Η γνωστική έκπτωση εμφανίζεται στο 40-70% των ασθενών με ΠΣ, επηρεάζει σημαντικά την ποιότητα ζωής τους και έχει συσχετισθεί τόσο με τη σωματική αναπηρία, όσο και με διάφορες απεικονιστικές παραμέτρους, όπως ο συνολικός όγκος βλαβών και δείκτες ατροφίας του εγκεφάλου. Μέθοδοι: Στην παρούσα μελέτη συμμετείχαν 80 ασθενείς με ΠΣ (50 με υποτροπιάζουσα-RRMS, 30 με δευτεροπαθώς προϊούσα-SPMS). Κατεγράφησαν δημογραφικά δεδομένα και η κλίμακα αναπηρίας EDSS. Παράλληλα, έγινε νευροψυχολογική εκτίμηση με το υπολογιστικό πρόγραμμα CNS-VS καθώς και με τη δοκιμασία οπτικονοητικής ιχνηλάτησης (TMT A και Β) και λεκτικής ροής. Μελετήθηκε η επίδραση στην καθημερινή λειτουργικότητα των ασθενών (κλίμακα IADL, ικανότητα για εργασία) και υπολογίσθηκε ο συνολικός όγκος βλαβών, η ατροφία μεσολοβίου, ατροφία θαλάμων και η διάταση της 3ης κοιλίας. Χρησιμοποιήθηκε επίσης ομάδα 31 υγιών μαρτύρων για τις νευροψυχολογικές δοκιμασίες και ξεχωριστή ομάδα 51 υγιών μαρτύρων για τα απεικονιστικά δεδομένα. Αποτελέσματα: Παρατηρήθηκε έκπτωση των γνωστικών λειτουργιών στο 38% των ασθενών με RRMS και στο 80% των ασθενών με SPMS. Οι ασθενείς μας, εμφάνισαν συχνότερα χαμηλές επιδόσεις στο χρόνο αντίδρασης (83,33% SPMS/ 58% RRMS), στη δοκιμασία TMT Β (76,67% SPMS/ 34% RRMS), στην ψυχοκινητική ταχύτητα (66,67% SPMS/ 20% RRMS), στη δοκιμασία TMT Α (63,33% SPMS/ 34% RRMS), στη δοκιμασία φωνολογικής λεκτικής ροής (50% SPMS/ 30% RRMS) και στη μνήμη (40% SPMS/ 16% RRMS). Στους ασθενείς με RRMS, η γνωστική έκπτωση εμφάνισε ασθενή συσχέτιση τόσο με τη σωματική αναπηρία, όσο και με τη διάρκεια της νόσου και το συνολικό όγκο βλαβών (p<.05). Αντίθετα, ισχυρή συσχέτιση παρατηρήθηκε μεταξύ της γνωστικής έκπτωσης και των δεικτών ατροφίας του εγκεφάλου (p<.001) Παράλληλα, η κλίμακα IADL εμφάνισε ισχυρή συσχέτιση με τη μνήμη, την ψυχοκινητική ταχύτητα, την ταχύτητα επεξεργασίας και με όλους τους δείκτες ατροφίας (p<.001). Στους ασθενείς με SPMS ανευρέθη ασθενή συσχέτιση μεταξύ γνωστικής έκπτωσης και πάχους 3ης κοιλίας (p<.05). Στο σύνολο των ασθενών με ΠΣ, συνυπολογίζοντας ως συμμεταβλητές την ηλικία, το φύλο, τα έτη εκπαίδευσης και τη διάρκεια της νόσου, η χαμηλή ψυχοκινητική ταχύτητα και οι χαμηλές επιδόσεις στη δοκιμασία TMT B αποτελούν τους πλέον ευαίσθητους δείκτες πρόβλεψης αυξημένης σωματικής αναπηρίας (p=.004 για ψυχοκινητική ταχύτητα και p=.007 για TMTB) και έκπτωσης καθημερινής λειτουργικότητας (p=.001 για ψυχοκινητική ταχύτητα), ενώ η έκπτωση της σύνθετης μνήμης (p=.002) και η χαμηλή επίδοση στη δοκιμασία TMT Β (p=.004) αποτελούν τους πλέον ευαίσθητους προγνωστικούς δείκτες της ανικανότητας των ασθενών για εργασία. Στο σύνολο των ασθενών με ΠΣ, η ατροφία των θαλάμων αποτελεί τον καλύτερο προγνωστικό δείκτη χαμηλής επίδοσης στη δοκιμασία TMT Β (p=.000) και έκπτωσης της σύνθετης μνήμης (p=.000), ενώ η ατροφία τοu μεσολοβίου αποτελεί τον πλέον ευαίσθητο δείκτη πρόβλεψης μειωμένης ψυχοκινητικής ταχύτητας (p=.000). Συμπεράσματα: Παρόλο που η έκπτωση των γνωστικών λειτουργιών είναι παρούσα από τα αρχικά στάδια της νόσου, είναι συχνότερη, πλέον έκδηλη και βαρύτερη στη χρόνια προιούσα ΠΣ. Δεν ανευρέθη διαφορετικό πρότυπο έκπτωσης γνωστικών λειτουργιών μεταξύ ασθενών με RRMS και ασθενών με SPMS. Το σφαιρικό αυτό πρότυπο, χαρακτηρίζεται από έκπτωση στην ταχύτητα επεξεργασίας πληροφοριών, ακολουθούμενο από ελλειμματικές εκτελεστικές λειτουργίες και έκπτωση της σύνθετης μνήμης. Η έκπτωση των καθημερινών δραστηριοτήτων είναι πολύ βαρύτερη στην SPMS, σε σύγκριση με την RRMS . Η επιφάνεια του μεσολοβίου και των θαλάμων αναδείχθηκαν οι πλέον ευαίσθητοι δείκτες στο διαχωρισμό των ασθενών με RRMS από SPMS. Παρατηρούμε δηλαδή, ότι παρόλο που η ατροφία είναι παρούσα από τα αρχικά στάδια της νόσου, με την πάροδο των ετών αυξάνεται σημαντικά. Η ψυχοκινητική ταχύτητα, η μνήμη και η δοκιμασία ΤΜΤ Β έχουν τη μεγαλύτερη προβλεπτική ικανότητα για την εξέλιξη της νόσου, τόσο σε επίπεδο σωματικής αναπηρίας, όσο και καθημερινής λειτουργικότητας. Οι δείκτες ατροφίας παρουσίασαν την ισχυρότερη συσχέτιση