Åke Edman

Neurofilament protein in cerebrospinal fluid: a marker of white matter changes.

The objective of this study was to compare cerebrospinal fluid (CSF) levels of the light subtype of the neurofilament proteins (NFL), tau, and β‐amyloid42 (Aβ42) in individuals with moderate or severe white matter changes (WMC) and in those with mild or no WMC. Twenty‐two patients with Alzheimers disease (AD), nine patients with subcortical vascular dementia (SVD), and 20 normal controls were included in the study. The occurrence of WMC was evaluated by a neuroradiologist using the Blennow‐Wallin scale. Thirty‐seven subjects had no or only punctate WMC; 14 had moderate to severe WMC. Both diagnostic group and WMC, but not gender or apolipoproteinE E4 inheritance, contributed to the variance in the CSF levels of tau, NFL, and Aβ42. In patients with moderate to severe WMC, CSF NFL (P < 0.01), but not CSF tau or CSF Aβ42, was increased also after correction for age, gender, and degree of cognitive impairment. A comparison between patients and controls with any signs of WMC and those without such signs yielded a similar result: CSF NFL (P < 0.001) was increased in the group with signs of WMC. As in numerous previous studies, we found that CSF tau was increased in AD (P < 0.001) compared with controls. Furthermore, CSF NFL was increased in both AD and SVD compared with controls (P < 0.001 for both). Although diagnostic group seems to be a stronger predictor of the variance found in CSF NFL, a clear association between the presence of WMC and increased CSF NFL was found. Because NFL is located mainly in large myelinated axons, increased CSF NFL in individuals with WMC probably reflects axonal degeneration. J. Neurosci. Res. 66:510–516, 2001.

Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years.

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimers disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

Stepwise Comparative Status Analysis (STEP): A Tool for Identification of Regional Brain Syndromes in Dementia

A method for clinical examination of patients with dementia, stepwise comparative status analysis (STEP), is presented. It combines psychiatric and neurologic status examination methods to identify certain common dementia symptoms by which the patients regional brain symptom profile can be determined. Fifty status variables (items) are estimated with respect to occurrence and severity. The analysis is performed in three steps. The scores on the primary variables reflect observations of single dementia symptoms. These scores form the basis for the assessment of the ‘compound’ variables, which in turn form the basis for evaluation of the ‘complex’ variables, one of which describes the patients regional (predominant) brain syndrome (subcortical, frontosubcortical, frontal, frontoparietal, parietal, or global). In 96 mildly and moderately demented inpatients, the global (42%) and frontosubcortical (31%) were the most common. Ninety-one percent of the patients with vascular dementia had a predominant frontal and/or subcortical symptomatology

Two-year outcome of MCI subtypes and aetiologies in the Göteborg MCI study

Objective The objective was to study the 2-year outcome of subjects diagnosed as having mild cognitive impairment (MCI). Methods Two hundred and nine subjects diagnosed as having MCI were examined with a comprehensive neuropsychological test battery and followed up after 2 years. Results After 2 years, 34 subjects (16%) were lost for follow-up. Those subjects did not differ significantly in terms of MCI subclassification, MMSE score or age and education. Of the 175 subjects followed up, eight (4.5%) had improved to normal, two with amnestic MCI, one from multiple domains MCI, three with single domain MCI and two without any significant impairment at baseline. Forty-four subjects (25%) had progressed to dementia. Of these, 35 were from the multidomain amnestic group and nine from the multidomain non-amnestic group. The combination of Alzheimer-typical biomarkers (total-τ and amyloid beta) and multidomain amnestic MCI was the strongest predictor of progression to Alzheimers disease, while vascular disease and multidomain amnestic MCI preceded mixed and vascular dementia. Conclusion The results suggest that memory impairment alone, or impairment in any one cognitive domain alone, is a rather benign condition. Impairment in several cognitive domains is associated with a more severe outcome over 2 years. Also, 20% of the subjects who progressed to dementia, including Alzheimers disease, did not show memory impairment at baseline, which suggests that memory impairment is not always the first symptom of even the most common dementia disorders.

