A neuroimaging feature extraction model is designed to extract region-based image features whose values are predicted by base learners trained on raw neuroimaging morphological variables. The main objectives are to identify Alzheimer’s disease (AD) in its earliest manifestations, and be able to predict and gauge progression of the disease through the stages of mild cognitive impairment (EMCI), late MCI (LMCI) and AD. The model was evaluated on the ADNI database and showed 75.26% accuracy for the challenging EMCI diagnosis based on the 10-fold cross-validation. Our approach also performed well for the other binary classifications: EMCI vs. LMCI (72.3%), EMCI vs. AD (95%), LMCI vs. AD (84.3%), CN vs. LMCI (77.5%), and CN vs. AD (96.5%). By applying the model to the Genome-wide Association Study, along with the sparse Partial Least Squares regression method, we successfully detected risk genes such as the APOE, TOMM40, RVRL2 and APOC1 along with the new finding of rs917100. Moreover, the research aimed to investigate the relationship of different biomarkers; especially the imaging biomarkers to better understand the precise biologic changes that characterize Alzheimer’s disease. The unique and independent contribution of APOE4 allele status (E4+\E4-), amyloid (Aβ) load status (Amy+\Amy-) and combined APOE4 and Aβ status on regional cortical thickness (CTh) and cognition were evaluated via a series of two-way ANCOVAs with post-hoc Tukey HSD tests. Results showed that decreased CTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4+ status is associated with increased CTh, in medial and inferior temporal regions. Diverging association patterns of global and regional Aβ load with cortical volume were found in the entorhinal, temporal pole and parahippocampal regions, which were positively associated with regional Aβ load, but with a negative correlation for global Aβ load in MCI stages. In addition, strong positive correlations were shown between baseline regional CTh and the difference of CTh in each region between the CN and AD, even after adjusting for the regional Aβ and APOE genotype (E4+: r = 0.521 and E4-: r = 0.694).

近來教育的研究，特別是輕度智能障礙的研究有減少的趨勢。通常這一類的學生會合併其他高出現率的障別，而不同的研究認為這些障別會有不同的特質。本研究旨在著重中學階段輕度智能障礙學生尤其是個別化教育，因為學者專家共同指出這些學生需要個別化教育。台灣、荷蘭在中學階段與輕度智能障礙有關的政策也強調符合學生個別需求、興趣和能力，所以這兩個國家可以在個別化教育這一方面做比較。 本論文的目的將研究與比較以下兩方面： (1) 台灣與荷蘭在中學階段之個別輕度智能障礙學生有何全國教育政策；期許和需求與關於達成 (2) 兩國的學校與老師如何落實個別輕度智能障礙學生的教學。為達成此目的，研究者擬蒐集兩國相關教育政策資料，以及與學校主要成員進行深入的半結構訪談。在資料分析過程中，會著重在兩國的政策和個案學校特殊狀況。而後將相互比較兩國對輕度智能障礙學生之個別化教育政策與學校執行情況，能對兩國的輕度智能障礙學生的個別化教育有所了解。以增進兩國在此方面的相互學習與借鏡。 本研究指出在台灣和荷蘭個別化教育的歷程皆受到不同世界潮流的影響。最明顯的是現標準化本位改革在台灣已經成為一種趨勢，而學生導向的個別化教育計畫概念在荷蘭的學校個案是受到支持的。此外，在台灣教育政策和規範的訂定是由中央到地方，而在荷蘭教育方案的發展則由各校自行訂定。在個案學校的主要研究發現是，荷蘭個案在個別化教育歷程中被賦予比較多正式責任，而台灣個案相形之下較少。 此外，在台灣、荷蘭組成個別化教育的項目在個別的中學低年級和高年級相當不同，而兩國的中學個別化教育項目同時呈現相同與相異之處。該研究基於研究發現提出部分建議，並針對未來可能的研究提出建議。 / Research into education for, specifically, the mildly mentally impaired has in recent years decreased. Often this population of students is combined with other high incidence disabilities while significant differences in characteristics have been recognized. This research project, therefore, specifically focuses on the population of mildly mentally impaired students in secondary education and particularly individualized education, since there is a consensus among academics that this population of students has a need for a system that allows for individualized education. Policies regarding education for mildly mentally impaired in secondary education in both Taiwan and the Netherlands also stipulate a program tailored to a student’s individual needs, interests and abilities and, thus, a level of comparability between these two countries is assured. The purpose of this dissertation is to investigate and compare (1) the national policies for meeting the individual educational wishes and needs of mildly mentally impaired secondary education students in Taiwan and the Netherlands and (2) how these policies are implemented in high-quality school cases in both countries. To achieve this purpose, the researcher collected relevant policy documents and performed in-depth, semi-structured interviews with key