Biomedical subjects

K Blennow

Publications and source records attributed to K Blennow.

At least 109 records · Page 6Linked to original sources

PubMed1999

Analysis of intact proteins from cerebrospinal fluid by matrix-assisted laser desorption/ionization mass spectrometry after two-dimensional liquid-phase electrophoresis.

A novel combination of methods, two-dimensional liquid-phase electrophoresis (2D-LPE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS), have been used for the analysis of intact brain-specific proteins in cerebrospinal fluid (CSF). 2D-LPE is especially useful for isolating proteins present in low concentrations in complex biological samples. The proteins are separated in the first dimension by liquid-phase isoelectric focusing (IEF) in the Rotofor cell and in the second dimension by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in the Preparative cell. The removal of SDS by chloroform/methanol/water, followed by sample preparation with the addition of n-octylglucoside, easily interfaced 2D-LPE with MALDI-TOFMS for analysis of intact proteins. Further characterization by proteolytic digestion is also demonstrated. The knowledge of both the molecular weights of the protein and of the proteolytic fragments obtained by peptide mapping increases specificity for protein identification by searching in protein sequence databases. Two brain-specific proteins in human CSF, cystatin C and transthyretin, were isolated in sufficient quantity for determination of the mass of the whole proteins and their tryptic digest by MALDI-TOFMS. This approach simplified the interface between electrophoresis and MALDI-TOFMS.

Blotting, Western↗

PubMed1999

Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing.

Synaptic pathology is central in the pathogenesis of several psychiatric disorders, for example in Alzheimer's disease (AD) and schizophrenia. Quantification of specific synaptic proteins has proved to be a useful method to estimate synapitc density in the brain. Using this approach, several synaptic proteins have been demonstrated to be altered in both AD and schizophrenia. Until recently, the analysis of synaptic pathology has been limited to postmortem tissue. In living subjects, these synaptic proteins may be studied through analysis of cerebrospinal fluid (CSF). In an earlier study performed by us, one synaptic vesicle specific protein, synaptotagmin, was detected in CSF for the first time using a procedure based on affinity chromatography, reversed-phase chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chemiluminescence immunoblotting. However, other synaptic proteins were not detectable with this procedure. Therefore, we have developed a procedure including precipitation of CSF proteins with trichloroacetic acid, followed by liquid-phase isoelectric focusing using the Rotofor Cell, and finally analysis of Rotofor fractions by Western blotting for identification of synaptic proteins in CSF. Five synaptic proteins, rab3a, synaptotagmin, growth-associated protein (GAP-43), synaptosomal-associated protein (SNAP-25) and neurogranin, have been demonstrated in CSF using this method. The major advantage of liquid-phase isoelectric focusing (IEF) using the Rotofor cell is that it provides synaptic proteins from CSF in sufficient quantities for identification. This method may also be suitable for identification of other types of trace amounts of brain-specific proteins in CSF. These results demonstrate that several synaptic proteins can be identified and measured in CSF to study synaptic function and pathology in degenerative disorders.

Calcium-Binding Proteins↗

PubMed1999

Mitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics.

In the present study, we have applied a novel strategy involving the postmortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c oxidase (COX; complex IV) to identify regional changes in energy metabolism in the basal ganglia of chronic, medicated schizophrenics. COX activity was decreased in the caudate nucleus but increased in the putamen and nucleus accumbens. An increase in succinate dehydrogenase (complex II) was evident in the putamen and nucleus accumbens, but changes were not seen with NADH dehydrogenase (complex I). An analysis of interregional correlations in energy metabolism revealed several anomalies in the connections between the caudate and putamen and the globus pallidus in schizophrenics. Results provide strong evidence that changes in baseline energy metabolism in specific regions of the basal ganglia may exist in the disease. Based upon the high degree of input it receives from associative cortical areas, results suggest that a defect in the caudate may underlie certain aspects of cognitive decline in schizophrenics. In contrast, an increase in COX in the putamen, which receives extensive projections from the sensorimotor cortex, may reflect an effect of chronic neuroleptic treatment on motor function.

Adult↗

PubMed1999

Reduction of chromogranin A and B but not C in the cerebrospinal fluid in subjects with schizophrenia.

