will provide an overview of the cognitive dysfunctions characterizing these disorders, as well as evidence on the biological mechanisms and structural changes underlying cognitive alterations. The second and third parts are composed by studies I conducted during my doctoral research. Namely, in Chapter 3, I report results of my studies on cognitive screening instruments most sensitive in detecting cognitive alterations in atypical parkinsonisms compared to PD. In the following study, I characterized the progression of cognitive decline in these disorders (Chapter 4). Finally, I investigated with magnetic resonance imaging the structural changes underlying cognitive alterations in PD (Chapter 5), and MSA (Chapter 6). I conclude this thesis by discussing the clinical consequences of these cognitive and imaging findings (Chapter 7). PART I - Theoretical background Chapter 1: Parkinsonian disorders Parkinsonian disorders are characterized by different underlying pathologies. In PD and MSA there are synuclein aggregates respectively in dopamine neurons or in glial cells, while PSP patients present pathological aggregation of the tau-protein, resulting in neurofibrillary tangles formation (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Clinical manifestations depend by the characteristics of protein aggregation and by the extent of disease spread to cortical and subcortical regions (Halliday, Holton, Revesz, & Dickson, 2011). Thus, the present chapter will overview the underlying pathology of PD, MSA and PSP; and it will describe the different clinical features; and lastly review the most recent diagnostic criteria (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Chapter 2: Cognitive features and their underlying mechanisms in parkinsonian disorders Non-motor symptoms represent a crucial part of the parkinsonian disorders spectrum; and cognitive dysfunctions, including dementia, are probably the most relevant, since they affect functional independence of patients, increase caregiver burden as well as wield a considerable socioeconomic impact (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). The first part of this chapter will provide an overview on cognitive dysfunctions in PD, MSA, and PSP. Moreover, the clinical criteria for the diagnosis of mild cognitive impairment and dementia in PD will be reported (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), while so far there are no available criteria to assess cognitive syndromes in PSP and MSA. Lastly, the second and third parts of this chapter will review the evidence on biological mechanisms and structural changes underlying cognitive alterations in these disorders. PART II - Studies on cognitive manifestations in parkinsonian disorders Chapter 3: Montreal Cognitive Assessment and Mini-Mental State Examination performance in progressive supranuclear palsy, multiple system atrophy and Parkinson’s disease There is general agreement that cognitive dysfunctions are common in PD as well as in other parkinsonian disorders (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Brief screening cognitive scales can be adopted in routine care, to support the clinician in the diagnostic process (Marras, Troster, Kulisevsky, & Stebbins, 2014). The Mini-Mental State Examination (MMSE) is the most widely used (Folstein, Folstein, & McHugh, 1975) although MMSE is relatively insensitive in detecting cognitive deficits in parkinsonian disorders mainly because it does not investigate the fronto-executive domain (Hoops et al., 2009). Conversely, the Montreal Cognitive Assessment (MoCA), another brief cognitive screening tool widely used with PD patients (Nasreddine et al., 2005), showed high sensitivity and specificity in the assessment of cognitive dysfunctions in PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), as well as also in several neurodegenerative conditions such as Alzheimer’s disease, dementia with Lewy bodies (DLB) and Huntington’s disease (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). However, MoCA has been poorly investigated in atypical parkinsonisms — especially in PSP and MSA (Kawahara et al., 2015). Thus, this study’s main aim was to determine if MoCA is more sensitive than the commonly used MMSE in detecting cognitive abnormalities in patients with probable PSP and MSA, compared to PD. In this multicenter study across three European institutions, MMSE and MoCA were administered to 130 patients: 35 MSA, 30 PSP and 65 age, and education and sex matched-PD. We assessed between-group differences for MMSE, MoCA, and their subitems and calculated receiver operating characteristic (ROC) curves. Our results show that the mean MMSE is higher than the mean MoCA score in each patient group: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), and PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Furthermore, MoCA total score as well as its letter fluency subitem differentiates PSP from MSA and PD with high specificity and moderate sensitivity. Namely, a cut-off score of seven words or less per minute would support a diagnosis of PSP (PSP vs. PD: 86% specificity, 70% sensitivity; PSP vs. MSA: 71% specificity, 70% sensitivity). On the contrary, MMSE presented a ceiling effect for most subitems, except for the ‘bisecting pentagons’, with PSP performing worse than MSA and PD patients. These findings suggest that PSP and MSA, similar to PD patients, may present normal performance on MMSE, but reduced performance on MoCA. To conclude, MoCA is more sensitive than MMSE in detecting cognitive dysfunctions in atypical parkinsonisms, and together with its verbal fluency subitem can be a valuable test to support PSP diagnosis. Chapter 4: Prospective assessment of cognitive dysfunctions in parkinsonian disorders Clinical and research evidence suggests cognitive impairments in parkinsonian disorders are progressive. However, there are only a few longitudinal studies in the literature that investigated cognitive progression in PSP and MSA compared to PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In addition, previous studies are based on brief cognitive screening scales or on neuropsychological assessments that do not extensively investigate the full spectrum of cognitive abilities across the five cognitive domains (i.e., attention/working-memory, executive, memory, visuospatial and language). Furthermore, even though clinical criteria for mild cognitive impairment (MCI) and dementia in PD have been formulated (Dubois et al., 2007; Litvan et al., 2012), it remains to be investigated whether similar criteria might be applied also for atypical parkinsonisms (Marras et al., 2014). Based on these observations, the aims of the present study were to: i) assess the severity of cognitive dysfunctions in PSP and MSA patients using PD-criteria for cognitive statuses (i.e., MCI or dementia); ii) investigate the sensitivity of two widely used cognitive screening instruments, the MMSE and MoCA, in differentiating MSA, PSP and PD global cognitive profile; iii) characterize the progression of cognitive decline on the five cognitive domains and behavioral features; and to compare the 15-month follow-up profile across the parkinsonian diseases. Our sample included 18 patients with PSP, 12 MSA; and 30 PD patients, matched for age, education and sex. They were evaluated at baseline and at a mean of 15-month follow-up. Demographic and clinical variables were collected. From the cognitive standpoint, I selected a comprehensive neuropsychological battery specifically designed to target cognitive deficits in PD, according to Level II criteria (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Thus, I applied these criteria also to MSA and PSP since there are no published criteria for atypical parkinsonisms. Statistical non-parametric analyses were used. I found PSP patients had more severe cognitive decline compared to PD and MSA. Namely, after 15-month follow-up, we noted a marked decline in the executive and language domains in the PSP group. Baseline and follow-up evaluations agreed, showing that PSP had a worse performance than PD and MSA patients: especially, in the Stroop test, verbal fluencies (semantic and phonemic) and MoCA. Assessing the severity of cognitive deficits, I found different percentages of cognitive status (i.e., normal cognition vs. MCI vs. dementia) among the three groups. In particular, the percentage of patients with dementia was higher in PSP compared to MSA (33% vs. no patients with dementia) even if disease duration was similar. Among MSA and PSP patients with multidomain MCI at baseline only PSP converted to dementia at follow-up. Then, although the disease duration was longer for PD patients compared with PSP, the proportion of patients who converted to dementia was lower in the PD group compared to PSP (7% vs. 16%), despite both groups having had similar baseline severity of MCI. Overall, these results suggest more rapid and severe cognitive decline in PSP while MSA patients generally have milder deficits. MoCA showed higher sensitivity than MMSE in detecting cognitive changes, especially in PSP. But MoCA was less sensitive than MMSE in detecting cognitive decline at 15-month in PD, suggesting that MMSE is better if one wants to track cognitive changes in PD. Neuropsychiatric features are more common in PSP than PD patients, especially apathy with accompanying low levels of anxiety and depression. Lastly, analysis of subitems revealed that PSP patients had a ‘clinically significant’ worsening after 15-month in the attentive/executive subitems (Trial Making Test part B and Clock drawing). But it has been observed that some patients also improved in specific subtasks at the follow-up. This improvement could be related to their higher medication dose (although the dopaminergic treatment was not significantly different between the baseline and follow-up). However, noteworthy alterations in performance have been seen for subitems sensitive to motor conditions (such as drawing figures and linking circles with a pen), which could affect cognitive outcome, leading to higher performance at follow-up. These limits of MoCA and MMSE scale have already been reported in PD patients (Biundo et al., 2016b; Hu et al., 2014), and maybe are more pronounced in atypical parkinsonisms. Taken together, these findings show that PSP patients were markedly impaired in comparison to the other parkinsonian disorders (MSA and PD) and six years after first symptoms, 33 percent of patients have dementia. This severe progression is possibly associated with the distribution of tau pathology that involves also cortical structures. On the contrary, the pattern of cognitive impairment in MSA is less severe, possibly due to the predominance of subcortical pathology with cortical involvement occurring only secondary to these abnormalities. Thus, these findings recommend using cognitive assessment to help differential diagnosis in atypical parkinsonisms, and to monitor disease progression. PART III - Neuroimaging studies of synucleinopathies Chapter 5: Amyloid depositions affect cognitive and motor manifestations in Parkinson’s disease Cognitive deficits, particularly executive problems, can be observed early in PD (Aarsland, Bronnick, Larsen, Tysnes, & Alves, 2009). Dysfunction of the frontostriatal dopaminergic system may influence the presence of executive and attention problems (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), but so far, evidence from dopamine transporter (DAT) imaging are inconsistent (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). In this regard, the neuropathology underlying cognitive impairment in PD is heterogeneous (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker, & Robbins, 2010) and amyloid deposit involvement with synuclein pathology remains poorly defined, particularly in the disease’s early stages. Thus, this study’s aims were to investigate the interplay between amyloid depositions in frontostriatal pathways, striatal