Göran Hagman

PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps<0.01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease

The effects of (−)‐phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimers disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

Summary Background Nutrition is an important modifiable risk factor in Alzheimers disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimers disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimers disease. Here, we report the 24-month results of the trial. Methods LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimers disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Findings Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. Interpretation The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimers disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. Funding European Commission 7th Framework Programme.

Midlife Work-Related Stress Increases Dementia Risk in Later Life: The CAIDE 30-Year Study

Objective To investigate the associations between midlife work-related stress and mild cognitive impairment (MCI), dementia, and Alzheimers disease later in life, in a large representative population. Method Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50 years). A random sample of 2,000 individuals was invited for two reexaminations including cognitive tests (at mean age 71 and mean age 78), and 1,511 subjects participated in at least one reexamination (mean follow-up 28.5 years). Work-related stress was measured using two questions on work demands that were administered in midlife. Analyses adjusted for important confounders. Results Higher levels of midlife work-related stress were associated with higher risk of MCI (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.08-1.76), dementia (OR, 1.53; CI, 1.13-2.07), and Alzheimers disease (OR, 1.55; CI, 1.19-2.36) at the first follow-up among the CAIDE participants. Results remained significant after adjusting for several possible confounders. Work-related stress was not associated with MCI and dementia during the extended follow-up. Discussion Midlife work-related stress increases the risk for MCI, dementia, and Alzheimers disease in later life. The association was not seen after the extended follow-up possibly reflecting selective survival/participation, heterogeneity in dementia among the oldest old, and a critical time window for the effects of midlife stress.

Abnormal platelet amyloid-β protein precursor (AβPP) metabolism in Alzheimer's disease: identification and characterization of a new AβPP isoform as potential biomarker.

Previous findings demonstrated an altered pattern of amyloid-β protein precursor (AβPP) expression in platelets of Alzheimers disease (AD) patients compared with either healthy control subjects or patients with non-Alzheimer-type dementia. In an attempt to explore the diagnostic potential of platelet AβPP metabolism, we have generated monoclonal antibodies directed to the N-terminal part of AβPP. We have observed two different antibody recognition patterns of AβPP: one resembling previously described 130 kDa and 105 kDa species and a novel AβPP 115 kDa form. This form was significantly increased in platelets of the mild cognitive impairment and AD group as compared to control subjects. The abundance of AβPP 115 kDa species correlated with the previously described AβPP 130/105 kDa ratio as well as with Mini-Mental State Examination score. Despite the inability of these particular monoclonal antibodies to recognize native forms of AβPP, identification of a new AβPP isoform in platelets as a potential AD biomarker can provide an additional tool for the development of a reliable diagnostic test to detect preclinical stages of AD.

A SLC20A2 gene mutation carrier displaying ataxia and increased levels of cerebrospinal fluid phosphate

Mutations in the SLC20A2 gene, encoding type III sodium-dependent phosphate transporter 2 (PiT-2), are themost common cause of primary familial brain calcifications (PFBC) [1,2]. The R467X mutation in SLC20A2 has been described only once in a young Japanese male with paroxysmal kinesigenic dyskinesia (PKD) responsive to carbamazepine [3]. This males mother was asymptomatic despite the presence of brain calcifications. Here we describe a Swedish 54 year-old female with symmetric brain calcifications affected by dementia, ataxia and supranuclear palsy (SNP). Her medical history consists of type 1 diabetes mellitus (T1DM)with poor glycemic control and complications (polyneuropathy and retinopathy), hypertension, obstructive sleep apnea (OSA) and cataracts. During childhood shewent through surgery for goiter. Her father was affected by tremor but was not available for evaluation. At age 42 insidious onset of personality change, impaired memory and a gait disorder was noticed. Her work performance as a nurse was questioned and she was dismissed from three jobs during the two years prior to evaluation. The patient became irritable and restless; these symptoms worsened at age 50 after an episode of diabetic ketoacidosis due to insulin pump malfunction. In addition to insulin, the patient was treated with metoprolol, felodipine and losartan. During the course of disease she reported persecutory delusions from time to time and lacked insight regardingher symptoms. These delusionswere somewhat responsive to reassurance; due to her unfavorablemetabolic profilewe refrained from treatment with neuroleptics. A CT-scan at age 50 revealed widespread and severe calcifications in the frontal and occipital cortex, basal ganglia, thalamus, cerebellum and midbrain including the substantia nigra (Figs. 1 and e-1). Her total calcification score (TCS)was 55 and remained unchanged 3 years later. Since age 53 the patient has been urine incontinent. Using coregistration, however [4], we found progression of brain calcifications in the cerebellum and thalamus (Tables e-1 and e-2). In addition, brain MRI demonstrated white matter hyperintensities outside of the calcified areas (Fig. e-2). Predominant gait ataxia, foot dystonia and SNP were evident at age 51 (Video). Her SARA score at age 51 was 5.5 and two years later 7.5. Significant impairment in executive functions, attention and working memory compatible with subcortical