The granins (secretogranins/chromogranins) are a family of soluble proteins stored and released from the secretory large dense-core vesicles of the synapse. Schizophrenia is a common and devastating brain disorder. Although the aetiology of schizophrenia is unknown, data are accumulating that synaptic disturbance or damage may be of importance. The objective of this study was to compare the levels of chromogranin A, B and C in the cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls. CSF chromogranin levels were measured by RIA in 33 subsequent admissions of patients with psychotic disorder and in 31 healthy controls. The levels of CSF chromogranin A (11.8+/-3.0 vs 14.8+/-4.8 nmol/l, P=0.004), chromogranin B (3.4+/-0.49 vs 3.7+/-0.58 nmol/l, P=0.02), but not chromogranin C (70.2+/-15.7 vs 65.3+/-20.4 pmol/l, P=0.29) were lower in the schizophrenic patients than in the healthy controls. These data indicate that two widespread constituents of large dense-core vesicles, i.e. chromogranin A and chromogranin B, are altered in chronic schizophrenic patients.

Adult↗

PubMed1999

Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.

Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour.

Adolescent↗

PubMed1999

Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia.

The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.

Aged↗

PubMed1999

Prevalence and incidence of clinically diagnosed memory impairments in a geographically defined general population in Sweden. The Piteå Dementia Project.

In the Piteå River Valley all persons with memory impairment that interferes with normal life are referred to one hospital department for clinical workup and diagnosis. 619 patients were assessed in the department during the years 1990-1995. Of these, 36.9% had Alzheimer's disease (AD), 30.4% had vascular dementia (VaD), 3.0% had a mixed AD/VaD, 3.2% had frontotemporal dementia and 5.3% had other forms of dementia. Another 7% had memory impairment but no dementia. The overall mean annual incidence rate of clinically relevant dementia was 295/100,000 persons at risk and the mean prevalence rate was 755/100,000 persons. For persons 65 years and older the incidence and prevalence rates were 840 and 2,150/100,000 persons, respectively. This means that annually, approximately 300 persons/100,000 population over the age of 40 need medical attention or social services.

Adult↗

PubMed1998

Delirium in dementia.

Delirium is a common mental disorder in the elderly with old age being a major risk factor for delirium. Another major risk factor is dementia. The aim of the present study was to identify differences in occurrence of episodes of delirium between the most common dementia diagnoses and the possible importance of age, gender, severity and duration of dementia for the development of delirium. Included in the study were 175 consecutive patients with probable Alzheimer's disease, vascular dementia (VAD) or frontotemporal dementia (FTD) who were admitted to a neuropsychiatric diagnostic unit. There were no significant differences in sex distribution or duration of dementia between the delirious and non delirious patients. The rate of delirium was higher in late onset Alzheimer's disease (LAD) than in early onset Alzheimer's disease (EAD) and FTD. It was also higher in VAD than in EAD. The differences in occurrence of delirium between the diagnostic groups in this sample could not be explained by differences in age. It seems that delirium is more common in brain disorders such as LAD and VAD in which the damage to the brain is more widespread. In the two brain disorders that are predominantly cortical, EAD and FTD, the occurrence of delirium was comparatively low.

Aged↗

PubMed1998

Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease.

We studied the multifunctional protein clusterin (apolipoprotein J, SGP-2, SP-40,40) in brain tissue using quantitative Western blotting and immunohistochemistry. The material included postmortem brains from 19 patients with Alzheimer's disease (AD), 6 with vascular dementia (VAD), and 7 age-matched control subjects. Intense clusterin staining was found in the soma of both neuronal and astroglial cells. In addition, positive staining was found in a portion of senile plaques (SP) in AD brains. Quantitative analysis showed that clusterin levels were significantly increased in AD, both in frontal cortex (150% of the control value, P = 0.002) and in the hippocampus (179% of the control value, P < 0.001), while normal clusterin levels were found in cerebellum (104% of the control value). No significant changes were found in VAD. Within the AD group, there was a significant negative correlation between clusterin levels in hippocampus and severity of dementia (r = -0.40), while no such correlation was found in frontal cortex (r = 0.12). No significant correlations were found between clusterin levels and the number of SP or neurofibrillary tangles. No significant differences in clusterin levels were found in any brain region between AD patients possessing different numbers of the ApoE4 allele. The increased clusterin levels in AD brain, together with the absence of a correlation between SP counts and clusterin levels, and the finding that clusterin is only found in a smaller portion of SP do not suggest a link between clusterin and beta-amyloid dependence. Instead we hypothesize that the increase is part of a regional response in AD brain.