staff members at the school cases. During the process of data analysis, due attention was given to the fact that both the countries’ policies, as well as the school cases, are embedded in their own unique contexts. Upon analyzing the gathered data, a comparison of both countries’ individualized education systems for mildly mentally impaired secondary education students was performed, highlighting similarities and differences. The findings of this research project indicate that the process of individualizing education has been shaped by national cultures as well as different worldwide trends in both Taiwan and the Netherlands. Most notably, there has been a drive for standards-based reform in Taiwan while in the Netherlands the concept of the student-led IEP has found an advocate in the school case researched. Furthermore, relevant educational policies and regulations are created and enforced in a top-down manner in Taiwan while the Netherlands shows elements of a bottom-up approach. Among the major findings from the school cases is that the Dutch case shows a student who is endowed with a greater degree of formal responsibility in the process of individualizing education than the Taiwanese counterparts at both the lower and upper level school cases. Furthermore, in both countries, individualized education at the lower and upper secondary education stages consists of different elements. The degree to which these elements are present in Taiwan and the Netherlands shows similarities and differences. This report concludes with recommendations based on the findings, and suggestions for possible future research are offered.

<p>Skrivning är en biomekaniskt invecklad process som kräver en viss nivå av såväl motorisksom kognitiv förmåga. Forskning om Alzheimers sjukdom tyder på att nedsättningar i flerakognitiva domäner förekommer innan den kliniska diagnosen ställs. Det finns även forskningsom tyder på att ett innehållsrikt skriftspråk i unga år minskar risken för demensutveckling påäldre dagar. För att studera om mått från texter kunde predicera demens på ett tidigt stadiumanalyserades 141 skriftliga bildbeskrivningar insamlade inom ramen för rutinmässigaminnesutredningar vid Karolinska universitetssjukhuset, Huddinge. Deltagarna delades in itre grupper utifrån diagnos (minnesutredning, lindrig kognitiv svikt och demens).Utgångspunkt för studien var de fyra textmåtten: idétäthet, verbtäthet, läsbarhetsindex (LIX)och T-enheter. Då texterna i de flesta fall var skrivna av personer med kognitiv nedsättninghar måtten varit tvungna att modifieras och särskilda instruktioner för bedömning av texternahar utformats. Resultaten tyder på att skriftliga bildbeskrivningar utförda av individer meddemens innehåller färre totalt antal ord än de skrivna av individer diagnostiserade medlindrig kognitiv svikt eller mindre svårigheter än så. De innehåller även färre propositioner,verb, långa ord, T-enheter, ord per T-enhet, har en kortare meningslängd samt har i snitt ettlägre LIX-värde. En logistisk regressionsanalys visade att demens (kontra minnesutredningarmed subjektiva besvär) predicerades signifikant (p < 0.01) av antalet verb samt av LIXvärdet.Totalt 85 % av fallen klassificerades korrekt.</p> / <p>Writing is a biomechanically complex process which demands a certain level of motor aswell as cognitive ability. Research concerning Alzheimer’s disease shows that impairmentsin multiple cognitive domains are notable before a clinical diagnosis can be made. There isalso research which indicates that written language ability in early life predicts the risk ofdementia in old age. The purpose of this study was to analyze whether measures derivedfrom narrative writing could predict dementia cross-sectionally. The material was 141 writtenpicture descriptions collected during routine investigations of cognitive disorders at theMemory Clinic, Karolinska University Hospital, Stockholm. The participants were classifiedinto three groups based on their diagnosis (subjective memory complaints, mild cognitiveimpairment and dementia). This study was based essentially on the four text measures: ideadensity, verb density, index of readability (LIX) and T-unit. As most of the texts were writtenby participants with some degree of cognitive decline the measures had to be modified tosome extent and detailed scoring protocols were worked out. The results indicate that writtenpicture descriptions made by individuals with dementia contained fewer words than thosewritten by individuals diagnosed with mild cognitive impairment or subjective cognitivecomplaints. They also contained fewer propositions, verbs, long words, T-units, words per Tunit,had a shorter mean sentence length and had a lower average LIX-value. A logisticregression analysis showed that cases of dementia, as opposed to subjective cognitivecomplaints, were significally predicted (p < 0.01) by the number of verbs and also by theLIX-value. Overall, 85 % of the cases were correctly classified.</p>

Skrivning är en biomekaniskt invecklad process som kräver en viss nivå av såväl motorisksom kognitiv förmåga. Forskning om Alzheimers sjukdom tyder på att nedsättningar i flerakognitiva domäner förekommer innan den kliniska diagnosen ställs. Det finns även forskningsom tyder på att ett innehållsrikt skriftspråk i unga år minskar risken för demensutveckling påäldre dagar. För att studera om mått från texter kunde predicera demens på ett tidigt stadiumanalyserades 141 skriftliga bildbeskrivningar insamlade inom ramen för rutinmässigaminnesutredningar vid Karolinska universitetssjukhuset, Huddinge. Deltagarna delades in itre grupper utifrån diagnos (minnesutredning, lindrig kognitiv svikt och demens).Utgångspunkt för studien var de fyra textmåtten: idétäthet, verbtäthet, läsbarhetsindex (LIX)och T-enheter. Då texterna i de flesta fall var skrivna av personer med kognitiv nedsättninghar måtten varit tvungna att modifieras och särskilda instruktioner för bedömning av texternahar utformats. Resultaten tyder på att skriftliga bildbeskrivningar utförda av individer meddemens innehåller färre totalt antal ord än de skrivna av individer diagnostiserade medlindrig kognitiv svikt eller mindre svårigheter än så. De innehåller även färre propositioner,verb, långa ord, T-enheter, ord per T-enhet, har en kortare meningslängd samt har i snitt ettlägre LIX-värde. En logistisk regressionsanalys visade att demens (kontra minnesutredningarmed subjektiva besvär) predicerades signifikant (p &lt; 0.01) av antalet verb samt av LIXvärdet.Totalt 85 % av fallen klassificerades korrekt. / Writing is a biomechanically complex process which demands a certain level of motor aswell as cognitive ability. Research concerning Alzheimer’s disease shows that impairmentsin multiple cognitive domains are notable before a clinical diagnosis can be made. There isalso research which indicates that written language ability in early life predicts the risk ofdementia in old age. The purpose of this study was to analyze whether measures derivedfrom narrative writing could predict dementia cross-sectionally. The material was 141 writtenpicture descriptions collected during routine investigations of cognitive disorders at theMemory Clinic, Karolinska University Hospital, Stockholm. The participants were classifiedinto three groups based on their diagnosis (subjective memory complaints, mild cognitiveimpairment and dementia). This study was based essentially on the four text measures: ideadensity, verb density, index of readability (LIX) and T-unit. As most of the texts were writtenby participants with some degree of cognitive decline the measures had to be modified tosome extent and detailed scoring protocols were worked out. The results indicate that writtenpicture descriptions made by individuals with dementia contained fewer words than thosewritten by individuals diagnosed with mild cognitive impairment or subjective cognitivecomplaints. They also contained fewer propositions, verbs, long words, T-units, words per Tunit,had a shorter mean sentence length and had a lower average LIX-value. A logisticregression analysis showed that cases of dementia, as opposed to subjective cognitivecomplaints, were significally predicted (p &lt; 0.01) by the number of verbs and also by theLIX-value. Overall, 85 % of the cases were correctly classified.