με τη γνωστική έκπτωση και την έκπτωση στην καθημερινή λειτουργικότητα. Από τους δείκτες αυτούς, η ατροφία των θαλάμων και του μεσολοβίου φαίνεται να έχουν την ικανότητα να προβλέψουν τη γνωστική έκπτωση στο σύνολο των ασθενών με ΠΣ. / Cognitive decline is present in 40%-70% of patients with MS and affects their quality of life. It has been significantly correlated with physical disability as well as with total lesion load and atrophy measures on MRI. Methods: In the present study, we evaluated 80 patients with MS (50 with RRMS, 30 with SPMS). We studied their demographic characteristics and assessed them clinically with EDSS. All patients underwent thorough Neuropsychological assessment with a computerized cognitive screening battery (CNS-VS) as well as with Trail Making Test A and B and verbal fluency task. We evaluated their everyday activities with the Instrumental Activities of Daily Living Scale, and we calculated the total lesion volume, thalamic atrophy, corpus callosum atrophy and 3rd ventricle width as apeared on the MRI. In addition, 31 healthy individuals underwent the same Neuropsychological assessment and 51 healthy individuals had brain MRI scans for comparison with our patients. Results: We found 38% of our RRMS patients and 80% of our SPMS patients to have cognitive deficits. More frequently affected measures were reaction time (83,33% SPMS/ 58% RRMS), TMT B(76,67% SPMS/ 34% RRMS), psychomotor speed (66,67% SPMS/ 20% RRMS), TMT A (63,33% SPMS/ 34% RRMS), phonological verbal fluency task (50% SPMS/ 30% RRMS) and memory (40% SPMS/ 16% RRMS). In our RRMS patients, cognitive impairment had a weak correlation with physical disability and total MR lesion load (p<.05) and a strong correlation with all atrophy measures (p<.001). Moreover, IADL were highly correlated with psychomotor speed, processing speed, memory and all MR atrophy measures (p<.001). On the other hand, our SPMS cognitively impaired patients had only a weak correlation with 3rd ventricle width (p<.05). When taking our MS patients as a single group and using as covariates age, sex, years of education and disease duration, we found that low psychomotor speed (p=.004) and poor performance on TMT B (p=.007) were the most sensitive predictors of increased physical disability, whereas psychomotor speed predicted impaired every day activities (p=.001). Employment status was predicted by impaired composite memory (p=.002) and poor performance on TMT B (p=.004). Thalamic atrophy was the most sensitive indicator for poor performance on TMT B (p=.000) and impaired memory (p=.000), while corpus callosum atrophy was the best indicator for slow psychomotor speed (p=.000). Conclusions: Although cognitive impairment is present from the early stages of MS, it is much commoner, more pronounced and severe at the progressive stage of MS. In the present study, we were not able to find a different pattern of cognitive decline between RRMS and SPMS patients. We observed a global pattern, consisting of impairment in information processing speed, followed by executive dysfunction and memory deficits. As disease progresses, everyday activities are affected more severely. Comparison of RRMS and SPMS patients revealed statistical significant difference in the surface of corpus callosum and thalami, indicating that although atrophy is present form the early stages of the disease, it is more prominent in the progressive stage. Psychomotor speed, composite memory and TMT B are the best predictors of EDSS and every day activities impairment (IADL). All of our MR atrophy measures had a strong correlation with cognitive decline and impaired every day activities. It seems that thalamic atrophy and corpus callosum atrophy are the best predictors of cognitive decline in our MS patients.

