Since neuroinflammation is present in patients with mild cognitive impairment (MCI) andAlzheimer's disease (AD) and since cholinesterase inhibitors increases the level ofacetylcholine, the aim was to investigate whether inflammatory markers of cholinoceptive cellsare affected in these patients. Near a biological hallmark of AD, amyloid plaque, activatedastrocytes and microglia can be found and higher levels of proinflammatory cytokines, i.e. IL-1β. To study the inflammatory response, proteins GFAP and S100B are used as CSF glialmarkers. IL-1β can bind to the membrane-bound IL-1 receptor or soluble sIL-1β-RII. When IL-1β binds to the soluble receptor instead of the membrane-bound receptor, no intracellular signalpropagation occur, thereby sIL-1βRII exerts an antagonistic effect and diminishedinflammatory responses. Thus a reduction in ratio of IL-1β to sIL-1RII levels may be indicativeof anti-inflammatory response. Available data on CSF GFAP, S100B, IL-1β and sIL-1β-RIIlevels in AD patients and MCI patients was used. MCI group were longitudinally followedafter start of treatment with a cholinesterase inhibitor (ChEI). AD group had data from baselineand after short-term treatment with a ChEI. The statistics application StatView was used toanalyse data. The activity of the cholinesterase enzymes, BuChE and AChE showed significantinhibition in the CSF of the MCI patients compared to baseline CSF GFAP level wassignificantly lower in MCI than AD patients at baseline. The levels of both GFAP and S100Bwere increased with time in MCI patients to comparable levels in the AD patients, indicative ofastroglial activation in MCI patients. However, the ratio of IL-1β to sIL-1RII showed alongitudinal reduction in the MCI patients after the treatment with the ChEIso that this ratiowas significantly higher in AD than in MCI patients. Thus despite the activation of astroglialcells in the treated MCI patients the proinflammatory effect of IL-1β was prevented byinduction of sIL-1βRII levels indicative of an anti-inflammatory outcome of treatment. Thisstudy suggests that proper activation of astroglial cells may have beneficial effect on ADpathogenesis, and conversion of MCI to AD. It also suggests that cholinesterase inhibitors may have an anti-inflammatory effect.

Purpose: Patients living with advanced heart failure experience dyspnea, fatigue, poor quality of life, depression and cognitive impairment which may threaten their ability to provide informed consent to undergo heart transplant (HTx) or mechanical support (LVAD). Using qualitative and quantitative methods, we asked how patients with advanced heart failure make decisions regarding HTx and LVAD. The variables chosen to reflect the elements of consent included quality of life and symptom severity (voluntariness), depression and cognitive impairment (capacity) and treatment preferences (decision-making). Methods: 76 patients enrolled in the quantitative arm completed the Minnesota Living with Heart Failure Questionnaire; Visual Analog scales for dyspnea, fatigue and overall health; Beck Depression Inventory; Montreal Cognitive Assessment; Standard Gamble and Time Tradeoff. Qualitative methods were used to discover concepts, relationships and decision-making processes described by 17 of the 76 patients considering HTx and LVAD. Results: Patients reported poor quality of life and high symptom severity scores which compelled them to consider surgery as a way to relieve unpleasant symptoms and improve quality of life. Although 30% of patients had evidence of depression and/or cognitive impairment, no patient was deemed incapable of decision-making. Patients were willing to take considerable risk (35%) and trade considerable time (4months) to improve their health. While heart failure-related concepts were important to the decision, entrustment emerged as the meaningful process for decision-making. Conclusions: Patients who participated in this study were capable of decision-making and understood the risks associated with the surgery. Voluntariness was diminished by disease but not absent, and decisions were free of coercion. These results suggest the entrustment model of decision-making is the dominant process for patients considering high-risk surgical procedures and meets criteria for informed consent. Understanding the process of decision-making will help clinicians support and enable treatment decisions made by patients living with advanced heart failure.

