Late-life depression (LLD) is common illness, frequently associated with neuropsychological impairment. Disruption of frontal-subcortical and limbic networks may play a key role in LLD and can be examined using magnetic resonance imaging (MRI). Grey matter (GM) can be examined using T1-weighted MRI, white matter (WM) using diffusion tensor imaging (DTI), and functional connectivity using resting-state functional MRI (fMRI). To clarify the roles of GM, WM and functional connectivity in LLD, systematic reviews and meta-analyses of T1-weighted MRI, DTI and resting-state fMRI studies of depression were performed. The literature provided evidence for GM and WM abnormalities within frontal-subcortical and limbic networks, and increased functional connectivity within the default-mode network, in depression. To examine whether results gained from different techniques are complementary, multi-modal MRI was used to compare GM, WM and functional connectivity between thirty-six participants with LLD and twenty-five control participants. WM integrity was widely reduced in LLD, without significant group differences in GM or functional connectivity. To investigate whether neuropsychological deficits represent independent processes with specific neural correlates, or whether they can be explained by a core deficit, the relationships between neuropsychological and MRI measures were explored. Executive function and processing speed were found to represent core deficits that contribute to impairment in other domains; and impaired performance was correlated with reduced frontal WM integrity. Episodic memory deficits were dependent on executive function and processing speed; and associated with reduced frontal and hippocampal WM integrity. The relationships between age at onset, severity and MRI measures of GM, WM and functional connectivity were also investigated. Later onset was associated with reduced WM integrity, in line with the vascular hypothesis. Earlier onset was associated with greater duration of illness and reduced hippocampal volume, consistent with the glucocorticoid cascade hypothesis. Severity was not associated with any MRI measure. This thesis strongly supports the hypothesis that WM abnormalities in frontal-subcortical and limbic networks play a key role in LLD, with abnormalities related to neuropsychological impairment and compatible with the vascular hypothesis.

The aim of the research presented in this thesis was to improve the characterisation of the changes in brain structure and function that occur at different stages of Alzheimer’s disease (AD) progression, from pre-symptomatic AD, to mild cognitive impairment (MCI), to clinically evident dementia, using magnetic resonance imaging (MRI) techniques. Baseline structural MRI data from a cohort of healthy older adults who were followed prospectively for ten years, during which time some developed MCI and some AD, were analysed. It was found that structural MRI could detect volume loss in medial-temporal lobes up to 7-10 years before clinical symptoms of AD appear. In addition, volumetric variability of medial-temporal regions detected by structural MRI across cognitively healthy older adults correlated with their performance on a task of visuospatial associative memory, and functional activation of the same regions occurred during successful performance of the same task on functional MRI (fMRI). Three groups of participants - cognitively healthy controls, people with MCI, and patients with probable AD - were then recruited and underwent a multimodal MRI protocol, which included functional sequences acquired at rest and during the execution of two different cognitive tasks (visuospatial associative memory and self-appraisal). Cross-sectional comparisons showed: (i) that successful visuospatial associative memory performance was associated with increased functional activity (measured with task fMRI) in lateral prefrontal regions in AD patients relative to controls and (ii) that increased functional activity overlapped with frontal brain networks showing increased functional connectivity (measured with resting fMRI) in the same AD patients. Further, by demonstrating group- and condition-specific decreased frontal activity in AD patients relative to controls during a self-appraisal fMRI task, it was shown the specific utility of fMRI to unravel cognitive mechanisms underlying specific neuropsychological symptoms such as unawareness of cognitive impairment (anosognosia) in MCI and AD. In conclusion, structural MRI can detect morphological changes in the preclinical stage of AD, possibly earlier than previously described, and these reliably match cognitive functioning in older adults. In the MCI and AD stages, once symptoms of cognitive impairment are clinically evident and measurable, task-related and resting functional MRI can inform on residual brain function detectable over and above the known changes in brain morphology and cognitive performance that have already occurred at these stages, emerging as a sensitive marker of residual ability that could potentially be used to measure the effect of new treatments.

Hensikt: Hensikten med oppgaven har vært å undersøke om sykepleierapport, epikrise og dagens samhandlingspraksis ved utskrivning fra alderspsykiatrisk spesialisthelsetjeneste oppleves som nyttig av leger og sykepleiere i kommunene. Metode: Tverrsnittsundersøkelse. Et spørreskjema ble utviklet og sendt til 497 leger og sykepleiere. Data ble analysert med både kvalitative og kvantitative metoder Resultat Informantene vurderer innhold i epikrise og sykepleierapport som nyttig for videre arbeid med pasienten. Dokumentene beskrives som grundige, nyttige og informative. Dagens samhandlingspraksis vurderes som nyttig. Ambulante pasientrettede tiltak, deltagelse i møter, pasientrettet undervisning og veiledning vurderes som positive tiltak kommunene ønsker mer av. Medarbeidere i kommunene har i varierende grad erfaring med og kjenn-skap til det tilbudet Seksjon for alderspsykiatri gir. Konklusjon Undersøkelsen viser at samarbeidspartnere i kommunene i Telemark er tilfreds med epikrise, sykepleierapport og dagens samhandlingspraksis. De ønsker enda bedre tilgjengelighet / Aim: This study aimed to examine the opinions of physicians and nurses in the municipalities in Telemark, Norway regarding information given in written reports from the old age psychiatri unit and to examine the usefulness of collaboration when patients leave the hospital. Methods: This study used a cross-sectional survey. A questionnaire was developed and sent to 497 health professionals. The data were analyzed by both qualitative and quantitative methods. Results: Physicians and nurses in the municipalities have different knowledge and experiences regarding the services offered by the old-age psychiatry hospital. They described the reports from the hospital as informative and useful for further treatment of the patient. Collaboration practices were also evaluated as useful. Ambulant examination of patients and participation in meetings, education and guidance were evaluated as positive approaches. Conclusions: Physicians and nurses in the municipalities in Telemark county expressed satisfaction with the information in the reports and the existing collaboration practice when old age psychiatry patients leave the hospital. They want more of the services offered today. / <p>ISBN 978-91-86739-24-9</p>