Visuomenės senėjimą sąlygoja ligos, kuriomis dažniausiai serga vyresnio amžiaus žmonės. Vyresniame amžiuje blogėja kognityvinės funkcijos, kurios neigiamai veikia mitybos būklę. Pagyvenusių žmonių, su kognityvinių funkcijų sutrikimais, mitybai reikia skirti didesnį dėmesį. Svarbu reguliariai vertinti pacientų mitybos būklę, norint laiku nustatyti blogą mitybą ar jos riziką. Todėl atliktas tyrimas, kurio tikslas buvo nustatyti pagyvenusių žmonių mitybos ypatumus, esant kognityvinių funkcijų sutrikimui. Anketinės apklausos metu apklausta 120 pacientų, vyresnių nei 65 m., kurie gydėsi Kauno II klinikinės ligoninės Vidaus ligų skyriuje 2007 m. gruodžio ir 2008 m. sausio, vasario mėnesiais. Tiriamąją grupę sudarė 60 respondentų, su kognityvinių funkcijų sutrikimais, ir kontrolinę – 60, kurių kognityvinės funkcijos nesutrikusios. Šių grupių pagyvenę žmonės buvo suskirstyti pagal amžių: 65–74, ≥75 metų. Naudoti tyrimo metodai: standartizuotas protinės būklės mažasis tyrimas ir mitybos mažoji anketa, sociodemografinė rodiklių ir slaugytojų anketos. Darbo rezultatai parodė, kad 65–74 m. amžiaus tiek tiriamosios ir kontrolinės grupės respondentai turėjo blogos mitybos riziką (43,3 proc. ir 50,0 proc.) ar gerą mitybą (50,0 proc. ir 43,3 proc.). ≥75 m. skirtingų grupių respondentai taipogi pasižymėjo blogos mitybos rizika (63,3 proc. ir 66,7 proc.). Pagyvenę žmonės, su normaliomis ir sutrikusiomis kognityvinėmis funkcijomis, priklausė blogos mitybos rizikos grupei (58,3 proc. ir 53,3... [toliau žr. visą tekstą] / Society ageing is determined by diseases with which people of elderly age are most often ill. In senior age cognitive functions which negatively act on the state of nutrition worsen. Bigger attention must be devoted to the nutrition of elderly people with cognitive function impairment. Regular assessment of the nutrition state of the patients wishing to establish malnutrition or its risk is important. So investigation the aim of which has been to establish the peculiarities of nutrition of elderly people under cognitive function impairment has been performed. During questionnaire interrogation 120 patients older than 65 who were treated in Kaunas Clinical Hospital No. 2 Internal Disease Department in December of 2007 and January, February of 2008 have been interrogated. The investigated group consisted of 60 respondents with cognitive function impairments and control group of 60 patients whose cognitive functions were not impaired. The elderly people of these groups were divided according to the age: 65-74, ≥ 75. Employed investigation methods: standardized mini mental state exam and mini nutrition assessment test, socio-demographic and nurse questionnaires. The work results have indicated that at 65-74 both the investigated and control group respondents had risk of malnutrition (43.3 per cent and 50.0 per cent) or good nutrition (50.0 per cent and 43.3 per cent). ≥ 75 respondents of different groups also distinguished themselves of the risk of malnutrition (63.3 per cent... [to full text]

Background: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease. The diagnosis is based on a combination of the motor signs: tremor, bradykinesia, rigidity and postural abnormalities. Mild Cognitive Impairment (MCI) is common early in the disease and a large proportion of patients with PD develop dementia (PDD). Associations between motor symptoms and cognitive decline have been suggested but the results are inconclusive due to differences in the selection of participants and variables tested. Large population based studies with comprehensive neuropsychological investigation in newly diagnosed cases with PD followed prospectively are rare. The aim of this thesis was to improve characterization and understanding of cognition in PD, and to explore the relationship to motor impairment in the early phase of PD. Methods: All new patients with suspected idiopathic parkinsonism in the catchment area (142 ooo inhabitants) were examined during a period of five years and four months. Among other investigations, a comprehensive neuropsychological evaluation was carried out in 119 of 148 patients with PD together with 30 age matched healthy