Aged↗

PubMed1998

Combination of the different biological markers for increasing specificity of in vivo Alzheimer's testing.

In view of existing drugs (acetylcholine esterase inhibitors) and emerging therapeutic compounds (e.g. neuroprotective and anti-inflammatory compounds), CSF markers would be of great use to improve the clinical diagnostic accuracy of Alzheimer's disease (AD). Correct identification of AD would be especially important early in the course of the disease, when the clinical diagnosis is difficult, and drugs have the greatest potential of being effective. Biochemical markers for AD include ApoE genotyping, where the ApoE epsilon 4 allele has proven to have a high predictive value for AD. Biochemical markers for AD also include several potential cerebrospinal fluid (CSF) markers: beta-amyloid(1-42), possibly reflecting amyloid deposition and formation of senile plaques; PHFtau protein a marker for the phosphorylation state of tau, and formation of neurofibrillary tangles; (total)tau protein, a normal axonal protein, as a marker for ongoing neuronal and axonal degeneration; synaptic vesicle proteins, e.g. synaptotagmin, a synaptic vesicle protein which is found in the CSF, as markers for synaptic activity or degeneration; neuromodulin or growth-associated protein GAP-43, as a marker for synaptic degeneration, and the CSF/serum albumin ratio, as a marker for blood-brain barrier damage, used to exclude patients with concomitant cerebrovascular pathology. However, although CSF markers may identify different pathogenic processes in AD, there is no such process that is specific for AD, and thus little hope of ever finding a single CSF biochemical marker that gives an absolute discrimination between AD and other dementia disorders. Instead, combination of several CSF biochemical markers, each reflecting a pathogenic process, may increase both the sensitivity and specificity. Further, the accuracy of the clinical diagnosis of AD may increase if the diagnosis is based on the summarised information gained from the clinical examination, brain-imaging techniques (SPECT, CT/MRT scans), and biochemical markers. Using this approach, CSF markers have a large potential to help to differentiate AD from the most problematic differential diagnoses, especially age-associated memory impairment, depressive pseudo-dementia, Parkinson's disease, and frontal lobe dementia.

Aged↗

PubMed1998

Processing of neuropeptide Y and somatostatin in human cerebrospinal fluid as monitored by radioimmunoassay and mass spectrometry.

The processing of four neuropeptides, neuropeptide Y (NPY) 1-36, NPY (18-36), somatostatin (SOM) 1-28, and SOM (15-28) was studied in human cerebrospinal fluid (CSF) by using a novel combination of methods that included radioimmunoassay (RIA) and mass spectrometry. Untreated CSF samples were chromatographed using reversed-phase high pressure liquid chromatography (RP-HPLC) followed by NPY-RIA or SOM-RIA. These results were compared with those obtained by incubating CSF with exogenous synthetic peptides and directly detecting peptide fragments by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS). Using this combination of methods, we were able to determine the probable identities of peptides/peptide fragments recognized in radioimmunoassays. The most important NPY-immunoreactive components in CSF were found to be NPY (1-36) and NPY (3-36). Metabolic products of SOM (15-28) were found to contribute to SOM-like immunoreactivity (SOM-LI) in CSF, but SOM (1-28) only to a lesser degree. Differences in the rate of neuropeptide processing were observed. These differences depended more on the length of the peptide than its sequence. NPY (18-36) and SOM (15-28) were rapidly and extensively processed, whereas NPV (1-36) and SOM (1-28) were processed much more slowly in CSF. The production of SOM (15-28) from SOM (1-28) by enzymes in CSF was not observed. Also, the presence of a disulfide bond in the somatostatins appeared to stabilize them against enzymatic digestion of the ring structure. The results detailed in this report confirm MALDI-MS important role in studies of neuropeptide processing in CSF.

