Alzheimer Disease: Sjögren M

Pei JJ, Sjögren M, Winblad B. · Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, KI-ADRC, Novum, Stockholm, Sweden. · Curr Opin Psychiatry. · Pubmed #18852562 No free full text.

Abstract: PURPOSE OF REVIEW: Great progress has been made in understanding the pathogenesis of neurofibrillary degeneration in Alzheimer's disease brains in the last two decades. In this review we summarize how neurons are degenerated in Alzheimer's disease brains and highlight the evidence of using kinases such as glycogen synthase kinase 3 and p70 S6 kinase and phosphatases such as protein phosphatase 2A as drug targets to prohibit the formation of neurofibrillary degeneration of Alzheimer's disease. RECENT FINDINGS: In general there are two types of neuronal degeneration in Alzheimer's disease brains: neurofibrillary formation and apoptosis. The microtubule-associated protein tau that stabilizes neuronal microtubules under normal physiological conditions is abnormally hyperphosphorylated in Alzheimer's disease brains, resulting in the generation of aberrant aggregates that are toxic to neurons. The processes of tau hyperphosphorylation and the formation of neurofibrillary tangles are caused by the imbalance of the activities of protein kinases and protein phosphatases in Alzheimer's disease brains. Recent findings from our and other groups have suggested glycogen synthase kinase 3 and p70 S6 kinase as main tau kinases and protein phosphatase 2A as the main tau phosphatase involved in the formation of these processes. Activities of these targets are implicated by Abeta peptide, the major component of another hallmark in Alzheimer's disease brains, senile plaques. SUMMARY: To prevent the clinical progression of neurodegeneration, a combination strategy is suggested to target both senile plaques with immunization and neurofibrillary tangles with drugs to prevent the synthesis and phosphorylation of tau.

Sjögren M, Mielke M, Gustafson D, Zandi P, Skoog I. · Department of Experimental Geriatrics, Neurotec, Karolinska Institute, Huddinge, Sweden. · Mech Ageing Dev. · Pubmed #16332384 No free full text.

Abstract: The predominating theory on the pathophysiology of Alzheimer's disease (AD) concerns the mis-metabolism of amyloid precursor protein (APP). As a result of this mis-metabolism, there is an increased production of the 42 amino acid form of beta-amyloid (Abeta42) that rapidly will form oligomers that initiates a cascade of events leading to the accumulation of amyloid plaques. Commonly recognised as vascular factors, hypertension, hypercholesterolemia and diabetes and the inheritance of the epsilon4 allele of the APOE gene, are also risk factors for AD. These risks have been found to promote the production of Abeta42. An association between cholesterol and the development of AD was suggested in the early 1990s and ever since, an increasing amount of research has confirmed that there is a link between cholesterol and the development of AD. A high cholesterol levels in mid-life is a risk for AD and statins, i.e., cholesterol-lowering drugs, reduce this risk. Statins may not only inhibit enzymes involved in the endogenous synthesis of cholesterol but also affect enzymes involved in Abeta metabolism, i.e., alpha-secretase and beta-secretase. This normalises the breakdown of APP thereby promoting the non-amyloidogenic pathway. In this review, investigations focusing on cholesterol and Alzheimer's disease are presented.

Sjögren M, Blennow K. · Section of Experimental Geriatrics, Neurotec, Karolinska Institute KFC, Novum Plan 4, SE-14186 Huddinge, Sweden. · World J Biol Psychiatry. · Pubmed #16156481 No free full text.

Abstract: A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease.

Davidsson P, Sjögren M. · Discovery Medicine/Molecular Sciences, AstraZeneca R&D, Mölndal, Sweden. · Dis Markers. · Pubmed #15920295 No free full text.

Abstract: Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.

Andreasen N, Sjögren M, Blennow K. · Karolinska Institute NEUROTEC, Neurotec, Huddinge University Hospital, Sweden. · World J Biol Psychiatry. · Pubmed #14608585 No free full text.

Abstract: Today we have the first therapeutic compounds for treatment of Alzheimer's disease (AD) e.g. acetylcholine esterase inhibitors and in the near future we may expect new compounds such as gamma- and beta-secretase inhibitors. This has demanded increased accuracy in the diagnosis of AD and thus, among other possible approaches, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Especially early in the course of the disease, when correct diagnosis is most difficult, such biomarkers would be especially valuable as one might expect the compounds to have the greatest potential of being effective. Two of the defining lesions in AD brains are senile plaques and neurofibrillary tangles with beta-amyloid (Abeta) and tau proteins as the main components respectively. Abeta and tau proteins are secreted to body fluids including plasma and cerebrospinal fluid (CSF). In this paper we review CSF markers for AD, with focus on their role in the clinical diagnosis. Reduced CSF levels of the 42 amino acid form of Abeta (Abeta42) and increased CSF levels of total tau (T-tau) in AD have been found in numerous studies, with high sensitivity figures. However, the specificity against other dementias is lower. The addition of phospho-tau (P-tau) seems to increase the specificity, since normal levels are found in other dementias and in cerebrovascular disease. An increasing number of studies suggests that these CSF markers perform well enough to have a role in the clinical work-up of patients with dementia if used together. We stress that the CSF markers should be combined with the clinical information and brain-imaging techniques.