SAMMANFATTNING För att möjliggöra öppen hjärtkirurgi används hjärt-lungmaskin som leder blodet i en bana utanför kroppen sammankopplat med kroppscirkulationen. Möjliga komplikationer efter kirurgi med stöd av hjärt-lungmaskin kommer från det centrala nervsystemet och kan ge upphov till kognitiva symtom, dessa komplikationer har ökat sedan 70-talet. Kognitiva nedsättningar kan påverka både patientens livskvalitet och sjukvårdens ekonomi. Risker med att opereras med stöd av hjärt-lungmaskin är embolier, hypoperfusion, anestesi och inflammation. Detaljerad information till patienter som ska genomgå hjärtkirurgi gör dem mer förberedda på eventuella komplikationer. För att som vårdpersonal kunna bemöta och informera dessa patienter krävs kunskap om kognitiva nedsättningar postoperativt. Syftet var att belysa kognitiva förändringar hos patienter som opererats med stöd av hjärt-lungmaskin. Litteraturöversikt genomfördes där alla typer av hjärtkirurgi som utförts med stöd av hjärt-lungmaskin valdes att inkluderas. Originalartiklar på svenska och engelska eftersöktes med åtkomst via "full text", ingen begränsning på publikationsår gjordes. Både kvalitativa och kvantitativa artiklar eftersöktes. Sökord som användes var "cardiopulmonary bypass", "heart-lung machine", "cognition disorders", "neurobehavioral manifestations", "patients", "postoperative" och "experience". Databaser som användes var Cinahl, PsycINFO och PubMed. Slutresultatet blev 15 kvantitativa artiklar som granskades enligt mallar från Sophiahemmets högskola. Ingen artikel exkluderades pga. låg kvalitet, sju stycken bedömdes ha medelkvalitet och åtta bedömdes ha hög kvalitet. Artiklarnas resultat analyserades med studiens syfte som utgångspunkt för att sedan sammanfattas och sammanställas till rubriker. Bedömning gällande artiklarnas etiska ställningstagande har gjorts i samtliga inkluderade artiklar. Resultatet visade att kognitiva nedsättningar var vanligt förekommande. Typer som beskrevs var påverkan på minne, koncentration och visuomotorisk konstruktionsförmåga. Depressiva tillstånd beskrevs och även en koppling till nedsatt minne beskrevs. Det var vanligare att utveckla kognitiva nedsättningar med att opereras med stöd av hjärt-lungmaskin än att opereras utan dess stöd. Kognitiva nedsättningar beskrevs upp till fem år efter operation. Det beskrevs också kognitiv försämring som förvärrades efter ett år till tre år efter operation. Hjärt-lungmaskinen visade sig bidra till utveckling av kognitiva nedsättningar där det också framkom att aortatångtid var associerat med kognitiv nedsättning. Risker för att utveckla kognitiva nedsättningar var hög ålder. Kognitiva nedsättningar utgjorde inte ett hinder för arbete eller vardagliga aktiviteter. Kognitiva nedsättningar är förekommande både på kort och på lång sikt efter att ha genomgått hjärtkirurgi med stöd av hjärt-lungmaskin. Att symtom inte alltid är uppenbara, förutom vid tester ställer krav på att vårdpersonal erbjuder den information som krävs inför operation för att förbereda patienten. Då kognitiva symtom kan debutera senare kan detta tolkas som åldringsprocess och etiologin är inte säkerställd. För att kvalitetssäkra vården kring dessa patienter bör vårdpersonal vara uppmärksamma på kognitiva symtom postoperativt. / ABSTRACT To enable open heart surgery, a heart-lung machine is used which carry blood in a path outside the body coupled to the body circulation. Complications after surgery with support of the heart-lung machine may be derived from the central nervous system and can cause cognitive symptoms, these complications have increased since the 70's. Cognitive impairments can affect both patient quality of life and healthcare economics. Risks of surgery with the support of the heart-lung machine are emboli, hypoperfusion, anesthesia and inflammation. Detailed information for patients about to undergo cardiac surgery makes them more prepared for possible complications. For the nursing staff to respond and inform these patients requires knowledge of cognitive impairment postoperatively. The aim was to illuminate the cognitive changes in patients after undergoing cardiac surgery with the support of the heart-lung machine. Literature review was conducted where all types of heart surgery performed with the support of the heart-lung machine was chosen to be included. Original articles in Swedish and English whereabouts with access via the "full text", no restriction in years of publication was made. Keywords used was "Cardiopulmonary Bypass", "heart-lung machine", "cognition disorders", "neurobehavioral manifestations," "patient," "post-operative" and "experience". Databases used were Cinahl, PsycINFO and PubMed. The end result was 15 quantitative articles which underwent examination according to templates from Sophiahemmet University. No article was excluded due to low quality, seven were considered to have medium quality and eight were judged to be of high quality. Articles results were analyzed by the study's aim as a starting point and then summarized and compiled into headlines. Ethical consideration has been made in all included articles. The results showed that cognitive impairments were common. Cognitive impairments described were the impact on memory, concentration and visuoconstruction. Depressive condition was described and even a link to impaired memory was described. It was more common to develop cognitive impairments after undergoing cardiac surgery with the support of the heart-lung machine than to undergo surgery without its support. Cognitive impairment was described up to five years after surgery. It was also described cognitive decline that worsened after one year to three years after surgery. Heart-lung machine was found to contribute to the development of cognitive impairments, which also revealed that aortic cross-clamp duration was associated with cognitive impairment. Risks of developing cognitive impairment were advanced age. Cognitive impairments did not constitute an obstacle for work or everyday activities. Cognitive impairments are common in both the short and long term after undergoing cardiac surgery with the support of the heart-lung machine. That the symptoms are not always obvious, except when testing requires that health professionals provides the information required before surgery to prepare the patient. Cognitive impairments may have a later debut which can be interpreted as the aging process, and the etiology is not assured. In order to assure the quality of care of these patients, health professionals should be alert to the cognitive symptoms postoperatively.