dopaminergic deficit and brain atrophy rates; and their contribution to cognitive defects (i.e., fronto-executive functions) in early-PD. A multicenter cohort of 33 PD patients from the Parkinson's Progression Markers Initiative underwent [18F]florbetaben positron emission tomography (PET) amyloid, [123I]FP-CIT (see Abbreviations List) single-photon emission computed tomography (SPECT), structural magnetic resonance imaging (MRI), clinical and selective cognitive evaluations. Our results showed that high amyloid levels were associated with reduced dopaminergic deficits in the dorsal striatum (as compared to low amyloid levels), increased brain atrophy in frontal and occipital regions and a tendency to show more frequent cognitive impairment in global cognition (as assessed by MoCA) and fronto-executive tests. Of note, amyloid depositions in frontostriatal regions were inversely correlated with cognitive performance. Overall, our findings suggest that early-PD patients with amyloid burden have higher brain atrophy rates and may experience more cognitive dysfunctions (i.e., executive) and motor impairment as compared to amyloid negative subjects. In this regard, our results seem to be aligned with a recent neuropathological hypothesis that considers synaptic axonal damage and dysfunction as the PD key feature (Tagliaferro & Burke, 2016). Indeed, dopaminergic system neurons are particularly vulnerable to synuclein pathology due to their axonal characteristics — long, thin and unmyelinated. This is also confirmed by imaging studies with DAT-binding PET (Caminiti et al., 2017), suggesting that synuclein aggregations in PD can affect synaptic function, and thus signal transmission from the disease’s very early stages. Our findings suggested a possible interaction between synuclein and the coincident amyloid pathology, wherein amyloid burden may facilitate the spread of synuclein (i.e., Lewy bodies) (Toledo et al., 2016), and we speculate that this interaction can further contribute to axonal vulnerability. Thus, consistently with this hypothesis, we conclude that possibly amyloid depositions act synergistically with synuclein pathology and affect PD clinical manifestations. Chapter 6: Brain structural profile of multiple system atrophy patients with cognitive impairment In contrast to other synucleinopathies (e.g., PD and DLB), presence of dementia is considered a non-supporting feature for MSA diagnosis (Gilman et al., 2008), however there is growing evidence that MSA patients can experience cognitive impairment ranging from executive dysfunctions to multiple-domain cognitive deficits, and in a few cases, also dementia (Gerstenecker, 2017). MMSE is a commonly used global cognitive scale and recently a large multicenter study has suggested using a cutoff score below 27 to increase the MMSE sensitivity in identifying cognitive dysfunctions in MSA (Auzou et al., 2015). Underlying mechanisms of cognitive impairment in MSA are still not understood, and in this regard evidence from MRI studies suggested a discrete cortical and subcortical contribution to explain cognitive deficits (Kim et al., 2015; Lee et al., 2016a), even though these findings were based on a relatively small number of patients at various disease stages as well as being single-center. Thus, the aim of our multicenter study was to better characterize the anatomical changes associated with cognitive impairment in MSA and to further investigate the cortical and subcortical structural differences in comparison to a sample of healthy subjects. We examined retrospectively 72 probable MSA patients and based on the MMSE threshold below 27, we defined 50 MSA as cognitively normal (MSA-NC) and 22 with cognitive impairment (MSA-CI). We directly compared the MSA subgroup, and further compared them to 36 healthy subjects using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to healthy subjects, MSA patients showed widespread cortical (i.e., bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white matter alterations. However, the direct comparison MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These findings suggest only a marginal contribution of cortical pathology to cognitive deficits in MSA. Hence, we suggest that cognitive alterations are driven by focal frontostriatal degeneration that is in line with the concept of ‘subcortical cognitive impairment’.
La presente tesi è formata da tre parti principali: la prima teorica mentre le due seguenti sono sperimentali. La prima parte, composta di due capitoli, introdurrà le caratteristiche cliniche e neuropatologiche sottostanti ai disturbi parkinsoniani, in particolare nella malattia di Parkinson (PD) e nei parkinsonismi atipici — atrofia multisistemica (MSA) e paralisi progressiva sopranucleare (PSP) (Capitolo 1). Nello specifico, PD ed MSA sono definite come sinucleinopatie per la presenza di aggregati di sinucleina, mentre la PSP che è caratterizzata dall’accumulo di proteina tau rientra a far parte delle tauopatie. Invece, il Capitolo 2 fornirà una panoramica delle disfunzioni cognitive che caratterizzano questi disturbi e fornirà inoltre evidenze circa i meccanismi biologici e i cambiamenti strutturali che sono alla base delle alterazioni cognitive. Nella seconda e la terza parte sono riportati alcuni studi che ho condotto durante il dottorato di ricerca. In particolare, nel Capitolo 3 riporto i risultati dei miei studi sugli strumenti di screening cognitivo più sensibili nel rilevare alterazioni cognitive nei parkinsonismi atipici rispetto ai pazienti con PD. Nel successivo studio invece ho investigato la progressione del declino cognitivo in questi disturbi (Capitolo 4). Infine, ho investigato con studi di risonanza magnetica i cambiamenti strutturali che sottendono le alterazioni cognitive nel PD (Capitolo 5) e nella MSA (Capitolo 6). Seguiranno le conclusioni generali, in cui discuto le conseguenze cliniche dei risultati ottenuti negli studi cognitivi e di imaging (Capitolo 7). PARTE I – Background teorico