A Primary objective of the present research is the development of robust CAE (Computer-Aided Engineering)-based approaches for designing armour plates subjected to ballistic impact by small-calibre hardened peojectiles with or without a protective sheath. Amongst the challenges in simulation is the capturing of target plate material behaviour at high strain rates with possibilities of adiabatic heating. A comprehensive numerical study carried out has resulted in the identification of simulation guidelines using a commercially available explicit finite element anlaysis solver (viz. LS_DYNA). The interferences thus drawn in terms of modeling approach 9I.e. shell, solid or axisymmetric or a mixed representation). Mesh density and element type, contact condition, and constitutive model 9I.e. discrete strain-rate based, Cowper-Symonds, or Johnson-Cook) with failure criteria are verifiable and greatly beneficial for armour plate design. Confidence in the suggested procedures has been obtained through extensive correlation of numerical results with experimental residual velocities and ballistic limits as well as projectile and target plate failure modes. A wide range of impact velocities has been considered (from a low velocity of about 5m/s to an ordnance range velocity of 800+ m/s). Target plates made of variants of mild steel and aluminium alloys have been studied. The simulation approaches have been applied to single-layered as well as multi-layered target plates. Although a majority of the comparisons has been made against published test results, a new ballistic impact testing facility has been set up in course of the current research and excellent correlation of numerically predicted residual velocities and failure modes has been obtained against the tests carried out for aluminium plate using the latter facility. A unique feature of the current experimental effort is the capturing of the complete trajectory of projectile beginning with oblique impact through subsequent perforation/ricochet. Furthermore, projectiles of various nose-shapes such as ogival, conical, hemispherical and blunt have been employed. The power of simulation has been demonstrated with the help of a number of parametric studies with variables such as plate thickness and material properties, as well as projectile mass and diameter, and obtaining physically consistent results. Additionally, existing semi empirical models for residual velocity and ballistic limit prediction have been reviewed, and new user-friendly models have been proposed based on energy conservation and predominant shear plugging failure mode of target plate. Finally, the goal of applying the present research work as a design tool can be well-served by packaging the knowledge gathered here in the form of a user-friendly guide with a graphical user interface(GUI). To this end, an application using MS windows VC++ utilities has been created with the functionalities of: (a) viewing reference LS-DYNA input data files for selecting typical problems of impact on steel and aluminium plates; (b) computing complete lists of strain rate-based material quantities required in LS-DYNA material models like discrete strain rate-based, Cowper-Symonds and Johnson-Cook by specifying the minimum number of easily available quasi-static properties (such as elastic modulus, yield and ultimate strengths, etc.), and (c) estimating residual velocities using the semi-empirical relations for steel and aluminium plates derived in the current work.

There is significant interest by the food industry in applying milder processing conditions. A major area of research within predictive modelling has been the search for models which accurately predict the effect of combining multiple processes or hurdles. For a mild process, which has temperature as the major microbial injury step, the effect of the other combined hurdles in inhibiting growth of the injured organisms must be understood. The latter means that the inoculum size dependency of the time to growth must also be fully understood. This essentially links injury steps with the potential for growth. Herein, we have been developing the use of optical density (O.D) for obtaining growth rates and lag times using multiple inocula rather than using the traditional methods which use one single inoculum. All analyses were performed in the Bioscreen analyser which measures O.D. The time to detection (TTD) was defined as the time needed for each inoculum to reach an O.D=0.2 and O.D was related to microbial numbers with simple calibration curves. Several primary models were used to predict growth curves from O.D data and it was shown that the classic logistic, the Baranyi and the 3-phase linear model (3-PLM) were the most capable primary models of those examined while the modified Gompertz and modified logistic could not reproduce TTD data. Using the Malthusian approximation of the logistic model the effect of mild temperature shifts was studied. The data obtained showed that for mild temperature shifts, growth rates quickly changed to the new environment without the induction of lags. The growth of Listeria monocytogenes, Salmonella Typhimurium and Escherichia coli was studied at 30⁰C and/or 37⁰C, in different NaCl concentrations, pH and their combinations. The classical 3-parameter logistic with lag model was rearranged to provide the theoretical foundation for the