Magnus Sjögren

A New Rating Scale for Age-Related White Matter Changes Applicable to MRI and CT

Background and Purpose— MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Methods— Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using &kgr; statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Results— Interrater reliability was good for MRI (&kgr;=0.67) and moderate for CT (&kgr;=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. Conclusions— We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

High total cholesterol levels in late life associated with a reduced risk of dementia

Objective: To examine the longitudinal association between plasma total cholesterol and triglyceride levels and incident dementia. Methods: Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88. Results: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia. Conclusions: High cholesterol in late life was associated with decreased dementia risk, which is in contrast to previous studies suggesting high cholesterol in mid-life is a risk factor for later dementia. The conflicting results may be explained by the timing of the cholesterol measurements in relationship to age and the clinical onset of dementia.

Increased intrathecal levels of the angiogenic factors VEGF and TGF-β in Alzheimer’s disease and vascular dementia

The aim of the present study was to investigate, in patients with Alzheimers disease (AD), and vascular dementia (VAD), patterns of local release of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta), two cytokines having a pivotal role in hypoxia-induced angiogenesis. The intrathecal levels of these molecules were related to the clinical severity of these diseases and to the intrathecal levels of beta-amyloid protein. Significantly increased cerebrospinal fluid (CSF) levels of both VEGF and TGF-beta were observed in 20 patients with AD and in 26 patients with VAD compared to healthy controls. Interestingly, there was significant correlation between the CSF levels of TGF-beta and VEGF in all the individuals studied. Our study demonstrates, both in patients with AD and in patients with VAD, an intrathecal production of VEGF, a cytokine which plays a pivotal role in angiogenesis. These results suggest that vascular factors might not only play a role in the pathogenesis of VAD but also in the pathogenesis of AD. In addition, we show in AD and VAD an intrathecal production of TGF-beta, a cytokine exerting on one hand anti-inflammatory and angiogenic properties, but on the other promoting amyloidogenesis.

CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging

Summary. Cerebrospinal fluid (CSF) levels of tau, β-amyloid1–42 and growth-associated protein 43 (GAP-43) were studied in patients with frontotemporal dementia (FTD; n = 17), Alzheimers disease (AD; n = 60), subcortical white-matter dementia (SWD; n = 24), Parkinsons disease (PD; n = 23) and dysthymia (n = 19) and in age-matched controls (n = 32). CSF-tau was significantly increased only in AD, and CSF-β-amyloid1–42 was significantly decreased in AD and SWD as compared to controls, and in AD compared to FTD. CSF-GAP-43 was significantly decreased only in PD. The GAP-43/tau ratio was decreased in all the patient groups except the dysthymia group compared to controls. A positive correlation was found between CSF-GAP-43 and CSF-tau in all groups. The results suggest normal levels of CSF-tau and CSF-β-amyloid1–42 in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-β-amyloid1–42 suggest concomitant involvement of vascular and amyloid protein mechanisms.

Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients

&NA; By comparing the CSF proteome between Alzheimer disease (AD) patients and controls it may be possible to identify proteins that play a role in the disease process and thus to study the pathogenesis of AD. We used mini‐gel technology in a two‐dimensional electrophoresis procedure, sensitive SYPRO Ruby staining and mass spectrometry for clinical screening of disease‐influenced CSF proteins in 15 AD patients and 12 controls. The levels of six proteins and their isoforms, including proapolipoprotein, apolipoprotein E, &bgr;‐2 microglobulin, retinol‐binding protein, transthyretin, and ubiquitin, were significantly altered in CSF of AD patients. The most prominently altered proteins were the apolipoproteins, especially proapolipoprotein.