Capitolo 1: I disturbi parkinsoniani I disturbi parkinsoniani sono caratterizzati da una diversa patologia sottostante. Nel PD ed MSA ci sono aggregati di sinucleina rispettivamente nei neuroni dopaminergici o nelle cellule gliali, mentre i pazienti con PSP presentano delle aggregazioni di proteina tau che determina la formazione di ammassi neurofibrillari (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Le manifestazioni cliniche dipendono dalle caratteristiche di aggregati proteici e dall’entità di diffusione della malattia nelle regioni corticali e sottocorticali (Halliday, Holton, Revesz, & Dickson, 2011). Quindi, il presente capitolo illustrerà la patologia sottostante nel PD, MSA e PSP, saranno poi descritte le diverse caratteristiche cliniche ed infine, saranno presentati i più recenti criteri diagnostici di questi disturbi (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Capitolo 2: Caratteristiche cognitive e i sottostanti meccanismi nei disturbi parkinsoniani I sintomi non-motori rappresentano una parte cruciale dello spettro dei disturbi parkinsoniani, in particolare le disfunzioni cognitive, inclusa la demenza, sono probabilmente tra i sintomi non-motori più rilevanti, in quanto influenzano l'autonomia funzionale dei pazienti, incrementano il carico di gestione del caregiver ed hanno un notevole impatto socioeconomico (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). La prima parte di questo capitolo fornirà una panoramica sulle disfunzioni cognitive nel PD, MSA e PSP. Saranno inoltre riportati i criteri clinici per la diagnosi di declino cognitivo lieve e di demenza nel PD (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), al contrario invece non esistono al momento criteri disponibili per valutare le sindromi cognitive in PSP e MSA. Infine, la seconda e la terza parte di questo capitolo forniranno evidenze sui meccanismi biologici e sui cambiamenti strutturali sottostanti alle alterazioni cognitive in questi disturbi. PARTE II - Studi sulle manifestazioni cognitive nei disturbi parkinsoniani Capitolo 3: Performance al Montreal Cognitive Assessment e Mini-Mental State Examination nella paralisi sopranucleare progresiva, atrofia multisistemica e malattia di Parkinson Vi è un generale consenso nel riconoscere che le alterazioni cognitive siano frequenti nei PD e negli altri disturbi parkinsoniani (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Pertanto, nella pratica clinica possono essere adottate delle scale brevi di screening cognitivo, per supportare il clinico nel processo diagnostico (Marras, Troster, Kulisevsky, & Stebbins, 2014). Il Mini-Mental State Examination (MMSE) è la scala più utilizzata (Folstein, Folstein, & McHugh, 1975), anche se MMSE è relativamente insensibile nell’identificare rilevare disfunzioni cognitive nei disturbi parkinsoniani principalmente perché non indaga il dominio fronto-esecutivo (Hoops et al., 2009). Al contrario, il Montreal Cognitive Assessment (MoCA), un altro strumento di screening cognitivo ampiamente utilizzato nei pazienti con PD (Nasreddine et al., 2005), ha mostrato un’elevata sensibilità e specificità nell’identificazione di alterazioni cognitive nei PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), come anche in altre malattie neurodegenerative come l’Alzheimer, la demenza da corpi di Lewy (DLB) e la malattia di Huntington (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). Tuttavia, vi sono poche evidenze sull’uso del MoCA nei parkinsonismi atipici, in particolare nella PSP ed MSA (Kawahara et al., 2015). Pertanto, lo scopo del presente studio era di determinare se il MoCA fosse più sensibile del comunemente utilizzato MMSE nel rilevare alterazioni cognitive nei pazienti con probabile PSP e MSA, rispetto al PD. In questo studio multicentrico, che ha coinvolto altri tre centri europei, sono state somministrate le scale MMSE e MoCA a 130 pazienti: 35 MSA, 30 PSP e 65 pazienti PD appaiati per età, scolarità e sesso. Sono state valutate le differenze tra i gruppi per MMSE, MoCA, e i loro subitem; infine sono state calcolate le curve ROC (Receiver-Operating Characteristic). Dai risultati emerge che la media del MMSE è superiore al punteggio medio del MoCA in ogni gruppo di pazienti: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), e PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Inoltre, il punteggio totale MoCA così come il suo subitem di fluenza fonemica è in grado di differenziare la PSP da MSA e PD con un’alta specificità e moderata sensibilità. Specificamente, un punteggio uguale o inferiore a sette parole al minuto sembra supportare una diagnosi di PSP (PSP vs PD: 86% specificità, sensibilità al 70%, PSP vs MSA: 71% specificità, sensibilità al 70%). Al contrario, nel MMSE è stato possibile osservare un ‘effetto-soffitto’ per la maggior parte dei subitem, ad eccezione del subitem dei ‘due pentagoni’, in cui i pazienti con PSP hanno una prestazione peggiore rispetto a MSA e PD. I nostri risultati suggeriscono che PSP ed MSA, similmente al PD, possono presentare una prestazione normale al MMSE ma deficitaria al MoCA. In conclusione, il MoCA è più sensibile del MMSE nel rilevare disfunzioni cognitive nei parkinsonismi atipici ed insieme al suo subitem di fluenza verbale sembra essere un valido test per supportare una diagnosi di PSP. Capitolo 4: Valutazione prospettica delle disfunzioni cognitive nei disturbi parkinsoniani Evidenze in ambito clinico e di ricerca suggeriscono che le disfunzioni cognitive nei disturbi parkinsoniani siano progressive. Tuttavia, in letteratura vi sono pochi studi longitudinali che indagano la progressione cognitiva in pazienti con PSP ed MSA rispetto a pazienti PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In particolare, i precedenti studi si basano solo su scale globali di screening cognitivo, oppure su valutazioni neuropsicologiche parziali che non esaminano l'intero spettro delle abilità cognitive nei cinque domini (i.e., attenzione/memoria di lavoro, esecutivo, mnesico, visuospaziale