observed TTD and accurate growth rates and lag times could be estimated. As the conditions became more unfavourable, the lag time increased while the growth rate decreased. Also, the growth rate was found to be independent from the inoculum size; the inoculum size affected only the TTD. The Minimum Inhibitory Concentration (MICNaCl and MICpH) was calculated using the Lambert and Pearson model (LPM) and also the Growth/No Growth (G/NG) interface was determined using combinations of NaCl and pH. These data were transformed in rate to detection (RTD) and fitted with a response surface model (RSM) which was subsequently compared with the Extended LPM (ELPM). The LPM and the ELPM could analyse results from individual and combined inhibitors, respectively. Following a mild thermal process a lag due to thermal injury was also induced, the magnitude of which was dependent on the organism and environmental conditions; the observed distribution of the lags appeared, in general, to follow the Log-normal distribution. After the lag period due to injury, growth recommenced at the rate dictated by the growth environment present. Traditional growth curves were constructed and compared with the data obtained from the Bioscreen under the same conditions. From the results obtained, it can be suggested that the increased lag times and growth rates obtained from the traditional plate counts compared with the values obtained from the Bioscreen microbiological analyser, might be an artifact of the plating method or may be due to the use of the modified Gompertz to study the growth. In conclusion, O.D can be used to accurately determine growth parameters, to give a better understanding and quantify the G/NG interface and to examine a wealth of phenomena such as fluctuating temperatures and mild thermal treatments. The comparison between the traditional growth curves against the data obtained from the Bioscreen showed that the TTD method is a rapid, more accurate and cheaper method than the traditional plate count method which in combination with the models developed herein can offer new possibilities both to the research and the food industry.

Introduction Occupational therapists are concerned with enabling people to perform the daily life tasks they need, want, or are expected to perform for fullest possible integration into community living and participation in society. Children with mild disabilities have problems performing personal and instrumental activities of daily living (ADL) tasks at home or school, and that can limit their full integration and participation in their homes and school lives. There is a need, therefore, to identify their specific problems with ADL task performance so as to be able to develop effective interventions. Not only, there is a need for evidence related to effectiveness of occupational therapy interventions for children with mild disabilities, but also a need for valid occupational-therapy-specific evaluation tools for use with children. Purpose The purpose of this thesis was to contribute evidence to support the valid use of the Assessment of Motor and Process Skills (AMPS) with children, including children living in Middle Europe. More specifically, I aimed to evaluate validity evidence from different sources related to the use of the AMPS in occupation-based and occupation-focused evaluation and intervention. Method This thesis consisted of four studies, implemented in two phases. Phase one focused on evaluation of a) validity evidence of the AMPS scales in relation to internal structure and stability of item difficulty calibration values for a Middle European sample compared to samples from other world regions (Study I); b) the stability of the mean AMPS measures between typically-developing children from Middle Europe and from other world regions (Study II); and c) the sensitivity of the AMPS measures to discriminate between typically-developing children and children with and at risk for mild disabilities (Study III). Participants for phase one were from both Middle Europe and from other world regions and they were selected from the AMPS database, Ft. Collins, Colorado, USA. Data were analyzed using many-facet Rasch analyses, ANOVAs, regression analyses, related post-hoc tests, and effect size calculations. Phase two of the research project focused on evaluating validity evidence for the use of the AMPS as a standardized, occupation-based, and occupation-focused evaluation tool in the context of a feasibility study with children with mild disabilities implemented in a Swiss setting (Study IV). Data were analyzed based on feasibility objectives and the principles of deductive content analysis. The evaluation of validity evidence of the AMPS in relation to consequences of testing and test fairness was a focus of all studies (Studies I to IV). Results In Study I, data for 1346 participants from Middle Europe and 144,143 participants from other world regions were analyzed. The participants were between the ages of 3 and 103 years, and they were well or had a variety of diagnoses. The results revealed that overall the item difficulty calibration values of the AMPS remained stable and that only one out of 36 ADL items of the AMPS demonstrated DIF, but this DIF did not lead to DTF (i.e., all measures fell within 95% confidence bands). In Study II, data for 11,189 typically-developing children from Middle