Dementia is a clinical state caused by neurodegeneration and characterized by a loss of function in cognitive domains and behavior. Alzheimer’s disease (AD) is the most common form of dementia. Although the amyloid β (Aβ) protein and hyperphosphorylated tau aggregates in the brain are considered to be the key pathological hallmarks of AD, the exact cause of AD is yet to be identified. In addition, clinical diagnoses of AD can be error prone. Many previous studies have compared the clinical diagnosis of AD against the gold standard of autopsy confirmation and shown substantial AD misdiagnosis Hippocampal sclerosis of aging (HS-Aging) is one type of dementia that is often clinically misdiagnosed as AD. AD and HS-Aging are controlled by different genetic architectures. Familial AD, which often occurs early in life, is linked to mainly mutations in three genes: APP, PSEN1, and PSEN2. Late-onset AD (LOAD) is strongly associated with the ε4 allele of apolipoprotein E (APOE) gene. In addition to the APOE gene, genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in or close to some genes associated with LOAD. On the other hand, GRN, TMEM106B, ABCC9, and KCNMB2 have been reported to harbor risk alleles associated with HS-Aging pathology. Although GWAS have succeeded in revealing numerous susceptibility variants for dementias, it is an ongoing challenge to identify functional loci and to understand how they contribute to dementia pathogenesis. Until recently, rare variants were not investigated comprehensively. GWAS rely on genotype imputation which is not reliable for rare variants. Therefore, imputed rare variants are typically removed from GWAS analysis. Recent advances in sequencing technologies enable accurate genotyping of rare variants, thus potentially improving our understanding the role of rare variants on disease. There are significant computational and statistical challenges for these sequencing studies. Traditional single variant-based association tests are underpowered to detect rare variant associations. Instead, more powerful and computationally efficient approaches for aggregating the effects of rare variants have become a standard approach for association testing. The sequence-kernel association test (SKAT) is one of the most powerful rare variant analysis methods. A recently-proposed scan-statistic-based test is another approach to detect the location of rare variant clusters influencing disease. In the first study, we examined the gene-based associations of the four putative risk genes, GRN, TMEM106B, ABCC9, and KCNMB2 with HS-aging pathology. We analyzed haplotype associations of a targeted ABCC9 region with HS-Aging pathology and with ABCC9 gene expression. In the second study, we elucidated the role of the non-coding SNPs identified in the International Genomics of Alzheimer’s Project (IGAP) consortium GWAS within a systems genetics framework to understand the flow of biological information underlying AD. In the last study, we identified genetic regions which contain rare variants associated with AD using a scan-statistic-based approach.