Amino Acids↗

PubMed1998

Neurochemical dissection of synaptic pathology in Alzheimer's disease.

Synaptic pathology has attained increasing attention as being central in the pathogenesis of Alzheimer's disease (AD). To address the question whether synaptic pathology in AD involves the whole synapse, or is limited to specific components thereof, we studied three different synaptic vesicle proteins (rab3a, synaptotagmin, synaptophysin) and also the presynaptic membrane protein GAP-43 and the postsynaptic protein neurogranin. The material included postmortem brain tissue (frontal cortex, hippocampus, and cerebellum) from 8 patients with early-onset AD (EAD), 11 patients with late-onset AD (LAD), 6 patients with vascular dementia (VAD), and 9 control subjects. A reduction of all synaptic proteins was found in AD, more pronounced in EAD than in LAD, in both the frontal cortex (EAD 30% to 70% vs. LAD 82% to 88% of control value) and hippocampus (EAD 22% to 82% vs. LAD 76% to 89% of control value), whereas only minor changes were found in VAD. The finding that all synaptic proteins were reduced in AD suggests a degeneration and loss of whole synaptic elements that are more pronounced in EAD than in LAD.

Age of Onset↗

PubMed1998

A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality.

OBJECTIVES: To study the association of apoE genotypes with dementia and cerebrovascular disorders in a population based sample of 85 year old people. METHODS: A representative sample of 85 year old people (303 non-demented, 109 demented) were given a neuropsychiatric and a medical examination and head CT. The apoE isoforms were determined. Dementia was diagnosed according to DSM-III-R. RESULTS: At the age of 85, carriers of the apoE epsilon4 allele had an increased odds ratio (OR) for dementia (1.9; p<0.01) and its subtypes Alzheimer's disease (1.9; p<0.05) and vascular dementia (2.0; p<0.05). Among those categorised as having vascular dementia, the apoE epsilon4 allele was associated with mixed Alzheimer's disease-multi-infarct dementia (OR 6.5; p<0.05), but not with pure multi-infarct dementia (OR 1.5; NS). Only carriers of the apoE epsilon4 allele who also had ischaemic white matter lesions on CT of the head had an increased OR for dementia (OR 6.1; p=0.00003), and its main subtypes Alzheimer's disease (OR 6.8; p=0.002) and vascular dementia (OR 5.6; p=0.0007), whereas carriers of the apoE epsilon4 allele without white matter lesions had an OR for dementia of 1.0 (OR for Alzheimer's disease 1.8; NS and for vascular dementia 0.6; NS) and non-carriers of the apoE epsilon4 allele with white matter lesions had an OR for dementia of 2.2; NS (OR for Alzheimer's disease 2.7; NS and for vascular dementia 1.6; NS). The apoE allele variants were not related to mortality or incidence of dementia between the ages of 85 and 88. The epsilon2 allele was related to a higher prevalence of stroke or transient ischaemic attack at the age of 85 (OR 2.1; p<0.05) and a higher incidence of multi-infarct dementia during the follow up (OR 2.9; p<0.05). CONCLUSIONS: Neither the apoE epsilon4 allele nor white matter lesions are sufficient risk factors by themselves for dementia at very old ages, whereas possession of both these entities increases the risk for Alzheimer's disease and vascular dementia substantially.

Aged↗

PubMed1998

Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease: a community based follow up study.