Sjögren M, Andreasen N, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, SE 431 80, Göteborg, Sweden. · Clin Chim Acta. · Pubmed #12763273 No free full text.

Abstract: The diagnosis of Alzheimer's disease (AD) is still made by excluding other disorders with a similar clinical picture. In addition, an analysis of symptoms and signs, blood analyses and brain imaging are the major ingredients of the clinical diagnostic work-up. However, the sensitivity of a clinical diagnosis using these instruments is unsatisfactory and disease markers with high sensitivity and specificity for AD would be a welcome supplement. Ideally, such markers should reflect the pathophysiological mechanisms of AD, that is, according to the currently predominant hypothesis mismetabolism of beta-amyloid and neurofibrillary degeneration. Among several, we have focused on three candidates that have been suggested to fulfil the requirements for biomarkers of AD: beta-amyloid42 (Abeta42), total tau (T-tau) and tau phosphorylated at various epitopes (P-tau). The cerebrospinal fluid (CSF) levels of these proteins reflect the metabolism of these proteins in the central nervous system. Only published articles using established ELISA methods for the quantification of these markers in CSF and preferably also presenting sensitivity and specificity figures have been included in this review. The number of patients included in the different studies varies; some having included only a few patients. Furthermore, diagnostic criteria vary and clinicopathological studies are scarce. However, there are some large studies, including even minor studies, and most have found reduced CSF levels of Abeta42 and increased CSF levels of T-tau in AD. The sensitivity and specificity of these measures are high for separation of AD patients from controls, but their specificity against other dementias is moderate. It increases if P-tau is added. An increasing number of studies suggest that supplementary use of these CSF markers, preferably in combination, adds to the accuracy of an AD diagnosis.

Olsson A, Höglund K, Sjögren M, Andreasen N, Minthon L, Lannfelt L, Buerger K, Möller HJ, Hampel H, Davidsson P, Blennow K. · Institute of Clinical Neuroscience, Experimental Neuroscience Section, Göteborg University, Sahlgrenska University Hospital/, Mölndal, Sweden. · Exp Neurol. · Pubmed #12957490 No free full text.

Abstract: One of the major histopathological hallmarks of Alzheimer's 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.

Sjögren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12714796 No free full text.

Abstract: We investigated the clinical and biological effects of cholesterol-lowering treatment with a statin in 19 patients with Alzheimer's disease. They received simvastatin 20 mg/day for 12 weeks in an open trial. Primary efficacy parameters were the changes after 12 weeks in the cerebrospinal fluid (CSF) levels of beta-amyloid(42) (Abeta(42)), alpha-secretase-cleaved amyloid precursor protein (alpha-sAPP), beta-secretase-cleaved APP (beta-sAPP), tau, phospho-tau and the plasma levels of Abeta(42). A secondary efficacy parameter was the change in the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog) score. After 12 weeks, CSF alpha-sAPP and CSF beta-sAPP were significantly reduced (p < 0.001), but the CSF levels of tau, phospho-tau, Abeta(42) and the plasma levels of Abeta(42) were unchanged. The ADAS-cog score was slightly increased (p < 0.05). The results suggest that simvastatin acts directly on the processing of APP by inhibiting both the alpha- and the beta-secretase pathways.

Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjögren M, Wallin A, Xilinas M, Gottfries CG. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #11598313 No free full text.

Abstract: 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.

Sjögren M, Hesse C, Basun H, Köl G, Thostrup H, Kilander L, Marcusson J, Edman A, Wallin A, Karlsson I, Troell M, Wachtmaister G, Ekdahl A, Olofsson H, Sandström A, Andreasen N, Minthon L, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital/Mölndal, Sweden. · J Neural Transm. · Pubmed #11475012 No free full text.

Abstract: Today, cognitive impairment can be successfully treated with acetylcholine esterase inhibitors (AChE-I) in many, but not all, patients with Alzheimer's disease (AD). To investigate the relation between tacrine treatment, inheritance of ApoE epsilon4 alleles, and rate of progression, the differences in MMSE and CIBIC scores (efficacy parameters) after 6 and 12 months of tacrine (an AChE-I) treatment were investigated in 145 AD patients. Of these, 84 were ApoE epsilon4-positive (ApoE4) and 61 were ApoE epsilon4-negative (ApoE2-3). No differences were found after 6 months of treatment, but after 12 months the CIBIC scores revealed that the ApoE4 patients had declined more than the ApoE2-3 patients (p < 0.05). No differences were found for the last 6 months of treatment. The results primarily suggest a faster rate of decline in the ApoE4 AD compared to the ApoE2-3, but may also reflect that ApoE epsilon4 genotype inheritance is a negative predictor of treatment effect of tacrine in AD patients.