controls. Assessments were repeated after one three and five years. Results: Patients performed worse than healthy controls in a majority of neuropsychological tests. MCI at the time of diagnosis were found in 36% according to recently published MCI criteria. Thirty % were cognitively impaired using another definition. One fourth of the patients developed PDD within five years after diagnosis and 25 % of those with MCI at baseline reversed back to normal cognition. Age and MCI were significant predictors of dementia. Education was an independent predictor for severe cognitive dysfunction at diagnosis but did not predict PDD. Patients with MCI converting to PDD had worse performance on visuospatial function, semantic fluency, episodic memory, mental flexibility and conceptual thinking. There were no differences in cognitive performance between patients with predominant Postural and Gait Disturbances (PIGD) and the tremor dominant subtype at the baseline investigation and belonging to the PIGD subgroup at baseline did not predict PDD. Dementia converters declined more rapidly than non-converters in posture/gait function. Associations between bradykinesia and measures of executive functions and working memory were found, and between posture and gait disturbances and visuospatial function. Some of these associations were persistent after one year. Patients receiving the dopamine agonist pramipexole performed significantly worse on a measure of verbal fluency at the one year follow up. Conclusions: The differences in proportions of cognitively impaired in the different studies emphasize the value of joint criteria for PD-MCI. Even when using such criteria, a substantial proportion of patients revert back to normal function. The increase in motor disability in patients with PDD could have several different causes that need to be further investigated. Associated motor and cognitive dysfunctions could reflect common pathophysiological processes in partly shared networks. Both dopaminergic and non-dopaminergic motor and cognitive functions seems to be involved in PDD which suggests that pharmacological treatment in PD needs to go beyond the scope of dopaminergic deficiency in search for new therapies that would also be effective for non-motor symptoms. / NYPUM

Impaired attention can hinder information processing at multiple levels and may explain some aspects of the cognitive decline in aging. An inefficient inhibitory system can lead to deficits in focused attention (FA). FA deficits are observed in patients with mild cognitive impairment and Alzheimer’s disease (AD). The Stroop task was applied to functional magnetic resonance imaging (fMRI) to investigate the neural correlates of FA in cognitively normal older adults (NC), patients with amnestic MCI (aMCI) and patients with mild AD. Twenty-one NC, seven aMCI and fifteen mild AD patients performed a verbal Stroop- fMRI paradigm. Both structural and T2*-weighted functional scans were acquired. In Series 0, subjects were presented with colour words printed in black ink and were asked to read the word. In Series 1 and 2, subjects were presented with colour words printed in an incongruent ink colour. Series 1 had four blocks of the ‘Read the word’ condition followed by four blocks of the ‘Say the colour of the ink’ condition. Series 2 had eight blocks of alternating ‘Read the word’ and ‘Say the colour of the ink’ conditions. SPM5 was used to detect anatomical areas with significant signal intensity differences between the two conditions. The NC group performed significantly better in the Stroop-fMRI task than the aMCI and mild AD groups. The percentage of errors on incongruent trials was significantly lower in the NC group (2%) than the aMCI (14%) and mild AD (13%) groups. The ‘Say the colour of the ink’ minus ‘Read the word’ contrast for the NC and mild AD groups yielded common areas of activation in the supplementary motor area, precentral gyrus, and inferior frontal gyrus. aMCI patients also showed activation in the precuneus, temporal and postcentral gyri. Worse performance on the Stroop-fMRI task by the aMCI and mild AD groups suggests deficits in FA. This is the first study to investigate the neural correlates of FA using the Stroop task in aMCI and AD patients. The verbal Stroop-fMRI paradigm employed in the current study provides a means to study the neural correlates of FA in older adult and patient populations. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2009-12-31 11:57:52.374