Treatment of Alzheimer’s Disease with Clioquinol

As heavy metal ions may be implicated in the formation of senile plaques in Alzheimer-afflicted brains, treatment with clioquinol was tested in 20 patients with Alzheimer’s disease. Clioquinol is a chelator that crosses the blood-brain barrier and has greater affinity for zinc and copper ions than for calcium and magnesium ions. Treatment was given for 21 days at doses of 20 mg/day to 10 patients and 80 mg/day to another 10 patients. The study was blind to the dosages but included no controls. Cerebrospinal fluid (CSF) investigations revealed a significant increase at day 7 and a decrease at day 21 in Tau protein and growth-associated protein (GAP43). These proteins are increased in Alzheimer’s disease and considered as rather stable markers. The initial increase may indicate a temporary cytotoxicity to the brain and/or an increased release into the CSF from stores in the tissue, possibly from senile plaques where the proteins are accumulated. The levels of CSF-Tau protein correlated positively and significantly with the serum levels of copper and also with the serum copper/zinc ratio. Clinical ratings showed slight improvement after 3 weeks treatment with clioquinol in this open study.

The Goteborg MCI study: mild cognitive impairment is a heterogeneous condition

Background: Mild cognitive impairment (MCI) has been considered a transitional state between normal aging and dementia, characterised by memory impairment but normal general cognitive functioning. Recently other cognitive deficits have been reported. This has led to a modification of MCI criteria. Objective: To examine which neuropsychological tests most clearly distinguish MCI subjects from normal controls. Methods: 112 consecutive MCI subjects and 35 controls were included in the study. The diagnosis of MCI was based on an objective history of cognitive decline and a neuropsychiatric examination, comprising instruments STEP, I-Flex, MMSE, and CDR. Participants were examined with 21 neuropsychological tests in the cognitive domains speed/attention, memory and learning, visuospatial function, language, and executive function. Results: Controls were significantly older. No differences were found in education or general intellectual capacity. Controls performed significantly better than MCI on tests within all five cognitive domains. The clearest differences were seen on language tests, followed by executive function, and learning and memory. Only two subjects (1.8%) were purely amnestic; 17% showed no impairment compared with controls, with a cut off of 1.5 SD below age mean. These subjects were better educated and performed significantly better on measures of general cognitive capacity. Conclusions: The results illustrate the heterogeneity of MCI, with a significant degree of impairment in all five cognitive domains. When examined with a comprehensive neuropsychological battery, very few subjects had an isolated memory impairment.

Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism

Extensive animal studies suggest neuropeptide Y (NPY) to be involved in coping with a wide range of stressors, and that impaired central NPY signalling could be involved in the pathophysiology of anxiety and depression. Human studies of central NPY levels in depression have, however, been inconclusive. Here, we examined levels of NPY-like immunoreactivity (NPY-LI) in the cerebrospinal fluid (CSF) of medication-free subjects with treatment refractory unipolar depression. Patients were admitted to a research inpatient unit, examined under standardized conditions, and compared with a sample of volunteers in whom psychiatric morbidity was excluded. A robust suppression of NPY levels in patient CSF was found, while other putative CSF markers (monoamine metabolites, somatostatin) did not differ between the groups. We then explored whether this finding might be related to a recently described T1128C coding polymorphism which results in a Leu7-> Pro7 substitution of the signal peptide, and a previously not described T -399C polymorphism in the promoter region of the preproNPY gene. Preliminary evidence was found for an association of both markers with a diagnosis of depression, indicating the possibility of an underlying haplotype influencing the vulnerability for developing depressive illness. Our present findings are in line with an extensive animal literature, and further support the notion that impaired NPY function could contribute to depressive illness.

The future of blood-based biomarkers for Alzheimer's disease

Treatment of Alzheimers disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood‐Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood‐based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood–brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients

One of the major histopathological hallmarks of Alzheimers disease (AD) is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP (sAPP) and Abeta. We examined the cerebrospinal fluid (CSF) for alpha- and beta-secretase cleaved sAPP (alpha-sAPP and beta-sAPP) in 81 sporadic AD patients, 19 patients with mild cognitive impairment, and 42 healthy controls by using newly developed sandwich enzyme-linked immunosorbent assay methods. We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. These findings further support the conclusion that there is no change in APP expression in sporadic AD. However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. We also investigated the relationship between the CSF level of alpha/beta-sAPP and Abeta(42) and the apoE epsilon 4 (apoE4) allele. Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele. Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42) differed when comparing ApoE4 allele-positive with allele-negative individuals.