Objective: The nature of disaster research makes it difficult to adequately measure the impact that significant events have on a population. Large, representative samples are required, ideally with comparable data collected before the event. When Christchurch, New Zealand, was struck by multiple, devastating earthquakes, there presented an opportunity to investigate the effects of dose-related quakes (none, one, two or three over a 9-month period) on the cognition of Canterbury’s elderly population through the New Zealand Brain Research Institute’s (NZBRI’s) cognitive screening study. The related effects of having a concomitant medical condition, sex, age and estimated- full scale IQ (Est-FSIQ) on cognition were also investigated. Method: 609 participants were tested on various neuropsychological tests and a self-rated dementia scale in a one hour interview at the NZBRI. Four groups were established, based on the number of major earthquakes experienced at the time of testing: “EQ-dose: None” (N = 51) had experienced no quakes; “EQ-dose: One” (N = 193) had experienced the initial quake in September 2010; “EQ-dose: Two” (N = 82) also experienced the most devastating February 2011 quake; and “EQ-dose: Three” (N = 265) also the June 2011 quake at testing. Results: Two neuropsychological variables of Trail A and the AD8 were impacted by an EQ-dose effect, while having a medical condition was associated with poorer function on the MoCA, Rey Copy and Recall, Trail A, and AD8. Having a major medical condition led to worse performance on the Rey Copy and Recall following the major February earthquake. Males performed significantly better on Trail A and Rey Planning, while females better on the MoCA. Older participants (>73) had significantly lower scores on the MoCA than younger participants (<74), while those with a higher Est-FSIQ (>111) had better scores on the MoCA and Rey Recall than participants with a lower Est-FSIQ. Finally, predicted variable analysis (based on calculated, sample-specific Z-scores) failed to find a significant earthquake effect when variables of age, sex and Est-FSIQ were controlled for, while there was a significant effect of medical condition on each measure. Conclusion: The current thesis provides evidence suggesting resilience amongst Canterbury’s elderly population in the face of the sequence of significant quakes that struck the region over a year from September 2010. By contrast, having a major medical condition was a ‘more significant life event’ in terms of impact on cognition in this group.

Darbo tikslas: įvertinti ankstyva Parkinsono liga (PL) be demencijos sergančių asmenų pažinimo funkcijas naudojant Kembridžo kompiuterinės neuropsichologinio ištyrimo sistemos testų rinkinį, palyginti rezultatus su kontrolinės grupės asmenų duomenimis bei nustatyti kognityvinių rodiklių ryšius su biologiniais žymenimis ir klinikiniais nekognityviniais PL simptomais. Darbo uždaviniai: ištirti ankstyva PL sergančių asmenų dėmesio, atminties, regos erdvinę ir vykdomąsias funkcijas, naudojant kompiuterizuotų testų rinkinį CANTAB eclipse 3.0.0, ir palyginti juos su kontrolinių asmenų duomenimis; nustatyti pacientų kognityvinių funkcijų ryšį su UPLVS skale įvertintu ligos sunkumu, transkranijinės sonografijos (TKS) metodu nustatytu juodosios medžiagos (JM) echogeniškumu, presinapsinio dopamine transporterio koncentracija dryžuotame kūne, nustatyta radionuklidinės kompiuterinės tomografijos (RKT) su I¹²³-FP-CIT būdu, miego, nuovargio bei demografiniais veiksniais, gyvenimo kokybės rodikliais, PL gydyti skiriamų vaistų vartojimu; išanalizuoti kompiuterizuotais testais įvertintų kognityvinių funkcijų diagnostinę vertę sergant ankstyva PL. Metodai. Tyrimas atliktas Vilniaus universiteto ligoninės Santariškių klinikų Neurologijos centre. Atrinkta 115 pacientų, sergančių ankstyva kliniškai tikėtina PL, kurie atitiko įtraukimo kriterijus bei nebuvo neįtraukimo kriterijų, ir 42 pagal amžių, lytį, mokymosi trukmę atrinkti kontroliniai tiriamieji, kurie nesirgo PL ar kitomis... [toliau žr. visą tekstą] / The aim of the study: to evaluate the cognitive functions of patients with early-stage Parkinson‘s disease (PD) without dementia using Cambridge Neuropsychological Test Automated Battery (CANTAB Eclipse 3.0.0), to compare the obtained results with the data of control subjects, to determine the associations of the variables of cognitive testing with biological markers and clinical non-cognitive symptoms of PD. Objectives: to examine attention, memory, visuospatial and executive functions of patients with early-stage PD without dementia using CANTAB Eclipse 3.0.0 and to compare the obtained results with the data of control subjects; to investigate the relationship between the cognitive functions of patients with early-stage PD and the severity of disease measured by UPDRS score, the echogenic properties of brainstem nigral substance (SN) examined by transcranial sonography (TCS), the striatal binding of presinaptic dopamine transporter determined by single-photon emission computed tomography (SPECT) with I¹²³-FP-CIT, sleep, fatigue, demographic factors and quality of life scores, the usage of medications for early-stage PD; to analize the diagnostic characteristics of particular computerised tests for evaluation of cognitive function in patients with early-stage PD. Methods. The study was performed at the Department of Neurology of Vilnius University Hospital Santariškių Klinikos. 