Abstract Older adults with complex memory problems benefit when they have the opportunity to consult with a specialist for a comprehensive cognitive assessment. Specialists such as geriatricians, psychogeriatricians or neurologists often work in major cities or large metropolitan towns. Travelling to see a specialist either alone or with a carer is complicated for an older person because of medical issues or disability. The use of videoconferencing may provide a way to link a specialist with a patient without the need for the patient, or the specialist, to travel long distances. Two literature reviews were carried out. The initial review identified studies of the diagnosis of cognition via telemedicine. Thirty-two studies were identified which assessed cognition via telephone or video conference. The focus of the study was either the administration of a standardised cognitive assessment tool (n=30) or an unstructured comprehensive cognitive assessment interview (all via video conference) (n=2). The sample sizes were small but the levels of agreement were high, suggesting that further work in this area may identify that diagnosis of dementia via video conference is reliable. There has been limited work in the area of diagnostic agreement when a specialist is assessing a patient for the first time via video conference, even less work in the area of mental health assessment of older people. The second literature review identified 19 studies of diagnostic agreement using video conference with a sample size of 20 or more. The fields of research were: Dermatology (n=10); Mental Health (n=4); Minor Injuries (n=2); Neurology (n=2); and Rheumatology (n=1). Of the four studies in the area of mental health, one focused on the diagnosis of dementia with the publication of a protocol for assessing Alzheimer’s disease (AD) via video conference. The review highlighted that diagnosis via video conference in other medical fields had been shown to be reliable but that limited work was evident regarding the reliability of diagnosing dementia via video conference. A range of statistical analyses have been used to measure agreement in studies of diagnosis via VC. Overall Proportional Agreement (Po) and Cohen’s kappa (K) are the two most common calculations. There was little uniformity of reporting in the studies identified in the literature review. The variation in reporting made it difficult to compare results or provide data for a meta-analysis of similar studies. Consideration of the methods for analysing diagnostic agreement was undertaken using the approaches identified in the literature review as a starting point. The aim of this research was to identify if a diagnosis of the presence of dementia in an older adult by a specialist is reliable when the assessment interview occurs via video conference. A pilot study was carried out prior to the implementation of a National Health and Medical Research Council (NHMRC) funded multi-site project to test inter-rater agreement for the diagnosis of dementia and subsidiary questions. The candidate is a Chief Investigator (CI) on the NHMRC project grant and participated in writing the grant submission. A pilot study was completed for the purpose of refining the research protocol and establishing preliminary data for the calculation of sample size. A geriatrician carried out a cognitive assessment via video conference with the patient and the carer. The doctor had access to the patient’s chart and the results of a battery of standardised cognitive assessments administered face-to-face (FTF) by the clinic nurse earlier in the day. A second interview was carried out, face-to-face, by a second doctor on the same day. Inter-rater reliability was assessed between doctors. To place the level of agreement in context, inter-rater reliability between paired face-to-face assessments was also measured. Forty-two participants were divided into two groups: paired face-to-face assessments (FF, n=22) or paired video conference and face-to-face assessments (FV/VF, n=20). Twenty-two participants were male. Their average age was 70 years (SD=11.1, Range 50-90). The mean Standardised Mini-Mental State Examination (SMMSE) score was 23.93 (SD=5.42, Range 8-30)[1]. The outcome of agreement was measured using PO and Cohen’s K. FF group (PO=0.636; K=0.430, p=0.005) and the FV/VF group (PO=0.650; K=0.650, p=0.004) showed similar levels of agreement. The main study was a non-inferiority, prospective cohort study following a similar format as the pilot. Patients were randomised to two groups. The first group participated in two interviews; one via VC, the other was face-to-face (FV/VF). The second group was subjected to dual face-to-face assessments (FF). The video conference interview consisted of real-time video conference with the doctor interacting with both the carer and the patient. A battery of standardised assessments, a medical history, imaging and blood tests were prepared before hand and available to the doctor for use in the interview. One hundred and fifty-five participants were divided into two groups: paired face-to-face assessments (FF, n=73) or paired video conference and face-to-face assessments (FV or VF, n=82). Seventy-five of the participants were male. The average age was 76-years (SD=9, Range 54-95). The mean SMMSE was 23.8 (SD=4.4, Range 8-30). Overall proportional agreement (Po) and Weighted K were calculated as a measure of agreement for the presence of dementia. The FF group (Po=0.740; K=0.57, p<0.0001) and the FV/VF group (Po=0.780; K=0.64, p<0.0001) showed similar levels of agreement. Using the same study cohort, additional data were collected to identify the significance of the physical examination (PE) for diagnosing dementia. One of two doctors was allocated the task of completing a physical examination of the patient following initial assessment interview and after the diagnosis decisions had been recorded. Following the physical examination a second record of diagnosis decisions were recorded by the same doctor. The doctor was asked to identify if the diagnosis, formulation, treating options or additional investigations had altered as a result of the in-person physical examination. The physical examination supported clarity of the diagnosis particularly if a vascular element was involved. This dissertation provides evidence of the reliability of a diagnosis of dementia obtained via video conference. Furthermore, the work detailed in this dissertation represents the largest international study on assessing diagnostic accuracy of cognition and makes a significant contribution to the work in telemedicine in the area of mental health. This dissertation provides generalisations that can impact the use of video conference for diagnosis across a range of specialities, with the ultimate goal of improving access to specialist advice for people living in rural areas.