Patients with Amyotrophic lateral sclerosis (ALS) often experience cognitive impairment that accompanies degeneration of the motor system. A valuable tool for assessing cognitive control over behaviour is the antisaccade task which requires: 1) inhibition of the automatic response to look towards an eccentric visual stimulus (prosaccade) to instead 2) redirect gaze in the opposite direction of the stimulus (antisaccade). Psychometric tests were used to quantify the degree of impairment, while eye tracking, functional magnetic resonance imaging (fMRI) and structural MRI were combined to identify the neural correlates of cognitive impairment in ALS. We predict ALS patients will have executive dysfunction and grey matter loss in executive and oculomotor control areas that will affect antisaccade performance and will alter the corresponding brain activation. ALS patients and age-matched controls participated in a rapid-event-related fMRI design with interleaved pro- and antisaccade trials. Catch trials (no stimulus presented after instructional cue to prepare pro- or antisaccade) allowed us to discern the preparatory period from the execution period. ALS patients were biased towards automatic saccade responses, and had greater difficulty with antisaccades relative to controls in terms of correct and timely responses. We found that worsened antisaccade performance in ALS correlated with the degree of cognitive impairment. Generally, we found trends of increased brain activation during the preparatory period of antisaccades in ALS patients compared to controls in most oculomotor areas; meanwhile few differences were seen during execution. Structural analyses revealed ALS patients had decreased grey matter thickness in frontotemporal and oculomotor regions such as the frontal and supplementary eye fields (FEF, SEF) and the dorsolateral prefrontal cortex (DLPFC). These findings suggest that loss of structural integrity and executive dysfunction may elicit compensation mechanisms to improve functional and behavioural performance. Despite this compensation, ALS patients still performed worse on antisaccades than controls. Further investigation to expand the current data set should improve our ability to assuredly identify the neural correlates of cognitive decline in ALS, and may provide a model system to use for critical evaluation of future therapies and interventions for ALS. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-09-22 14:20:39.704

Normal ageing is associated with decline in visual, cognitive, and physical functioning, with concurrent increases in the incidence of chronic medical conditions, including cognitive disorders. Determining when age-related changes have adversely affected a person’s ability to drive safely is a complex task, particularly when cognitive disorders such as mild cognitive impairment and dementia are present. The aim of this research was to assess the utility of a number of off-road measures in predicting Pass and Fail outcomes for older drivers on a blinded on-road driving assessment with a driving specialist occupational therapist and a driving instructor, which is considered the ‘gold standard’ measure of driving ability. The off-road measures included standardized cognitive tests, computerized sensory-motor & cognitive tests, medical conditions, and personality measures. The research project comprised three studies. In Study 1 (Healthy Older Drivers study), 60 drivers with no diagnosed cognitive