Europe and other world regions who were between the ages of 2 and 15 were analyzed. The results of ANOVAs revealed significant effects for mean ADL motor and for ADL process ability measures by region and a significant age by region interaction effect for mean ADL process ability. Out of 168 estimated contrasts between Middle Europe and the other world regions for mean ADL motor and ADL process ability, only seven were statistically significant (4.17%), and only two were more than ±1 SE from the international means. In Study III, regression analyses of data for 10,998 children, 4 to 15 years, who were typically-developing or with mild disabilities, revealed significant age by group interaction effects. Post hoc t tests revealed significant group differences in ADL ability at all ages beyond the age of 4. ADL process ability effect sizes were moderate to large at all ages and ADL motor ability effect sizes were mostly moderate to large age 6 and above. In Study IV, the use of the AMPS within the context of a feasibility study based on data of 17 Swiss children with mild disabilities was evaluated. The analyses revealed several strengths and problems that were related to the time, equipment, and materials for administering the AMPS, the adherence to standardized administration procedures, the scope of the AMPS as a test of ADL performance, and the reliable rating by the blinded rater. Conclusion This thesis provided evidence to support the validity of the AMPS measures and scales when used to evaluate quality of ADL task performance of persons from Middle Europe. Additionally, this thesis provided evidence that the international age-normative means of the AMPS are likely applicable to children from Middle Europe. Moreover, the findings supported the sensitivity of the AMPS measures to discriminate between typically-developing children and children with and at risk for mild disabilities. When it comes to implementation of the AMPS in the context of a feasibility study, the findings indicated both strengths and problems in using the AMPS as an outcome measure that need to be considered when planning further studies.

Introduction : Les individus présentant des troubles cognitifs légers ou Mild Cognitive Impairment (MCI) sont plus à risque de développer une maladie d’Alzheimer (MA) que le reste de la population âgée. Objectif : Cette étude repose sur le recours à un devis de type étude de cas multiples dont l’objectif est de contribuer à l’identification d’indices biologiques en quantifiant, à l’aide de la résonance magnétique spectroscopique (MRS), des changements métaboliques précoces chez les individus avec MCI, susceptibles d’évoluer vers la MA. Méthodologie : Huit individus MCI sont comparés à huit individus âgés normaux. Chaque participant est soumis à un examen MRS. Résultats : Parmi les huit participants MCI recrutés, l’un d’entre eux présente désormais un profil cognitif concordant avec une MA. L’analyse spectrale des métabolites de cet individu montre des ratios de glutamate plus élevés au niveau du cortex préfrontal gauche et de la régioncingulaire postérieure gauche. Bien qu’une diminution de NAA/Cr soit fréquemment observée chez la population MCI en voie d’évoluer vers la démence, les résultats obtenus ne démontrent rien en ce sens. Discussion/Conclusion : Le rôle du glutamate dans les processus neurodégénératifs est encore mal établi. L’augmentation de glutamate observée est contraire à la diminution habituellement observée au cours de la MA. Ces résultats sont toutefois explicables par l’existence possible d’excitotoxicité précoce chez les MCI en voie de d’évoluervers la démence. Cela pourrait aussi illustrer des mécanismes de compensation présents avant qu’un déclin cognitif ne soit objectivable. / Background: Mild cognitive impairment (MCI) characterizes individuals who present some cognitive impairment without criteria for dementia. Known as a highly plausible transitional stage between normal aging and Alzheimer’s disease (AD), the majority of individuals with MCI will eventually evolve to AD. Objective: The general aim of this multiple-cases study is to explore the contribution of magnetic resonance spectroscopy (MRS) to the neurochemical identification individuals with MCI in the process of evolving toward an AD. Methodology: Eight individuals were compared to eight age and education matched-controls. For each participant, MRS measures for XX neurometabolites were taken from the left prefrontal and left posterior cingulate gyrus. Results: Among all the MCI participants, one of them converted to AD during the time of the study. The spectral analysis of this participant showed higher glutamate/glutamine ratios in both regions. Although a reduction of Naa/Cr is often/generally observed among the MCI population moving/headed toward dementia, the obtained/experimental results show/demonstrate nothing in this sense. Discussion/Conclusion: The role of glutamate in pathological processes is not well-known. These results suggest the probable existence of excitotoxicity mechanisms in MCI subjects who will convert to AD, a mechanism that could express the presence of some compensatory processes. While reporting the challenge of MRS measures in this population, this study provide indications of its potential for the early detection of AD in a MCI population.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.