<p>Sammanfattning Syftet med studien var att beskriva anhörigas upplevelser av att leva tillsammans med eller i närheten av en person som har drabbats av Alzheimers sjukdom. Studien utgick från ett socialt, fysiskt och psykiskt perspektiv. Studien byggde på 18 vetenskapliga artiklar som kvalitet granskades med hjälp av en granskningsmall. Artiklar söktes genom databaserna Academic Search Elite, Cinahl och Vård I Norden Online. Urvalskriterierna var att artiklarna svarade på studiens syfte, var skrivna på svenska eller engelska och publicerade mellan åren 2000 till 2008. Resultatet visade att anhöriga ställs inför en dramatisk förändring som är krävande, utmanande och de anhöriga upplevde oro, sorg, stress och skuld. Det sociala nätverket minskade och det leder oftast till ensamhet och isolering. Resultatet visade också att anhöriga är i behov av stöd från släkt och vänner samt från hälso- och sjukvården. Sammanfattningsvis upplevde majoriteten av anhöriga en ökad belastning av att vara anhörig till en person med Alzheimers sjukdom.</p><p>Nyckelord: Alzheimers sjukdom, familj, anhöriga, upplevelser.</p> / <p>Abstract The aim of the study was to describe relative’s experiences of living with or near a person that has Alzheimer’s disease. The study builds on social, physical and psychic perspectives. The studies were based on 18 scientific articles that were quality checked with the aid of a review model. Articles were applied for through the databases Academic Search Elite, Cinahl and Vård I Norden Online. The selection criteria’s were that the articles replied on the study's aim, were written on Swedish or English and published between the years 2000 to 2008. The result showed that relatives were set to a dramatic change that were requiring, challenging and the relatives experienced dread, sorrow, stress and debt. The social network decreased and the result was often decreased loneliness and isolation. The result also showed that the relatives were in need of aid from family and friends, and from the healthcare. To summary the majority experienced that the burden increased of being relatives to a person with Alzheimer’s disease.</p><p>Keywords: Alzheimer’s disease, family, relatives, experience.</p>

<p>Elderly committing suicide can be in a “preclinical phase” of dementia. Depressive symptoms may indicate a risk to develop a disease of dementia, for example Alzheimer’s Disease. Today almost 10% of the Swedish population older than 65 years suffer from a cognitive impairment diagnosed as dementia. Symptoms of dementia are associated with degenerative changes in the brain caused by a deposition of amyloid, leading among others things to a nerve cell death. A clinical diagnosis can be hard to set, and a definitive diagnose can only be set after a pathological examination, which only is possible after death. For this study we used Congo red staining of brains sections to find amyloid in autopsies from elderly people committing suicide. 35 cases (>60 year) were studied. Of the 35 cases 1/3 showed to be positive for amyloid deposition. This result in addition to other studies suggest that depressive symptoms is a “preclinical phase” of dementia, and therefore the suicide risk for this group must be consider to be elevated. However, more reliable prospective studies most be done to confirm this retrospective study.</p>

Identification of modifiable risk factors for Alzheimer’s disease (AD) is crucial in order to diminish suffering from this devastating disease. The aim of this thesis was to investigate if different aspects of glucose metabolism, insulin, fatty-acid composition or other vascular risk factors predict the future development of AD and dementia. This thesis is based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, which started in 1970. A total of 2322 men at age 50 were examined with focus on vascular risk factors. The cohort was re-examined at ages 60, 71, 77, 82 and 88. Incident diagnoses of AD, vascular dementia, other dementias and cognitive impairment were assessed in 2005–2010. The risk of AD was increased in subjects with lower early insulin response measured with both an intravenous glucose tolerance test at 50 years and an oral glucose tolerance test at 71 years of age. The presence of vascular risk factors such as hypertension, obesity, hypercholesterolemia and smoking increased the risk of future vascular dementia but not of AD. Furthermore, saturated fatty acids at midlife were inversely associated with risk of AD. No evidence of a protective effect of omega-3 fatty acids against dementia was found. The susceptibility allele, APOE ε4, was the strongest individual risk factor. APOE ε4 carriers with vascular risk factors had the greatest risk of developing dementia. Low insulin response was a risk factor for AD mainly in APOE ε4 non-carriers. Disturbances in insulin and glucose metabolism, vascular risk factors and fatty acids are linked differentially to the pathogenesis of AD and vascular dementia. These observations should be considered when future clinical approaches are planned to prevent and postpone the onset of dementia. / ULSAM