disorder (‘cognitively-unimpaired’), aged 70-84 years (mean age 76.7, 50% male), completed standard cognitive tests, computerized sensory-motor and cognitive tests (SMCTests™), and measures of personality. Results were used to form classification models for on-road assessment Pass and Fail outcome. Sixteen participants failed the on-road assessment. A backwards stepwise binary logistic regression model selected a measure of executive function and a computerized measure of visuomotor planning and coordination as the best predictors. Following leave-one-out cross-validation, this model was estimated to correctly predict 60% of an independent group of cognitively-unimpaired older drivers into on-road Pass and Fail groups. In Study 2 (Healthy Driver Follow-up study), 56 participants from the Healthy Older Drivers study were followed for 24 months using annual telephone interviews to assess driving behaviour, driving attitudes, medical conditions, and the occurrence of crashes and receipt of traffic offences. Official data regarding crashes and traffic offences were also obtained. The aim was to determine whether either the on-road Pass/Fail classification or the off-road measures could predict subsequent crashes and offences. Failing the on-road assessment was not associated with higher crash or offence rates and there were only two baseline measures that predicted crashes or offences (i.e., distance driven at baseline testing and, paradoxically, a lower error score on a measure of visuomotor planning and coordination). However, drivers who reported more distress associated with their medical condition(s) were more likely to have had a crash or offence at 24 months. The outcomes of the Healthy Older Drivers and Healthy Driver Follow-up studies suggest that there is little value in off-road or on-road assessment of cognitively-unimpaired older drivers due to the weak relationship with future negative driving outcomes. However, distress associated with medical conditions may be a useful measure. Study 3 (Dementia and Driving study) recruited a sample of 60 driving assessment centre referrals with mild cognitive impairment or Alzheimer’s dementia. These participants, aged 58-92 years (mean age 77.9, 60% male), performed a computerized battery of sensory-motor and cognitive tests and a formal blinded on-road driving assessment. A backwards stepwise binary logistic regression model selected measures of reaction time and movement speed of the upper limbs, visuomotor planning and coordination, and sustained attention. Following leave-one-out cross-validation, this model was estimated to correctly predict 68% of an independent group of drivers with mild cognitive impairment and Alzheimer’s dementia into on-road Pass and Fail groups. A subsample of 32 participants completed additional standard cognitive tests and provided information on medical conditions. A binary logistic regression model in this subsample was formed which selected measures of verbal fluency, the presence of heart disease, and a comprehensive cognitive screen. Following leave-one-out crossvalidation, this model would be expected to correctly classify 75% of an independent group of drivers with mild cognitive impairment and Alzheimer’s dementia into on-road Pass and Fail groups. The three measures in this model could be performed in around 35-50 min in a primary health setting. It is concluded that off-road and on-road assessment of older drivers with no diagnosis of cognitive or neurological disorder is an inaccurate and inefficient use of driving assessment resources, both for the prediction of on-road driving performance and for predicting future crashes and traffic offences. The Dementia and Driving study found a model comprising three measures that could be performed in a primary health setting with reasonable accuracy for correctly classifying people with mild cognitive impairment and Alzheimer’s dementia who go on to Pass and Fail an on-road driving assessment.

