Nils-Olof Hagnelius

A Novel Panel of Cerebrospinal Fluid Biomarkers for the Differential Diagnosis of Alzheimer’s Disease versus Normal Aging and Frontotemporal Dementia

Background: An early and accurate diagnosis of Alzheimer’s disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. Methods: Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. Results: We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. Conclusion: A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.

CSF/Serum Folate Gradient: Physiology and Determinants with Special Reference to Dementia

Background: Folate depletion has been implicated as a risk factor for neurodegenerative disorders. We hypothesized that transport of folate to the cerebrospinal fluid (CSF) compartment could be involved in the pathophysiology of these disorders. Methods: The CSF/serum folate gradient (RCSF/S) was studied in 205 subjects with suspected cognitive disorder. Its relation to clinical and biochemical indices, including the integrity of the blood-CSF barrier, were characterized. Results: In subjects who were diagnosed as nondemented (ND) the mean RCSF/S ± SD was 2.46 ± 0.62 versus 2.09 ± 0.67 (p = 0.008) in the dementia subgroup with a vascular component (VaD + mixed). The ND subgroup had higher CSF folate (p = 0.001) and lower serum homocysteine values (p = 0.001) than the VaD + mixed subgroup. The folate gradient RCSF/S was negatively correlated with serum folate (p < 0.001, R2 = 0.518) and to the albumin ratio, a blood-CSF barrier biomarker (β = –0.235). The Alzheimer patients had RCSF/S and albumin ratios similar to the ND subjects. Conclusion: The RCSF/S was significantly lower in the VaD + mixed dementia subgroup, suggestive of a defect in the transport of folate over the choroid plexus that seems to be characteristic of, and limited to, the VaD + mixed dementia subgroup.

Relative telomere length in patients with late-onset Alzheimer's dementia or vascular dementia.

Telomeres generally shorten with age. An accelerated shortening of the telomeres has been linked to several age-related disorders. We hypothesized that the relative length of telomeres could discriminate between patients with late-onset Alzheimers disease (AD) and vascular dementia (VaD). A quantitative real-time PCR method was used to calculate the relative telomere length in 76 age-matched and sex-matched, newly diagnosed late-onset AD or VaD patients recruited from our Memory Unit. No significant difference was found in the relative telomere length between AD and VaD cases neither in men (P=0.315) nor women (P=0.12). Thus, we could not confirm that the length of telomeres would predict which form of dementia, late-onset AD or VaD that develops.

Subjective well-being in Swedish active seniors or seniors with cognitive complaints and its relation to commonly available biomarkers

Well-being (WB) is a complex variable in its relation to physical health and other personal and social characteristics. The aim was to study subjective well-being (SWB) and its possible associations with traditional biomarkers of cardiovascular risk or dementia, in Swedish seniors. SWB was estimated by the Psychological General Well-Being (PGWB) index in two study groups. The active seniors (AS) group consisted of community-dwelling elderly Swedes leading an active life (n=389). The DGM cohort (n=300) consisted of subjects referred to the Memory Unit at the Department of Geriatrics, the cognitive problems had to be subjective, mild or moderate (MMSE≥10). There were differences in all six subdimensions of SWB or distress, and in the sum of PGWB scores, between the two study groups (p<0.001 for all), and adjustment for differences in biomarkers of somatic health (age, sex, blood pressure, BMI, HDL cholesterol, ApoB/ApoA1 ratio, creatinine, and homocysteine) did not attenuate these differences. In addition, cognition as assessed by the Clock-Drawing Test (CDT) showed independent associations with four of the PGWB subdimensions and with the PGWB sum. Among the subjects in the DGM cohort, SWB was equally low among subjects with an MCI (minor cognitive impairment) diagnosis or without a dementia diagnosis as among subjects diagnosed with dementia disorder. We conclude that the nosological grouping variable (AS vs. DGM cohort) and a cognitive factor were the main independent predictors of SWB in this sample of elderly Swedes, whereas biomarkers of somatic health played a subordinated role.

Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia - a case-referent study.

Fibrinolysis and von Willebrand factor in Alzheimers disease and vascular dementia - a case-referent study.

Blood Concentrations of Homocysteine and Methylmalonic Acid among Demented and Non-Demented Swedish Elderly with and without Home Care Services and Vitamin B(12) Prescriptions

Background and Aims: Total plasma homocysteine (tHcy) has been suggested as a risk factor of dementia. Our aim was to investigate potential differences in tHcy status in relation to the prescription of vitamin B12 and dementia diagnosis. We examined whether vitamin B12 prescriptions, a family history of dementia, or the need for home care service might be associated with tHcy values. Methods: A cross-sectional monocenter study comprising 926 consecutive subjects attending our Memory Care Unit was conducted. Results: Demented subjects being prescribed vitamin B12 had higher serum vitamin B12 (p = 0.025) but also higher tHcy (p < 0.001) and serum methylmalonate (p = 0.032), and lower serum folate (p < 0.001) than those who did not receive vitamin B12 prescriptions. tHcy levels were significantly higher in non-demented subjects receiving home care service (p = 0.007). This group also had lower serum albumin (dementia: p < 0.001; non-dementia: p = 0.004). There was no difference in renal function (estimated glomerular filtration rate) in demented or non-demented subjects with or without vitamin B12 prescriptions (dementia with/without vitamin B12 prescription: p = 0.561; non-dementia with/without vitamin B12 prescription: p = 0.710). Conclusion: Despite vitamin B12 prescriptions, demented subjects had higher tHcy and methylmalonate values. The elevated metabolite values could not be explained by differences in renal function. Thus, elderly subjects on vitamin B12 prescription appear to have unmet nutritional needs.

Novel biomarkers for the differential diagnosis of Alzheimer's disease and vascular dementia

Background: Alzheimer’s disease (AD) is the most common form of dementia found in all human populations worldwide, vascular dementia (VaD) is the second most common form of dementia. New biomarkers for early and specific diagnosis of AD and VaD are needed to achieve greater insight into changes occurring in the brain and direct therapeutic strategies. The objective of this study was to develop a multi-marker protein based test for early, differential diagnosis of AD and VaD that improves on the performance of current assays employing single biochemical markers. Methods: Dementia diagnoses and differential diagnoses were made using DSM-IV and ICD-10 criteria. Surface Enhanced Laser Desorption/Ionization (SELDI) TOF-MS was used to differentially profile proteins and peptides in CSF samples from 28 AD patients and 21 patients with VaD. Results: A total of 19 candidate biomarkers separating AD from VaD were found with ROC values above 0.7. Among them were two truncated forms of Ubiquitin (p1⁄4 0.0001) as well as Chromogranin B and Secretogranin V fragments (p1⁄4 0.0056 and p 1⁄4 0.0038, respectively). A multivariate model combining 5 peaks resulted in a ROC value of 0.835 Conclusions: This novel panel of biomarkers could potentially be used to improve early differential disease diagnosis of AD and VaD as well as provide complementary information to help decision making in the development of disease modifying compounds.