The present study evaluated olfactory and cognitive abilities of the Tg6799 (also called 5xFAD) strain of Alzheimer’s disease (AD) model mice of two different age groups (2-3 and 8-10 months of age), and one group of healthy control mice (9-10 months). Employment of an operant conditioning paradigm using an automated olfactometer, an olfactory habituation/dishabituation test and a spatial learning test with non olfactory cues resulted in data showing that the 5xFAD mice develop olfactory impairments already at 2-3 months of age. The impairments consisted in a robust impairment in olfactory sensitivity, decreased responsiveness to novel odors and an inability to discriminate between enantiomeric odor molecules in the 5xFAD mice compared to control mice. Spatial learning deficits were also detected at this age, suggesting that cognitive functions were also affected. No differences in magnitude of the olfactory or spatial learning impairments could be detected between the age groups of model mice tested. Histological examination of development and presence of amyloid β (Aβ) plaques in the brains showed that plaques develop mainly between the ages of 3 and 8 months. This indicates that soluble Aβ rather than the formation of plaques might be responsible for the olfactory impairment and spatial learning impairments found. By 10 months of age plaque load of the 5xFAD mice was massive. The results of the present study clearly show that the 5xFAD strain might be suitable for research on human AD with regard to the early onset of olfactory impairments.

The pathogenesis of Alzheimer’s disease (AD), the most common senile dementia, is a complex process. A crucial event in AD is the aggregation of amyloid-β protein (Aβ), a cleavage product from the Amyloid Precursor Protein (APP). Aβ40, a common component in amyloid plaques found in patients, aggregates in vitro at concentrations, much higher than the one found in vivo. But in the presence of charged lipid membranes, aggregations occurs at much lower concentration in vitro compared to the membrane-free case. This can be understood due to the ability of Aβ to get electrostatically attracted to target membranes with a pronounced surface potential. This electrostatically driven process accumulates peptide at the membrane surface at concentrations high enough for aggregation while the bulk concentration still remains below threshold. Here, we elucidated the molecular nature of this Aβ-membrane process and its consequences for Aβ misfolding by Circular Dichroism Spectroscopy, Differential Scanning Calorimetry and Nuclear Magnetic Resonance Spectroscopy. First, we revealed by NMR that Aβ40 peptide does indeed interact electrostatically with membranes of negative and positive surface potential. Surprisingly, it even binds to nominal neutral membranes if these contain lipids of opposite charge. Combined NMR and CD studies also revealed that the peptide might be shielded from aggregation when incorporated into the membrane. Moreover, CD studies of Aβ40 added to charged membranes showed that both positively and negatively membranes induce aggregation albeit at different kinetics and finally that macromolecular crowding can both speed up and slow down aggregation of Aβ.