e del linguaggio). Inoltre, sebbene siano stati formulati criteri clinici per la diagnosi di declino cognitivo lieve (MCI) e di demenza in pazienti PD (Dubois et al., 2007; Litvan et al., 2012), rimane ancora da investigare se tali criteri possano essere applicati anche nei parkinsonismi atipici (Marras et al., 2014). Date tali premesse, gli obiettivi del presente studio sono stati: i) valutare la severità delle alterazioni cognitive in pazienti PSP ed MSA utilizzando i criteri validati nei pazienti PD, per identificare gli stati cognitivi (i.e., MCI o demenza); ii) esaminare la sensibilità di due strumenti di screening cognitivo ampiamente utilizzati, (i.e., MMSE e MoCA), nel differenziare il profilo cognitivo globale di pazienti MSA, PSP e PD; iii) caratterizzare la progressione del declino cognitivo nei cinque domini, il profilo comportamentale e infine confrontare il profilo cognitivo al follow-up tra i vari disturbi parkinsoniani. Il nostro campione includeva 18 pazienti con PSP, 12 MSA e 30 pazienti con PD appaiati per età, scolarità e sesso, che sono stati valutati alla baseline e al follow-up a 15 mesi. Sono stati raccolti dati demografici e clinici; inoltre dal punto di vista cognitivo è stata selezionata una batteria di test neuropsicologici completa, specifica per l’identificazione di deficit cognitivi in pazienti PD, secondo i criteri pubblicati di ‘Livello II’ (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Abbiamo quindi applicato tali criteri anche a pazienti MSA e PSP, dato che non esistono criteri pubblicati per i parkinsonismi atipici. Infine, sono state utilizzate analisi statistiche di tipo non-parametrico. Dai nostri risultati emerge che i pazienti con PSP hanno un declino cognitivo più severo rispetto a pazienti PD ed MSA. Nello specifico, al follow-up è stato possibile osservare un marcato declino a carico del dominio esecutivo e del linguaggio nel gruppo con PSP. Le valutazioni cognitive alla baseline e al follow-up erano concordanti, ed entrambe confermano che i pazienti PSP hanno una prestazione peggiore rispetto ai pazienti PD ed MSA: in particolare, nello Stroop test, nelle fluenze verbali (semantica e fonematica) e nel MoCA. Valutando la severità dei deficit cognitivi, abbiamo inoltre trovato diverse percentuali di diagnosi cognitive (i.e., profilo nella norma, MCI vs. demenza) tra i tre gruppi. In particolare, la percentuale più elevata di pazienti con demenza era nel gruppo con PSP rispetto ai pazienti MSA (i.e., 33% vs. nessun paziente con demenza), anche se la durata di malattia era simile. Inoltre, tra i pazienti MSA e PSP con un profilo MCI-multidominio alla baseline, solo pazienti con PSP passano ad una diagnosi di demenza al follow-up. Infine nel gruppo di pazienti PD, nonostante avessero una durata di malattia più lunga, la percentuale di soggetti che passano ad una diagnosi di demenza era inferiore rispetto al gruppo con PSP (7% vs. 16%), nonostante entrambi i gruppi avessero una gravità di MCI simile alla baseline. Complessivamente questi risultati suggeriscono un più rapido e severo declino cognitivo in soggetti PSP, mentre i pazienti MSA mostrano generalmente deficit più limitati. La scala globale MoCA sembra essere maggiormente sensibile, rispetto al MMSE, nel rilevare cambiamenti cognitivi, in particolare nella PSP. Tuttavia il MoCA mostra una sensibilità inferiore rispetto al MMSE nell’identificare un declino cognitivo al follow-up in pazienti PD; quindi il MMSE sembra essere uno strumento migliore per monitorare longitudinalmente cambiamenti cognitivi in pazienti PD. Riguardo al profilo comportamentale, i pazienti PSP riportano più comunemente rispetto ai pazienti PD: apatia, ansia e depressione. Infine, l'analisi dei subitem rivela che i pazienti PSP mostrano un peggioramento ‘clinicamente significativo’ dopo 15 mesi soprattutto nei subitem attentivo-esecutivi (Trial Making Test parte B e il disegno di un orologio). Tuttavia è stato possibile osservare che alcuni pazienti hanno anche un miglioramento in specifici subitem al follow-up. Questo miglioramento potrebbe essere attribuibile ad una più elevata dose farmacologica (nonostante il trattamento dopaminergico alla baseline non fosse significativamente diverso al follow-up). Tuttavia, è importante notare che tali alterazioni erano presenti soprattutto in subitem sensibili alle problematiche motorie (i.e., disegno di figure e collegamento di cerchi con una penna) che quindi potrebbero aver alterato la performance. Questi limiti della scala MoCA e MMSE sono già stati osservati in precedenza nei pazienti con PD (Biundo et al., 2016b; Hu et al., 2014), e possibilmente sono ancora più pronunciati nei parkinsonismi atipici. In conclusione i nostri risultati rivelano che i pazienti PSP hanno una performance notevolmente alterata rispetto agli altri disturbi parkinsoniani (MSA e PD), e dopo circa 6 anni di durata di malattia, il 33% dei pazienti PSP ha una diagnosi di demenza. Questa severa progressione è probabilmente associata ad una diffusione di aggregati tau che coinvolge anche strutture corticali. Al contrario, il pattern di compromissione cognitiva in pazienti con MSA è meno severo, e probabilmente è associato ad una predominanza sottocorticale della patologia, con un coinvolgimento corticale solo secondario alle alterazioni sottocorticali. Pertanto, i nostri risultati suggeriscono che la valutazione neuropsicologica può essere utile nella differenziazione dei profili cognitivi nei parkinsonismi atipici e per monitorare la progressione della malattia. PARTE III – Studi di neuroimmagine sulle sinucleinopatie Capitolo 5: Effetti dei depositi di amiloide sulle manifestazioni cognitive e motorie nella malattia di Parkinson Alterazioni cognitive, in particolare deficit esecutivi, possono essere osservati anche nelle prime fasi del PD (Aarsland, Bronnick, Larsen, Tysnes & Alves, 2009). La disfunzione frontostriatale del sistema dopaminergico può influenzare la presenza di problemi esecutivi ed attentivi (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), tuttavia al momento le evidenze relative al trasportatore striatale di dopamina (DAT) sono inconsistenti (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). I meccanismi neuropatologici che stanno alla base delle alterazioni cognitive nei PD sono eterogenei (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker & Robbins, 2010), ed il contributo del deposito di amiloide in aggiunta alla sinucleinopatia rimane ancora poco definito, soprattutto nelle prime fasi della malattia. Pertanto, lo scopo del presente studio è stato quello di indagare l'interazione tra depositi di amiloide nel circuito frontostriatale, deficit dopaminergico striatale, grado di atrofia cerebrale ed il loro contributo nelle alterazioni cognitive (i.e., funzioni fronto-esecutive) nelle prime fasi del PD. Una coorte multicentrica di 33 pazienti con PD ricavata dal ‘Parkinson's Progression Markers Initiative’ è stata sottoposta a una tomografia ad emissione di positroni (PET) con radiofarmaco [18F]florbetaben, tomografia ad emissione di fotone singolo (SPECT) con radiofarmaco [123I]FP-CIT, risonanza magnetica (MRI) strutturale, valutazione clinica e cognitiva. Dai nostri risultati emerge che elevati livelli di depositi di amiloide erano associati ad una riduzione del deficit dopaminergico nello striato dorsale (rispetto ai bassi livelli di depositi di amiloide), ad un aumento dell’atrofia cerebrale in regioni frontali ed occipitali, e ad una tendenza a manifestare più frequentemente alterazioni cognitive globali (come valutato dal MoCA), ed in test fronto-esecutivi. Inoltre, le deposizioni di amiloide nelle regioni frontostriatali erano inversamente correlate alla performance cognitiva. Nel complesso i nostri risultati suggeriscono che pazienti con PD in fase iniziale di malattia e amiloidosi hanno un più elevato grado di atrofia cerebrale e possono esperire maggiori deficit cognitivi (i.e., disfunzioni esecutive) e alterazioni motorie rispetto a soggetti negativi all’amiloide. I nostri risultati sembrano essere in linea con una recente ipotesi neuropatologica che considera il danno e disfunzione assonale a livello sinaptico come un elemento caratteristico del PD (Tagliaferro & Burke, 2016). Infatti, i neuroni del sistema dopaminergico sono particolarmente vulnerabili alla sinucleinopatia a causa delle loro caratteristiche assonali: gli assoni sono lunghi, sottili e non mielinizzati. Questa ipotesi è confermata anche da studi di neuroimmagine PET con traccianti che si legano al DAT (Caminiti et al., 2017), suggerendo che le aggregazioni di sinucleina nel PD possono influenzare la funzione sinaptica e la trasmissione di segnale sin dalle prime fasi della malattia. I nostri risultati suggeriscono quindi una possibile interazione tra depositi di amiloide e sinucleinopatia, in cui la presenza di amiloide può facilitare la diffusione di sinucleina (i.e., corpi di Lewy) (Toledo et al., 2016), pertanto questa interazione può contribuire ulteriormente alla vulnerabilità assonale. In linea con questa ipotesi, i nostri risultati sembrano confermare che le deposizioni di amiloide agiscono sinergicamente con la sinucleinopatia, influenzando le manifestazioni cliniche del PD. Capitolo 6: Profilo neurostrutturale dell’atrofia multisistemica con alterazioni cognitive A differenza di altre sinucleinopatie (e.g., PD e DLB), la presenza di demenza è considerata un criterio di esclusione nella diagnosi di MSA (Gilman et al., 2008), tuttavia vi è una crescente evidenza che pazienti affetti da MSA possano manifestare alterazioni cognitive, che includono disfunzioni esecutive ma anche deficit cognitivi multidominio, e in alcuni casi anche demenza (Gerstenecker, 2017). Il MMSE è una scala cognitiva globale comunemente utilizzata nella pratica clinica, e recentemente uno studio multicentrico ha suggerito l’utilizzo di un cutoff <27 per aumentare la sensibilità di tale scala nell'identificare alterazioni cognitive in pazienti MSA (Auzou et al., 2015). I meccanismi che sottendono le disfunzioni cognitive in soggetti MSA non sono ancora stati identificati ed evidenze da studi di MRI suggeriscono un discreto contributo corticale e sottocorticale per spiegare tali alterazioni cognitive (Kim et al., 2015; Lee et al., 2016a). Tuttavia questi risultati sono basati su un numero relativamente piccolo di pazienti e in vari stadi di malattia, inoltre sono studi basati su singoli centri. Pertanto, lo scopo del nostro studio multicentrico è stato quello caratterizzare i cambiamenti anatomici associati ad alterazioni cognitive in pazienti MSA e di investigare le differenze strutturali corticali e sottocorticali rispetto ad un campione di soggetti sani. Abbiamo quindi esaminato retrospettivamente 72 pazienti MSA, e definito 50 MSA come cognitivamente normali (MSA-NC) e 22 con alterazioni cognitive (MSA-CI) utilizzando il cutoff del MMSE <27. Abbiamo inoltre confrontato direttamente i due sottogruppi di MSA, e comparato l’intero gruppo di MSA ad un campione di 36 controlli sani (HC) utilizzando un’analisi di ‘morfometria basata sui voxel’ che analizzava la sostanza grigia e bianca. Inoltre, abbiamo applicato anche una segmentazione automatizzata dei volumi sottocorticali. Dai nostri risultati emerge che i pazienti MSA, rispetto a soggetti sani, hanno una diffusa atrofia corticale (i.e., che coinvolge bilateralmente aree frontali, occipito-temporali e parietali), sottocorticale ed alterazioni alla sostanza bianca. Tuttavia, nel confronto diretto, i soggetti MSA-CI mostrano solo una focale riduzione del volume a carico della corteccia prefrontale dorsolaterale sinistra rispetto a pazienti MSA-NC. Tali risultati suggeriscono che la patologia corticale abbia un effetto marginale sulle alterazioni cognitive nei pazienti MSA. Suggeriamo quindi che le alterazioni cognitive siano piuttosto determinate da una degenerazione frontostriatale focale, che sembra essere in linea con il concetto di ‘alterazioni cognitive sottocorticali’.