115 patients diagnosed with clinically probable early-stage PD who met inclusion criteria and... [to full text]

The aim of the study: to evaluate the cognitive functions of patients with early-stage Parkinson‘s disease (PD) without dementia using Cambridge Neuropsychological Test Automated Battery (CANTAB Eclipse 3.0.0), to compare the obtained results with the data of control subjects, to determine the associations of the variables of cognitive testing with biological markers and clinical non-cognitive symptoms of PD. Objectives: to examine attention, memory, visuospatial and executive functions of patients with early-stage PD without dementia using CANTAB Eclipse 3.0.0 and to compare the obtained results with the data of control subjects; to investigate the relationship between the cognitive functions of patients with early-stage PD and the severity of disease measured by UPDRS score, the echogenic properties of brainstem nigral substance (SN) examined by transcranial sonography (TCS), the striatal binding of presinaptic dopamine transporter determined by single-photon emission computed tomography (SPECT) with I¹²³-FP-CIT, sleep, fatigue, demographic factors and quality of life scores, the usage of medications for early-stage PD; to analize the diagnostic characteristics of particular computerised tests for evaluation of cognitive function in patients with early-stage PD. Methods. The study was performed at the Department of Neurology of Vilnius University Hospital Santariškių Klinikos. 115 patients diagnosed with clinically probable early-stage PD who met inclusion criteria and... [to full text] / Darbo tikslas: įvertinti ankstyva Parkinsono liga (PL) be demencijos sergančių asmenų pažinimo funkcijas naudojant Kembridžo kompiuterinės neuropsichologinio ištyrimo sistemos testų rinkinį, palyginti rezultatus su kontrolinės grupės asmenų duomenimis bei nustatyti kognityvinių rodiklių ryšius su biologiniais žymenimis ir klinikiniais nekognityviniais PL simptomais. Darbo uždaviniai: ištirti ankstyva PL sergančių asmenų dėmesio, atminties, regos erdvinę ir vykdomąsias funkcijas, naudojant kompiuterizuotų testų rinkinį CANTAB eclipse 3.0.0, ir palyginti juos su kontrolinių asmenų duomenimis; nustatyti pacientų kognityvinių funkcijų ryšį su UPLVS skale įvertintu ligos sunkumu, transkranijinės sonografijos (TKS) metodu nustatytu juodosios medžiagos (JM) echogeniškumu, presinapsinio dopamine transporterio koncentracija dryžuotame kūne, nustatyta radionuklidinės kompiuterinės tomografijos (RKT) su I¹²³-FP-CIT būdu, miego, nuovargio bei demografiniais veiksniais, gyvenimo kokybės rodikliais, PL gydyti skiriamų vaistų vartojimu; išanalizuoti kompiuterizuotais testais įvertintų kognityvinių funkcijų diagnostinę vertę sergant ankstyva PL. Metodai. Tyrimas atliktas Vilniaus universiteto ligoninės Santariškių klinikų Neurologijos centre. Atrinkta 115 pacientų, sergančių ankstyva kliniškai tikėtina PL, kurie atitiko įtraukimo kriterijus bei nebuvo neįtraukimo kriterijų, ir 42 pagal amžių, lytį, mokymosi trukmę atrinkti kontroliniai tiriamieji, kurie nesirgo PL ar kitomis... [toliau žr. visą tekstą]

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Introduction: Idiopathic Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that is characterised by motor symptoms. However, there is increasing awareness that a range of neuropsychiatric and cognitive problems also accompanys PD. The objective of this thesis was to examine the profile of neuropsychiatric and cognitive problems for patients with PD without dementia. Parkinson's disease patients who could be identified at the time of this study were invited to participate. Each patient was individually matched to a healthy control in terms of age, premorbid intelligence, and years of education. Results: Neuropsychiatric symptoms were common for this patient group, over 40% self reported symptoms consistent with depression, 40% with physical fatigue, 38% with mental fatigue, 38% with apathy and 32% with sleep problems. More than 77% of patients with PD reported symptoms associated