Individuals with Parkinson’s disease (PD) often show cognitive impairments in addition to motor symptoms, with the majority of PD patients converting to dementia as the disease progresses. The changes in the microstructural integrity of key nodes in resting state networks (RSNs) could be a good indicator of the cognitive effects of PD on brain regions as it progresses to dementia. To assess the association between cognitive effects and microstructural change, the microstructural integrity of the regions of interest (ROIs) in 4 resting state networks (RSN), specifically the default mode network (DMN), based on DTI were obtained in three separate groups of patients with PD. One group of patients (PD-N) were cognitively normal, while the second group of patients (PD-MCI) reflect the transitional phase of mild cognitive impairment prior to dementia, and the third group of patients (PD-D) possessed a clear diagnosis of dementia. A comparison group of healthy controls (HC) were included, matched across the three patient groups. The PD-D group showed worse microstructural integrity for the majority of the ROIs across the 4 networks. The loss of structural integrity in the PD-MCI group was more selective, with some ROIs showing similar changes to PD-D, and others showing similar changes to the PD-N group. The PD-N group fail to show any changes in the structural integrity of any ROIs, relative to HC. For future study, a combined structural / functional study should be performed to examine if there are similar changes across both measures.

Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.

Functional Magnetic Resonance Imaging (fMRI) was used to examine brain activity in women with early stage Breast Cancer (BC) and to compare their neural profiles to a matched control group. This was accomplished as participants performed two working memory tasks, before and at two time points following the chemotherapy intervention of the BC group. Nineteen BC patients between the ages of 18 and 65 years were recruited from the Ottawa Hospital Regional Cancer Centre. The nineteen control participants were matched on sex, language, age and education. The results, from whole brain analyses, show significant differences in neural activity between BC patients and matched control participants during both verbal and visuospatial working memory tasks, before and right after chemotherapy. However, these differences were no longer observed one year post chemotherapy for verbal WM processing. Performance results were not significantly different between groups until the third imaging sessions when patients made significantly more errors of omission than controls for both tasks. Importantly, mood, anxiety and fatigue all played significant roles in the observed findings demonstrating the multifaceted nature of the impact of both cancer and chemotherapy on neural function during working memory. This is one of the first fMRI studies to measure neural activations during cognitive performance both before and after chemotherapy in BC patients and a control group while controlling for many potentially confounding variables. While BC patients should be made aware of the potential cognitive challenges they might face before, during and shortly after treatment, they can also feel reassured that these impairments may not be long lasting.