OBJECTIVES: Biochemical markers for Alzheimer's disease would be of great value, especially to help in diagnosis early in the course of the disease. A pronounced increase in CSF tau protein (CSF-tau) is found in most patients with Alzheimer's disease. However, the specificity has to be further studied, as an increase in CSF-tau has also been found in other dementias, especially in vascular dementia. As most previous CSF studies have been based on selected inpatients, it was considered of special interest to examine the diagnostic potential of CSF-tau in a community population based sample of consecutive patients with dementia. Such patient material has been examined at the Piteå River Valley Hospital in Northern Sweden since 1986, and includes all those with memory disturbances in the community. The aim was also to study if an increase in CSF-tau is found early in the disease process, and whether CSF-tau changes during the progression of disease. METHODS PARTICIPANTS: Community population based sample of 75 demented patients (43 with Alzheimer's disease, 21 with vascular dementia, and 11 with mixed Alzheimer's disease/vascular dementia), 18 healthy subjects, and 18 neurological controls. A follow up investigation (including analysis of a new CSF sample) was performed in all patients after about one year. MAIN OUTCOME MEASURES: Concentrations of total (both normal tau and PHF-tau) tau in CSF, clinical measures (duration and severity of dementia), and apoE polymorphism. RESULTS: CSF-tau was markedly increased in Alzheimer's disease, 41/43 (95%) patients had values above the cut off level (mean+2 SD) in controls (306 pg/ml). High CSF-tau concentrations were also found in most patients with vascular dementia, preferentially in patients with vascular dementia without progressive leukoaraiosis on CT, whereas patients with vascular dementia with progressive leukoaraiosis had normal CSF-tau. Concentrations of CSF-tau were stable at one year follow up in both patients with Alzheimer's disease and patients with vascular dementia, and there was no correlation between CSF-tau and either duration or severity of dementia. CONCLUSIONS: The findings confirm the high sensitivity of CSF-tau for the diagnosis of Alzheimer's disease, but high CSF-tau was also found in vascular dementia, resulting in a lower specificity. However, high CSF-tau is preferentially found in patients with vascular dementia without progressive leukoaraiosis, which may constitute a group with concomitant Alzheimer's disease pathology. High CSF-tau may be present during the whole course of the disease in Alzheimer's disease. Possibly, therefore, the same high CSF-tau concentrations may be present before the onset of clinical dementia. Follow up studies on such patients will tell whether analysis of CSF-tau is useful as a biochemical marker for early Alzheimer's disease.

Aged↗

PubMed1998

A population study on blood-brain barrier function in 85-year-olds: relation to Alzheimer's disease and vascular dementia.

We investigated blood-brain barrier (BBB) function in relation to Alzheimer's disease (AD) and vascular dementia (VAD) in the very elderly. Sixty-five 85-year-old persons from a population-based sample were followed for 3 years; 29 were demented at age 85 (13 with AD, 14 with VAD, and 2 with other dementias), 7 developed dementia during follow-up, and 29 remained nondemented. CSF/serum albumin ratio was used as as a measure of BBB function. Dementia was defined according to the DSM-III-R, AD according to the NINCDS-ADRDA criteria, and VAD according to the NINDS-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria. Mean CSF/serum albumin ratio was higher in all dementias (8.5 +/- 4.3; p = 0.007) and in the subtypes AD (8.9 +/- 5.3; p = 0.046) and VAD (8.7 +/- 3.5; p = 0.002) than in nondemented individuals (versus 6.5 +/- 2.0), but it was not related to dementia severity. Nondemented women at age 85 (n = 3) who developed dementia during the follow-up had a higher CSF/serum albumin ratio than those not developing dementia (10.4 +/- 2.0 versus 6.0 +/- 1.9; p = 0.007). Nondemented individuals lacking the apolipoprotein E epsilon3 allele (n = 4) had a higher CSF/serum albumin ratio (9.3 +/- 0.8 versus 6.6 +/- 2.1; p = 0.029) than other individuals. A relative BBB dysfunction is associated with both AD and VAD among very elderly individuals. This finding is possibly found early in the disease before the onset of clinical dementia.

Aged↗

PubMed1997

Serotonergic, noradrenergic, and dopaminergic measures in suicide brains.

Concentrations of the three main monoamines (5-HT, NA, and DA), their metabolites (5-HIAA, DOPAC, and HVA), and the serotonin precursor 5-hydroxy-L-tryptophan were simultaneously measured in frontal cortex, gyrus cinguli, and hypothalamus from 23 controls and 18 suicide victims. Overall suicides did not show significant differences with respect to the control group in any of the measured compounds. Significant increases in noradrenaline and dopamine concentrations were noted in the carbon monoxide poisoning suicides, together with a significant increased hypothalamic dopamine in the drug overdose suicides. It is suggested that the suicidal behavior is not related to substantial changes in cortical and hypothalamic monoaminergic function; however, the reported results could be secondary to the rapid effect of hypoxia and of the acute self-administration of certain drugs in specific metabolic pathways.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

The apolipoprotein E epsilon4 allele frequency is normal in fronto-temporal dementia, but correlates with age at onset of disease.