Mid-life work-related stress increases dementia risk in late-life: The caide 30-year study

Background: The associations between work-related stress and various health outcomes in mid-life are well documented, yet less is known about the effects on late-life cognitive process and dementia. The current study investigated the associations between work-related stress in mid-life and the development of cognitive impairment and Alzheimer’s disease in late-life. Methods: The data was derived from the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) study; a prospective cohort study. Participants were randomly selected from four independent population-based samples that completed cardiovascular surveys. First baseline examinations occurred when participants were 50 years old on average, in 1972, 1977, 1982, or 1987. A random sample of 2,000 individ- uals was selected for re-examinations (carried out in 1998 and 2005-2008), where 1,511 subjects participated in at least one re-examination. The re- examinations included an extensive neuropsychological and cognitive assessment. Follow-up time was on average 28 (S.E.M. 1⁄4 0.17) years. Work-related stress comprised the total score of two questions adminis- tered in mid-life. The questions asked participants to rate their stress related to meeting demands at work, and constant hurry at work. Groups were categorized so that those with high or medium levels of stress were compared to those with low levels or no work-related stress. Results: High levels of work-related stress in mid-life were associated with higherrisk of cognitive impairment (where participants with cognitive impair- ment and dementia were compared to the group with no cognitive impair- ment) [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.1-2.1], and Alzheimer’s disease [OR, 2.1; CI, 1.1-3.9], when assessed at the first or second follow-up. Results remained significant after adjusting for age, ed- ucation, marital status, chronic health conditions, apolipoprotein E e 4 allele (APOE e 4), measures of hopelessness and loneliness. Conclusions: High levels of mid-life work-related stress predict the risk of developing dementia in late-life. The evidence suggests that individuals experiencing high levels of work-related stress form an important at-risk population. Preventive interventions are needed for this population in order to post- pone or prevent the development of cognitive impairment and Alzheimer’s disease.

Slow alpha background activity in EEG is a prevalent finding in memory clinic populations and related to biological markers and vascular lesions

cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Results: 31.5% of survivors (N 1⁄4 412) dropped-out. The cognitive function of the subjects declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances was linear. Neither of them showed regional differences. The functional decline tended to progress more rapidly in Southern Europe (p 1⁄4 0.09). The progression of caregiver burden was most rapid in Northern Europe (5.6 pts/y, p 1⁄4 0.04). The incidences of hospital admission (10.44, 95%CI: 13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe.Conclusions: Cognitive and functional decline in AD under AChE-I treatment was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden. For the first time, geographical reference data are given on AD progression in Europe.

Midlife hopelessness and white matter lesions two decades later: A population-based study

Background: Hopelessness has been associated with increased cardiovas- cular disease mortality and morbidity, subclinical atherosclerosis and meta- bolic syndrome. This study investigates the relation between midlife hopelessness and white matter lesions (WMLs) 20 years later in a Finnish population of men and women. Methods: Participants of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland were derived from random, population-based samples previously surveyed in 1972,1977, 1982 or 1987. In 1998, 1449 (73%) individuals aged 65-79 years participated in the re-examination. A subgroup (n1⁄4112, including 39 dementia cases, 31 mild cognitive impairment (MCI) cases and 42 con- trols) underwent 1.5T MRI scanning at re-examination, and WMLs were as- sessed from FLAIR-images using a semi-quantitative visual rating scale. Hopelessness was measured by 2 questionnaire items (expectations about future and reaching goals). Results: Subjects with increased hopelessness had a significantly higher risk of developing more severe WMLs two de- cades later. OR (95% CI) was 4.35 (1.36-13.46) in ordinal regression anal- yses adjusted for age, sex education, follow-up time, presence of the APOEe4 allele, systolic blood pressure, BMI, history of stroke, heart infarct, smoking and level of midlife leisure physical activity. Conclusions: Higher levels of hopelessness at midlife seem to be related to more severe WMLs later in life. Since WMLs may contribute to late-life cognitive impairment, lifestyle management of midlife vascular risk factors (which also increase the risk of dementia and cognitive impairment) may have better effects if people’s expectations are more thoroughly discussed.

P2-303: Amyloid depositions in MCI-patients studied with PIB-PET

Anton Forsberg, Henry Engler, Gunnar Blomquist, Ove Almkvist, Göran Hagman, Anders Wall, Anna Ringheim, Bengt Långström, Agneta Nordberg, Karolinska Institutet, Neurotec Department, Stockholm, Sweden; Uppsala University Hospital, Uppsala, Sweden; Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden; Department of Geriatric Medicine Karolinska University Hospital Huddinge, Stockholm, Sweden; Uppsala Imanet AB, Imanet, GE Healthcare, Uppsala, Sweden; Department of Organic Chemistry, Uppsala University, Uppsala, Sweden. Contact e-mail: anton.forsberg@ki.se