Amnestic mild cognitive impairment (aMCI) has been established as a significant risk factor for Alzheimer‟s disease (AD) and in many cases this state appears to represent an early or incipient stage of AD. Due to difficulties with the diagnosis and prognosis of aMCI and AD, as well as with the projected significant socioeconomic ramifications of AD, there is a need to establish sensitive and reliable biomarkers. The application of event related potentials (ERPs) has been recommended in this context due to their reliability, non-invasive nature, inexpense and relatively widespread availability. This thesis aims to further assess the potential efficacy of ERP markers for such applications. These aims are pursued via investigations of ERPs in healthy ageing, MCI and AD utilising an explicit recognition task that requires the use of key cognitive/memory processes which are often impaired in aMCI and AD. Two ERP effects were analysed: the N400effect which is assumed to index familiarity or trace strength, and the Late Positive Complex (LPC) which appears to index recollection or decision-related factors such as accuracy. Chapter 3 reports ERP and recognition accuracy comparisons between samples of 15 young (mean age = 21.73 years) and 15 older, cognitively healthy adults (mean age = 66.67 years). ERP data were acquired during performance of a word recognition task with high and low memory load conditions (long and short encoding lists, respectively). At test, participants were required to make old/new judgements to visually presented words. There was a trend for young participants to perform more accurately than the older sample, especially on the long list; although these differences only approached significance. However, the N400 old/new effect was found to be significantly reduced in the old compared with the young participants across memory load conditions. LPC old/new effects were generally not observed and this is likely due to the nature of the task which generally places minimal demands on controlled retrieval processes. These results indicate that the N400 effect may be more sensitive to the deleterious effects of ageing on recognition memory-related process(s) than behavioural measures of memory accuracy. Consistent with the view that the N400 indexes familiarity, these results are in accordance with other evidence that familiarity is affected in healthy ageing. The same methodology was used to compare ERPs between aMCI (n = 11) and healthy older adults (n = 11) in Chapter 4. The aMCI participants performed significantly worse than vi healthy elderly participants in discriminating „old‟ from „new‟ words. In the corresponding ERP data, healthy control sample demonstrated significant N400 old/new effects at parietal electrode locations, whereas aMCI participants failed to demonstrate significant N400 old/new effects at any electrode location. Again, LPC effects were not observed in either sample. The absence of significant N400 effects in aMCI participants may reflect a disruption of familiarity-based recognition in aMCI. These results converge with other evidence that the N400 effect may be a sensitive ERP marker useful for detecting, monitoring and/or predicting amnestic related cognitive decline. There are reported variations in underlying causes and sequelae of aMCI (e.g., not all progress to AD). Chapter 5 reports an exploratory investigation aimed at determining whether baseline ERPs differentiate between aMCI participants on the basis of their clinical diagnosis at follow-up. Baseline ERP data were compared in a small sample (n = 7) of aMCI participant who remained cognitively stable at 12-month follow-up (SMCI) with two aMCI participants who progressed to meet an AD diagnosis (PMCI) at the latter time-point. There was a trend for PMCI participants to display smaller old/new effects. However, only one participant displayed significantly smaller N400 old/new effects under low memory load conditions. Interestingly, this participant was also more impaired in baseline cognitive functioning. Chapter 6 examines the relationship between baseline ERPs and performance on neuropsychological assessment at 12-month follow-up in a sample of aMCI and AD participants (n =13) in order to investigate whether ERPs may prove informative for prognoses regarding general trajectories of cognitive decline, irrespective of diagnostic status. Smaller N400 old/new effects (at Fz and CPz) were associated with poorer performance on tasks assessing global cognitive functioning and auditory attention span. Reduced LPC old/new differences were related to poorer performance on tasks assessing global cognitive functioning, verbal learning and memory and better performance on a task assessing working memory at follow-up. In contrast to these results, no relationships were observed between ERP effects and concurrent performance on neuropsychological assessment in this sample, or in 42 elderly participants (including healthy, aMCI and AD), as described in Chapter 7. Taken together these results suggest that ERPs may be more sensitive in predicting future rather than concurrent cognitive functioning and may provide a more objective measure/classification of cognitive impairment vii irrespective of diagnosis. These outcomes are particularly novel as the relationship between baseline ERP data and follow-up neuropsychological measures does not appear to have been systematically reported in the literature to date. Collectively these findings indicate that ERP measure(s), particularly the N400 old/new effect, are sensitive to neurocognitive changes associated with ageing and aMCI, and may prove a useful biomarker for the early detection of AD. This is interesting as the effects of healthy ageing and pathological decline on the N400 from explicit recognition tasks have not been thoroughly explored. Moreover, the N400 (and perhaps, to a lesser degree, LPC) effect(s) appear to have substantial value for informing future prognoses of subsequent cognitive trajectories, at least for persons with amnestic impairment. These results may have significant clinical implications pertaining to the selection and application of efficacious therapeutic interventions in aMCI and AD.