Le rôle que pourrait jouer l’interaction des systèmes cholinergiques (ACh) et dopaminergiques (DA) semble crucial dans la physiopathologie de certaines maladies neurodégénératives, en particulier dans la démence à corps de Lewy (DCL). Ce travail de thèse se propose de valider un protocole d’imagerie moléculaire en tomographie d’émission monophotonique, consistant en un marquage de l’ACh et de la DA chez un même individu, afin de pouvoir étudier in vivo les interactions ACh/DA.Après avoir mis au point chez des sujets âgés et des patients atteints de maladie d’Alzheimer une méthode d’imagerie cérébrale quantitative des neurones ACh utilisant un radioligand sélectif du transporteur vésiculaire de l’ACh, le [123I]-IBVM, et basée sur une modélisation pharmacocinétique, nous avons montré le potentiel de cette méthode à mettre en évidence une atteinte différentielle des circuits ACh dans la Paralysie Supranucléaire Progressive et l’Atrophie Multisystématisée. Dans la dernière partie de ce travail de thèse, nous avons pour la première fois réalisé un double marquage des systèmes ACh et DA dans la DCL, en utilisant, en plus du [123I]-IBVM, un radioligand sélectif du transporteur de la dopamine et validé en routine clinique, le [123I]-FP-CIT. En parallèle, une étude comportementale évaluant la présence d’hallucinations, de fluctuations cognitives, d’altérations des rythmes circadiens ainsi qu’un bilan des performances neuropsychologiques, ont été menés. Cette étude est actuellement en cours de réalisation. Les tous premiers résultats montrent l’existence de liens cohérents entre les données d’imagerie moléculaire et les données cliniques
The question of how acetylcholine (ACh) and dopamine (DA) could be involved together in the pathophysiology of some neurodegenerative disorders is essential, particularly in dementia with Lewy bodies (DLB). The present study aims at assessing an in vivo molecular imaging method of both ACh and DA brain systems using single photon emission computed tomography. In the first part of the present study, a method based on pharmacokinetic analysis making it possible to quantify ACh neurons in vivo, using [123I]-IBVM, a specific radioligand of vesicular acetylcholine transporter, was developed and validated in healthy subjects and Alzheimer’s disease patients. Then, we showed the ability of our method to demonstrate a differential alteration of ACh pathways in Progressive Supranuclear Palsy and Multiple System Atrophy patients. In the last part of this study, we imaged for the first time both ACh and DA systems in DLB patients, using not only [123I]-IBVM, but also [123I]-FP-CIT, a specific radioligand of dopamine transporter. Concomitantly, a behavioral exploration of hallucinations, fluctuating cognition and disturbances of circadian rhythms was achieved in these patients, as well as a neuropsychological examination. This study is currently in progress. The first results show consistent links between imaging and clinical data

Background: Progressive supranuclear palsy is an adult onset neurodegenerative condition. Progressive supranuclear palsy is an aggressive condition associated with a continual loss of function and commonly, death due to aspiration pneumonia. Currently there is no cure, and dopaminergic medications have limited symptomatic benefit for patients. Physiotherapy, occupational therapy, and speech therapy strategies to optimize independence and function are important and show promising effectiveness in practice. Mobility, speech and swallowing problems are some of the most commonly experienced symptoms and are experienced across all stages of the disease. Objectives:This systematic review aimed to identify and examine the effectiveness of physical, occupational, and speech therapy interventions in the symptomatic management of progressive supranuclear palsy. Inclusion criteria: This review included participants with progressive supranuclear palsy as per the National Institute for Neurological Disorders and Stroke and the Society of Progressive Supranuclear Palsy criteria, aged over 40 years of age from all community and clinical settings. This review included studies evaluating any physical, occupational or speech therapy interventions that addressed mobility, vision, swallowing, communication or cognitive/neuropsychiatric difficulties experienced by patients with progressive supranuclear palsy compared with usual care and/or baseline measurements. Outcomes of interest included the degree of change, or no change in common symptoms including mobility, vision, swallowing, communication and cognition. All types of quantitative study designs were eligible for inclusion. Methods: A three-step search strategy was utilized to identify published and unpublished English language studies from between 1996 and 2014 from 11 databases. Methodological appraisal was conducted by two independent reviewers using standardized instruments and relevant data was extracted from included papers using standardized data extraction tools and presented in narrative form due to heterogeneity of interventions. Results: Six studies of varying methodological quality and small sample sizes were included. No occupational therapy or speech therapy interventions were identified. Five studies examined physiotherapy rehabilitation programs and one study examined non-invasive brain stimulation. There is preliminary evidence to support the use of various physiotherapy rehabilitation programs. Physiotherapy rehabilitation programs that combine a dynamic antigravity postural system and a vibration sound system or combine balance and posture exercises with audiobiofeedback appear to improve balance. Combined balance and eye movement training appear to improve stance time and gait speed. Balance training appears to improve step length. Balance and eye movement training may improve vertical gaze fixation and gaze error scores. Balance and posture exercises with audiobiofeedback may improve cognition and communication aspects of quality of life. Conclusion: Research into the effectiveness of allied health therapeutic interventions for progressive supranuclear palsy symptoms is in its infancy with what can be understood as preliminary evidence for the effectiveness of a number of physiotherapy interventions. High quality studies with large sample sizes are needed. Further research is urgently required to both add further evidence to these results and to identify and investigate effective interventions including occupational therapy and speech therapy interventions to manage mobility, vision, swallowing, communication and cognitive/neuropsychiatric symptoms associated with this devastating condition.