This thesis investigates rest-activity and sleep profiles in neurodegeneration and brain cancer. Study 1 comprised longitudinal field assessments of rest-activity, sleep and memory in controls and memory-impairment individuals with: subjective memory complaint (SMC), amnestic mild cognitive impairment (aMCI), mild and moderate Alzheimer’s disease (AD). Four questions were addressed: (1) is SMC a prodromal stage of AD? (2) do characteristics of SMC predict future decline? (3) does cholinergic medication (ChEI) impact rest-activity and sleep of moderate AD patients? and (4) are there factors predicting response to ChEI? Study 2 assessed rest-activity and melatonin rhythms in a brain cancer patient (JJB), and post-mortem analysis of brain tissue assessed infiltration of cancer cells on the circadian clock (SCN). Both studies used questionnaires, cognitive tests, electroencephalography and actigraphy simultaneously at patients’ homes. In Study 1, the SMC group showed a reduced activity amplitude to be correlated with increasing memory impairment severity, lower sleep quality and efficiency. Increased sleep fragmentation was observed in all memory-impaired groups, although not correlated to impairment severity. Increased fragmentation of rest-activity rhythm correlated with increasing memory impairment severity in all groups except SMC. Following ChEI medication with donepezil, moderate AD patients showed increased sleep fragmentation, probably due to potentiation of available acetylcholine known to maintain arousal. Higher daytime-activity and lower activity in the rest-phase, when drug-naïve, predicted improved cognition following ChEIs. In Study 2, cancer cell infiltration of the patient’s SCN was confirmed. However, a robust circadian rest-activity period with a misaligned melatonin phase, was recorded, indicating that the effects of partial SCN lesions in humans are complex and this result was possibly in part are due to the masking effect of social behaviour.

Neurodegeneration is a progressive loss of neuron function or structure, including death of neurons, and occurs at many different levels of neuronal circuitry. In this thesis I discuss Parkinson’s Disease (PD), the second most common neurodegenerative disease (NDD). PD is a devastating progressive NDD often with delayed diagnosis due to detection methods that depend on the appearance of visible motor symptoms. By the time cardinal symptoms manifest, 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra are irreversibly lost. Although there is currently no cure, earlier detection would be highly beneficial to manage treatment and track disease progression. However, today’s clinical diagnosis methods are limited to subjective evaluations and observation. Onset, symptoms and progression significantly vary from patient to patient across stages and subtypes that exceed the scope of a standardized diagnosis. The goal of this thesis is to provide the basis of a more general approach to study the brain, investigating early detection method for NDD with focus on PD. It details the preliminary development, testing and validation of tools and methods to objectively quantify and extrapolate motor and non-motor features of PD from behavioral and cognitive output during everyday life. Measures of interest are categorized within three domains: the motor system, cognitive function, and brain activity. This thesis describes the initial development of non-intrusive tools and methods to obtain high-resolution movement and speech data from everyday life and feasibility analysis of facial feature extraction and EEG for future integration. I tested and validated a body sensor system and wavelet analysis to measure complex movements and object interaction in everyday living situations. The sensor system was also tested for differentiating between healthy and impaired movements. Engineering and design criteria of the sensor system were tested for usability during everyday life. Cognitive processing was quantified during everyday living tasks with varying loaded conditions to test methods for measuring cognitive function. Everyday speech was analyzed for motor and non-motor correlations related to the severity of the disease. A neural oscillation detection (NOD) algorithm was tested in pain patients and facial expression was analyzed to measure both motor and non-motor aspects of PD. Results showed that the wearable sensor system can measure complex movements during everyday living tasks and demonstrates sensitivity to detect physiological differences between patients and controls. Preliminary engineering design supports clothing integration and development of a smartphone sensor platform for everyday use. Early results from loaded conditions suggest that attentional processing is most affected by cognitive demands and could be developed as a method to detect cognitive decline. Analysis of speech symptoms demonstrates a need to collect higher resolution spontaneous speech from everyday living to measure speech motor and non-motor speech features such as language content. Facial expression classifiers and the NOD algorithm indicated feasibility for future integration with additional validation in PD patients. Thus this thesis describes the initial development of tools and methods towards a more general approach to detecting PD. Measuring speech and movement during everyday life could provide a link between motor and cognitive domains to characterize the earliest detectable features of PD. The approach represents a departure from the current state of detection methods that use single data entities (e.g.one-off imaging procedures), which cannot be easily integrated with other data streams, are time consuming and economically costly. The long-term vision is to develop a non-invasive system to measure and integrate behavioral and cognitive features enabling early detection and progression tracking of degenerative disease.