Sjögren M, Gustafson L, Wikkelsö C, Wallin A. · Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #10940679 No free full text.

Abstract: Sixteen patients with frontotemporal dementia (FTD), 27 with early-onset Alzheimer's disease, 25 with late-onset Alzheimer's disease, 19 with subcortical white matter dementia (SWD) and 28 normal controls underwent semiquantitative regional cerebral blood flow measurement (rCBF) using single-photon emission tomography (SPET; (99m)Tc-HMPAO) and either computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain. An anterior-to-posterior rCBF-SPET ratio (mesial superior frontal gyrus/medial temporal lobes) was calculated, which significantly separated the FTD group from the other dementia groups and controls with a sensitivity of 87.5% and a specificity of at least 78.6%. CT/MRI was found to be helpful in the differential diagnosis between FTD and SWD. In FTD patients, the mesial superior frontal gyrus, near the polus frontalis, was found to be the region with the most reduced rCBF values.

Sihlbom C, Davidsson P, Sjögren M, Wahlund LO, Nilsson CL. · Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy at Goteborg University, 440, SE-405 30 Goteborg, Sweden. · Neurochem Res. · Pubmed #18288611 No free full text.

Abstract: Glycoproteins in cerebrospinal fluid (CSF) are altered in Alzheimer's Disease (AD) patients compared to control individuals. We have utilized albumin depletion prior to 2D gel electrophoresis to enhance glycoprotein concentration for image analysis as well as structural glycoprotein determination without glycan release using mass spectrometry (MS). The benefits of a direct glycoprotein analysis approach include minimal sample manipulation and retention of structural details. A quantitative comparison of gel-separated glycoprotein isoforms from twelve AD patients and twelve control subjects was performed with glycoprotein-specific and total protein stains. We have also compared glycoforms in pooled CSF obtained from AD patients and control subjects with mass spectrometry. One isoform of alpha1-antitrypsin showed decreased glycosylation in AD patients while another glycosylated isoform of an unassigned protein was up-regulated. Protein expression levels of alpha1-antitrypsin were decreased, while the protein levels of apolipoprotein E and clusterin were increased in AD. No specific glycoform could be specifically assigned to AD.

Mielke MM, Zandi PP, Blennow K, Gustafson D, Sjögren M, Rosengren L, Skoog I. · Center on Aging and Health, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493233 No free full text.

Abstract: Low serum potassium increases risk of hypertension and stroke, and cardiovascular factors increase the risk of Alzheimer disease (AD). We examined the association between serum potassium and the biologic marker cerebrospinal fluid amyloid-beta (Abeta42), which is decreased in Alzheimer disease patients. Psychiatric examinations, laboratory and other tests were conducted on a population-based sample of 1080 women aged 46 to 60 in 1968, with follow-ups in 1974, 1980, and 1992. In 1992, cerebrospinal fluid Abeta42 levels were obtained from 81 women. Increasing serum potassium in 1968 was associated with increasing cerebrospinal fluid Abeta42 (beta = 153.9, P = 0.041) in 1992 using age-adjusted linear regression. Compared with the lowest tertile of potassium, the middle (beta = 95.3, P = 0.138) and highest tertiles (beta = 193.5, P = 0.004) had incrementally increased cerebrospinal fluid Abeta42 levels. Associations remained after controlling for blood pressure and other factors, and were similar among the 17 women in 1974 with available serum potassium. Potassium in 1980 and 1992 was not associated with cerebrospinal fluid Abeta42. Findings suggest low serum potassium in mid life, but not late life, is associated with low cerebrospinal fluid Abeta42 levels in late life. It is possible potassium co-varies with another variable that is associated with cerebrospinal fluid Abeta42. Nonetheless, serum potassium is a modifiable risk factor and further examination of the potassium-dementia relationship is warranted.

Lind K, Jonsson M, Karlsson I, Sjögren M, Wallin A, Edman A. · Institute of Clinical Neuroscience, Göteborg University, Sweden. · Int J Geriatr Psychiatry. · Pubmed #16416468 No free full text.