The apolipoprotein (apoE) epsilon4 allele was studied in fronto-temporal dementia (FTD), a diagnostic category including the specific disorders Pick's disease and frontal lobe degeneration of non-Alzheimer type (FLD). These dementing diseases have neuronal and synaptic degeneration in common with Alzheimer's disease (AD), for which the presence of the apoE epsilon4 allele is a known risk factor, and lowers the age of onset of disease. Previous studies on the apoE epsilon4 allele frequency in FTD have been inconclusive. The structural hallmarks of AD, allegedly linked to apoE presentation, neuritic plaques (NP), primarily composed of aggregates of beta-amyloid, and neurofibrillary tangles (NFT), primarily composed of hyperphosphorylated tau, are lacking in FTD. However, tau-positive cytoskeletal pathology is found in Pick's disease, but not in FLD. Resolving whether the epsilon4 frequency is increased in FTD or not may thus give clues to the pathogenetic mechanism of apoE in AD. We therefore studied apoE alleles in a well characterized material of FTD patients. The epsilon4 allele frequency was similar in 25 patients with FTD (14.0%) as compared with 26 healthy controls (13.5%). A post-mortem neuropathological examination was performed in 10 cases (nine had FLD and one Pick's disease). Our finding of a normal epsilon4 allele frequency in our group of FTD, principally consisting of FLD cases, support hypotheses involving differential binding of apoE to beta-amyloid and/or tau, in the development of beta-amyloid deposition and NP formation and/or tau hyperphosphorylation and NFT formation, for the pathogenetic role of apoE in AD. The age at onset was significantly lower (P < 0.01) in FTD patients possessing the epsilon4 allele (48.7 +/- 8.0 years) than in patients not possessing this allele (58.9 +/- 7.6 years). We conclude that, although the apoE epsilon4 allele frequency is not increase in FTD, the epsilon4 allele is not an etiological factor, but may rather be an accelerating factor in the degenerative process of FTD, thereby resulting in an earlier presentation of the disorder in individuals predisposed to develop FTD.

Adult↗

PubMed1997

Apolipoprotein E in cerebrospinal fluid in 85-year-old subjects. Relation to dementia, apolipoprotein E polymorphism, cerebral atrophy, and white matter lesions.

OBJECTIVE: To further elucidate the pathogenetic role of apolipoprotein E (Apo E) in degenerative brain disorders, we analyzed cerebrospinal fluid (CSF) levels of Apo E in 85-year-old subjects with dementia disorders. DESIGN: Survey. SETTING: Community. PARTICIPANTS: Population-based sample of 27 demented (12 with Alzheimer disease [AD]; 13, vascular dementia [VAD]; and 2, other types of dementia) and 35 nondemented individuals. MAIN OUTCOME MEASURES: Cerebrospinal fluid levels of Apo E, Apo E polymorphism, and brain atrophy and white matter lesions (WMLs) measured by computed tomography (CT) of the brain. Dementia was defined according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria; AD, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria; and VAD, National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neuroscience criteria. RESULTS: The mean (+/- SD) CSF levels of Apo E were lower in the AD (2.6 +/- 1.5 mg/L; P < .02) and VAD groups (2.5 +/- 0.9 mg/L; P < .002) than in the nondemented group (3.8 +/- 1.7 mg/L). Cerebrospinal fluid levels of Apo E decreased with increasing severity of dementia and with increasing temporal cortical and central frontal atrophy. In nondemented individuals, CSF levels of Apo E decreased with increasing degree of WMLs. Cerebrospinal fluid levels of Apo E were not influenced by the Apo E4 isoform. CONCLUSIONS: Whether our finding of an association between low CSF levels of Apo E and dementia disorders (both degenerative, such as AD, and vascular, such as VAD) is related to the pathogenesis of these disorders or is a secondary consequence of the disease process remains to be established. Although statistical correlations do not give direct evidence of causal relations, the correlations between CSF level of Apo E and severity of dementia and cortical atrophy suggest that CSF level of Apo E follows the disease process.

Aged↗