Cerebrospinal Fluid Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Combination with Subcortical and Cortical Biomarkers in Vascular Dementia and Alzheimer's Disease

Alzheimers disease (AD) and vascular dementia (VaD) are intertwined by mixed dementia (MD) harboring varying degrees of AD pathology in combination with cerebrovascular disease. The aim was to assess whether there is a difference in the cerebrospinal fluid (CSF) profile, of selected proteins, between patients with VaD and MD with subcortical vascular disease (SVD), AD, and healthy controls that could contribute in the separation of the groups. The study included 30 controls, 26 SVD patients (9 VaD and 17 MD) and 30 AD patients. The protein panel included total tau (T-tau), hyperphosphorylated tau 181 (P-tau(181)), amyloid β 1-42 (Aβ(1-42)), neurofilament light (NF-L), myelin basic protein (MBP), heart fatty acid binding protein (H-FABP), matrix metalloproteinases (MMP-1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinases (TIMP-1 and -2). Immunochemical methods were utilized for quantification of the proteins in CSF and data analysis was performed with a multivariate discriminant algorithm. The concentrations of MBP, TIMP-1, P-tau(181), NF-L, T-tau, MMP-9, Aβ(1-42), and MMP-2 contributed the most to the separation between SVD and AD, with a sensitivity of 89% and a specificity of 90% (AUC = 0.92). MBP and NF-L performed the best in discriminating SVD from controls, while T-tau and Aβ(1-42) contributed the most in segregating AD from controls. The CSF biomarkers reflecting AD pathology (T-tau, P-tau(181), and Aβ(1-42)), white matter lesions (NF-L and MBP) and matrix remodeling (MMP-9 and TIMP-1) perform well in differentiating between SVD and AD patients.

Symptoms, Vascular Risk Factors and Blood-Brain Barrier Function in Relation to CT White-Matter Changes in Dementia

The aim was to study the frequently found white-matter changes on computerized tomography (CT) in patients with dementia and to relate these changes to clinical regional brain symptomatology, vascular factors, albumin ratio [indicator of blood-brain barrier (BBB) function] and other CT changes. The study included 85 patients, average age 71 ± 8, with Alzheimer’s disease (n = 56) and vascular dementia (n = 29), who underwent CT (Siemens Somatome DR 1) of the brain. They were inpatients in a psychiatric department specialized in dementia investigations. The degree of CT white-matter changes (absence, mild-moderate, severe) was the basis for the division of the patients into three groups. As the patients without white-matter changes were significantly younger than those with such changes, all statistical analyses were controlled for age. Subcortical symptomatology was significantly more frequent in the group with severe white-matter changes, whereas the reverse was true for parietal symptomatology. Diabetes mellitus, hypertension, ischemic cardiac disease and lacunas were significantly more common in patients with white-matter changes, whereas the freqeuncy of transient ischemic attack/stroke episodes did not differ significantly between the groups. The albumin ratio was significantly higher in the groups with white-matter changes and highest in the group with severe white-matter changes. The findings indicate that white-matter changes in demented patients are at least partially an age- and stroke-independent disease manifestation of the vascular system and is associated with a specific symptom pattern. BBB dysfunction may be the link between the vasculature and the tissue damage.

Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: The Göteborg MCI study

BACKGROUND Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. OBJECTIVE To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. PATIENTS The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. METHODS The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. RESULTS Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. CONCLUSIONS In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.

Cerebrospinal fluid biomarkers of white matter lesions – cross-sectional results from the LADIS study

Background and purpose:  White matter lesions (WMLs) caused by small vessel disease are common in elderly people and contribute to cognitive impairment. There are no established biochemical markers for WMLs. We aimed to study the relation between degree of WMLs rated on magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) levels of structural biomarkers associated with Alzheimer’s disease (AD) and subcortical vascular dementia.

Objective assessment of the degree of dementia by means of EEG.

The aim of the study was to elaborate a method to estimate the degree of cognitive impairment in Alzheimer’s disease from the EEG quantitative indicators. We examined 38 unmedicated patients with a diagnosis of Alzheimer’s disease, with various stages (mild, moderate, and severe) of dementia. The EEG recordings were evaluated both visually and by means of computer analysis. The EEG spectra and coherences in 6 frequency bands were calculated in 16 EEG derivations. Among various EEG indicators, a decrease in the alpha coherence and an increase in the delta coherence was found to be most significantly correlated to the degree of dementia. Combining 6 variables from the spectrum and coherence analysis by means of the multiple regression model, a high correlation (r = 0.87) between a set of EEG variables and the Mini-Mental State Examination score could be obtained. The results suggest that the EEG can supplement the clinical examination by providing an independent assessment of the degree of dementia. The results also suggest that the EEG coherences are of particular interest in dementia, being an indicator of the signal transfer between various parts of the brain cortex.

Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium

Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.