with at least one problem and over 46% with 3 or more problems. Increased symptoms consistent with depression and anxiety and the presence of hallucinations also predicted poorer quality of life after controlling for motor symptoms. However, the of level agreement between patient report and that of a person who know them well was low: 40.9% for apathy, 28% for hallucinations, 39% for depression, 25% for sleep problems and only 7.7% agreement for the presence of anxiety. To obtain an accurate profile of cognitive impairments patients were assessed on measures of higher order language ability and a broad range of commonly used cognitive tests. Overall, PD patients were impaired on aspects of higher-order language. However, results indicated that these deficits were not a primary effect of PD, but could be explained in terms of deficits in speed of information processing associated with the disease. Compared to healthy controls, PD patients also showed deficits on measures of executive function, working memory, problem solving, and visuospatial skills. However, they were unimpaired on measures of planning, attention and memory/learning. Deficits in problem solving were only evident for tasks with a high visuospatial content and were no longer significant when visuospatial skills were controlled for. Further investigation indicated that planning in PD patients was not impaired in general and was dependent on the sensitivity of tests used. To further examine cognitive deficits, patients were divided into groups according to their cognitive performance. Three sub-groups of patients were identified that formed a continuum of cognitive impairment from none/mild to severe. Compared to controls, one subgroup showed no or minimal impairment (PD-NCI), a second group showed a more variable pattern of severe and mild impairments (PD-UCI), and a third group had evidence of severe impairment across most of the cognitive domains tested. This latter group was labelled PD-Mild Cognitive Impairment (PD-MCI). The PD-UCI and PD-MCI groups were also significantly different from their controls with respect to their ability to carry out functional activities of everyday living. The PD-MCI group had evidence of global cognitive decline, possibly reflecting a stage of pre-clinical dementia. The severity of cognitive deficits was not associated with other clinical and demographic characteristics such as motor impairments, age or disease duration. These results were confirmed when patients were retested one year later. Conclusions: Comorbid neuropsychiatric and cognitive problems are common for patients with PD prior to any overt signs of dementia. However, PD patients are heterogeneous with regard to their presentation and different subgroups of patients are identifiable based on cognitive performance. This information has both theoretical and clinical relevance.

The works presented in this dissertation provide insights into the mechanisms of chemotherapy-induced cognitive impairment (CICI or “ChemoBrain”) and take steps toward outlining a preventive strategy. CICI is now widely recognized as a complication of cancer chemotherapy experienced by a large percentage of cancer survivors. Approximately fifty percent of existing FDA-approved anti-cancer drugs generate reactive oxygen species (ROS). Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, produces the reactive superoxide radical anion (O2-•) in vivo. Dox treatment results in oxidation of plasma proteins, including ApoA-I, leading to TNF-α-mediated oxidative stress in plasma and brain. TNF-α elevation in brain leads to further central nervous system toxicity including mitochondrial dysfunction, neuronal death, and cognitive impairment. Co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma without interfering with the cancer-killing ability of Dox. In studies presented in this dissertation, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline(phosphocholine)/creatine (Cho/Cr) ratios in mouse hippocampus. The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D(PLD) were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox. In the absence of TNF-α, MRS-indexed Cho/Cr ratio, PLD activity, and mitochondrial oxygen consumption are preserved in brain, and markers of oxidative stress are reduced. Together with results from our previous studies, these results provide strong evidence that TNF-α is strongly associated, if not responsible for CICI. We also tested the notion that O2-• is responsible for Dox-induced plasma protein oxidation and TNF-α release. O2-• resulted in increased oxidative damage to proteins when added to plasma and increased levels of TNF-α in macrophage culture, providing strong evidence that O2-• is responsible for these Dox-induced toxicities.