Alzheimers sjukdom påverkar både patienten och den som vårdar honom eller henne. En anhörig vårdar ofta patienten och det har visat sig att de är utsatta för olika svårigheter.  Syftet med denna studie var att beskriva anhörigas upplevelser av att vårda en familjemed­lem med Alzheimers sjukdom. Metoden som användes för att besvara syftet var att göra en litteraturstudie enligt Polit och Becks (2004) beskrivning av genomförandet av en litteratur­studie. Dataanalysen skedde med kvalitativ ansats genom att artiklarna lästes igenom nog­grant och gemensamheter och mönster bland anhörigvårdares upplevelser söktes. Studiens resultat baserades på åtta veten­skapliga artiklar från vilka fem teman framkom. Resultatet visade att många anhörigvår­dare upplevde en förlust av relationer. De saknade relationen både med patienten och med vänner. De tyckte även att det var viktigt att ha fritid och tid för sig själva, vilket ofta var svårt att åstadkomma. Viljan till att söka ny kunskap blev stor när de tog på sig rollen som anhörigvårdare, och många upplevde olika lidanden och besvär såsom skuld och de­pression. Upplevelserna i resultatet åskådliggjorde att en stor del av de anhöriga inte kände välbefinnande. Detta resultat pekar på vikten av att sjuksköterskor är medvetna om de upplevelser och känslor anhörigvårdare har. / Alzheimer’s disease afflicts both the patient and the person caring for him or her. A relative often provides care for the patient and it appears as though they are exposed to different adversities. The aim of this study was to describe the experiences of relatives which care for a family member suffering from Alzheimer’s disease. The method used to answer the aim was to do a literature review by using Polit and Becks (2004) description of how to make a literature review. The data analysis was made with a qualitative approach by reading the articles accurately and patterns among the experiences family caregivers have been sought. The results of the study are based on eight scientific articles. Five themes emerged from these articles. The results show that many family caregivers experienced a loss of relationships. They missed the relationship with the patient as well as the relationship with friends. They also thought that it was important to have leisure, which often is hard to accomplish. The desire to seek for new knowledge became large when they became family caregivers, and many of them experienced different sufferings and troubles such as guilt and depression. The results show that many of the relatives did not experience well-being. On account of this it is important that nurses know about the experiences and feelings family caregivers have.

Elderly committing suicide can be in a “preclinical phase” of dementia. Depressive symptoms may indicate a risk to develop a disease of dementia, for example Alzheimer’s Disease. Today almost 10% of the Swedish population older than 65 years suffer from a cognitive impairment diagnosed as dementia. Symptoms of dementia are associated with degenerative changes in the brain caused by a deposition of amyloid, leading among others things to a nerve cell death. A clinical diagnosis can be hard to set, and a definitive diagnose can only be set after a pathological examination, which only is possible after death. For this study we used Congo red staining of brains sections to find amyloid in autopsies from elderly people committing suicide. 35 cases (&gt;60 year) were studied. Of the 35 cases 1/3 showed to be positive for amyloid deposition. This result in addition to other studies suggest that depressive symptoms is a “preclinical phase” of dementia, and therefore the suicide risk for this group must be consider to be elevated. However, more reliable prospective studies most be done to confirm this retrospective study.

Sammanfattning Syftet med studien var att beskriva anhörigas upplevelser av att leva tillsammans med eller i närheten av en person som har drabbats av Alzheimers sjukdom. Studien utgick från ett socialt, fysiskt och psykiskt perspektiv. Studien byggde på 18 vetenskapliga artiklar som kvalitet granskades med hjälp av en granskningsmall. Artiklar söktes genom databaserna Academic Search Elite, Cinahl och Vård I Norden Online. Urvalskriterierna var att artiklarna svarade på studiens syfte, var skrivna på svenska eller engelska och publicerade mellan åren 2000 till 2008. Resultatet visade att anhöriga ställs inför en dramatisk förändring som är krävande, utmanande och de anhöriga upplevde oro, sorg, stress och skuld. Det sociala nätverket minskade och det leder oftast till ensamhet och isolering. Resultatet visade också att anhöriga är i behov av stöd från släkt och vänner samt från hälso- och sjukvården. Sammanfattningsvis upplevde majoriteten av anhöriga en ökad belastning av att vara anhörig till en person med Alzheimers sjukdom. Nyckelord: Alzheimers sjukdom, familj, anhöriga, upplevelser. / Abstract The aim of the study was to describe relative’s experiences of living with or near a person that has Alzheimer’s disease. The study builds on social, physical and psychic perspectives. The studies were based on 18 scientific articles that were quality checked with the aid of a review model. Articles were applied for through the databases Academic Search Elite, Cinahl and Vård I Norden Online. The selection criteria’s were that the articles replied on the study's aim, were written on Swedish or English and published between the years 2000 to 2008. The result showed that relatives were set to a dramatic change that were requiring, challenging and the relatives experienced dread, sorrow, stress and debt. The social network decreased and the result was often decreased loneliness and isolation. The result also showed that the relatives were in need of aid from family and friends, and from the healthcare. To summary the majority experienced that the burden increased of being relatives to a person with Alzheimer’s disease. Keywords: Alzheimer’s disease, family, relatives, experience.