Thesis (M.Clin.Sc.) -- University of Adelaide, Joanna Briggs Institute, 2016.

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVIII

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
As Síndromes Parkinsonianas (PS) são doenças neurodegenerativas que refletem a função anormal da via cortico-basal. O comprometimento de diferentes partes do SNC leva a diferentes achados oculares em cada síndrome, tornando a análise dos movimentos oculares fulcral para o diagnóstico. No entanto, os movimentos oculares vestibulares nas PS têm sido menos estudados e há falta de análises de regressão multivariável para identificar alterações dos movimentos oculares preditoras da clínica entre os grupos. Neste trabalho, foi feita uma revisão retrospetiva dos movimentos oculares e dados vestibulares de doentes com PS (Doença de Parkinson [PD], Paralisia Supranuclear Progressiva [PSP], Atrofia de Sistemas Múltiplos [MSA] e Síndrome Cortico-basal [CBS]) que realizaram análise video-oculográfica detalhada e foi comparada entre grupos, correlacionando-a com os dados clínicos iniciais e um ano depois, e foram aplicadas análises de regressão multivariável para determinar o seu valor como preditor independente da progressão clínica. Encontrámos instabilidade da fixação do olhar significativa, sacadas lentas e hipométricas, e uma menor prevalência do nistagmo posicional na PSP, e diminuição do ganho na perseguição e sacadas com latência prolongada na CBS. O ganho na perseguição descendente foi um preditor independente da disfunção motora 1 ano depois da avaliação ocular entre grupos, e o ganho das sacadas verticais juntamente com a latência das sacadas horizontais e verticais constituíram um preditor significativo da dose de agonistas dopaminérgicos, tanto da dose inicial como da dose após um ano. A análise vestibular e dos movimentos oculares permitiu-nos distinguir os grupos PD, PSP, MSA e CBS. Adicionalmente, a perseguição vertical parece ser um preditor útil da progressão clínica das PS. A correlação potencial entre os agonistas dopaminérgicos e os movimentos oculares deve ser interpretada com cautela visto que podem simplesmente refletir a estratégia terapêutica de evitar o uso dos agonistas dopaminérgicos no parkinsonismo atípico. A avaliação detalhada dos movimentos oculares e vestibulares constitui uma ferramenta diagnóstica útil e um marcador da progressão clínica nas PS.
Parkinsonian Syndromes (PS) are neurodegenerative disorders that reflect abnormal function of basal ganglia–cortical circuits. Distinctive CNS impairment leads to specific ocular features in each syndrome, making eye movement analysis crucial for their diagnosis. However, vestibular eye movements have been less studied in PS and multivariate regression methods to find independent ocular motor predictors of clinical disability across groups are lacking.In this work, we retrospectively review ocular motor and vestibular data from PS patients (Parkinson’s disease [PD], Progressive Supranuclear Palsy [PSP], Multiple System Atrophy [MSA], and Cortico-Basal Syndrome [CBS]) who underwent detailed video-oculographic analysis and compared it between groups, correlated it with clinical data at baseline and 1-year after, and applied multivariate regression methods to ascertain their value as an independent predictor of clinical progression.We found significant ocular fixation instability, slow and hypometric saccades, and lower prevalence of positional nystagmus in PSP, and low gain pursuit and prolonged saccadic latency in CBS. Downward pursuit gain was an independent predictor of motor disability 1 year after ocular assessment across groups, and vertical saccade gain together with horizontal and vertical saccade latency constituted a significant predictor of dopaminergic agonists dosage at baseline and after 1 year.Ocular motor and vestibular analysis allowed us to clearly distinguish between PD, PSP, MSA and CBS groups. Additionally, vertical pursuit seems to be a helpful predictor of PS disability. Potential correlations between dopaminergic agonists and eye movement data should be cautiously interpreted since these might simply reflect overall clinician’s therapeutic strategy in avoiding the use of dopaminergic agonists in atypical parkinsonism. Detailed ocular motor assessment including ocular motor and vestibular data constitutes a powerful diagnostic tool and marker of clinical progression in PS.