Abstract: OBJECTIVE: The aim of the present study was to investigate if depressive symptoms in demented patients are associated with white matter changes (WMCs) in the brain. BACKGROUND: WMCs are frequently found in patients with dementia, as well as among elderly nondemented patients with depressive symptoms. However, it is less established whether or not WMCs are related to depressive symptoms in demented patients. METHODS: 67 (26 men, 41 women) patients with primary degenerative dementia (Alzheimer's disease, frontotemporal dementia), vascular dementia (VaD), or mixed Alzheimer/VaD dementia were included in the study. The patients were young-old (mean 68.1, SD 7.3). All patients underwent a standardized examination procedure and MRI of the brain. The degree of WMCs was visually rated, blindly. Depressive symptoms were rated according to the Gottfries-Bråne-Steen scale (anxiety, fear-panic, depressed mood). RESULTS: No significant relationship was found between WMCs and depressive symptoms in the demented patients. CONCLUSION: The possible involvement of WMCs in the pathogenesis of depressive symptoms in dementia is unclear. A link between disruptions of frontal-subcortical pathways, due to WMCs, and depressive symptomatology in dementia has been hypothesised from earlier findings, which would imply common elements of pathogenesis for depressive symptomatology and cognitive impairment in dementia. However, the results of the present study do not add further support to this hypothesis.

Sacuiu S, Sjögren M, Johansson B, Gustafson D, Skoog I. · Psychiatry Section, Institute of Clinical Neuroscience, Sahlgrenska Academy, Göteborg University, Sweden. · Neurology. · Pubmed #16380609 No free full text.

Abstract: OBJECTIVE: To evaluate the utility of assessing four cognitive domains obtained from four information sources to identify individuals at risk for developing dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A representative population sample of nondemented 85-year-olds (n = 313) from Gothenburg, Sweden, was examined regarding memory, language, and visuospatial and executive functions, using self- and key informant reports and neuropsychiatric and psychometric examinations. The sample was followed 3 years for incident dementia, AD, or possible VaD. RESULTS: All cases of dementia, AD, and VaD were preceded by low performance in most domains irrespective of information source. Isolated low memory performance or low cognitive performance with unimpaired memory did not predict dementia. Positive predictive values increased with number of domains affected. Self- and key informant reports were less useful for predicting dementia than neuropsychiatric and psychometric examinations. The best positive predictive value (88%) was for low cognitive performance in all domains using neuropsychiatric and psychometric examinations; however, sensitivity was only 18%. CONCLUSIONS: Although memory impairment was necessary to predict dementia, it was not sufficient. Other cognitive domains needed to be affected. Relying on self-reports or key informants for early detection of dementia excluded a large group at risk. In addition, vascular dementia appeared to have a prodromal stage.

Davidsson P, Sjögren M. · Discovery Medicine/Molecular Pharmacology, AstraZeneca R&D, Mölndal, SE-431 83 Mölndal, Sweden. · Mech Ageing Dev. · Pubmed #16293296 No free full text.

Abstract: Proteins in cerebrospinal fluid (CSF) may often serve as indicators of neurodegenerative diseases, and are a rich source for biomarker discovery. However, a large dynamic range of proteins in CSF makes the analysis very challenging because high abundant proteins tend to mask those of lower abundance. Therefore, advances in the proteomic analysis had to be applied in the screen for new specific biomarkers for Alzheimer's disease (AD). In this study, we have summarised the studies regarding two-dimensional gel electrophoresis (2-DE), and surface enhanced laser desorption/ionisation mass spectrometry (SELDI) technology that have been used in CSF of AD patients. Many proteins have shown to be altered in CSF of AD patients compared to controls, by using a protein pattern, from 2-D gel analysis or from SELDI analysis. Several studies show that the use of a panel of biomarkers derived from proteomic analysis is an advantageous way to distinguish AD from normal, and other dementia subjects.

Wallin A, Milos V, Sjögren M, Pantoni L, Erkinjuntti T. · Göteborg University, Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Mölndal, Sweden. · Int Psychogeriatr. · Pubmed #16191214 No free full text.

Abstract: Vascular dementia (VaD) is a heterogeneous entity with a large clinicopathological spectrum. It has been classified and subclassified in many different ways. The difficulty in identifying the various subtypes is a problem in the diagnostic process. For clinical purposes, it is desirable to find subtypes of VaD that are homogeneous enough to allow meaningful comparisons across studies. This article presents candidates for such subtypes: poststroke dementia, subcortical VaD, and combined Alzheimer's disease and VaD (AD + VaD). The first two candidates are easy to identify. Poststroke dementia occurs with cognitive decline in close temporal relation to a transient ischemic attack. Subcortical VaD has a relatively homogeneous clinical picture for which detailed criteria are suggested. AD + VaD is more difficult to identify but is possible, sometimes with the aid of neuroimaging and/or biological markers.

Mielke MM, Zandi PP, Sjögren M, Gustafson D, Ostling S, Steen B, Skoog I. · Center on Aging and Health, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Neurology. · Pubmed #15911792 No free full text.

Abstract: 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.

Wallin AK, Gustafson L, Sjögren M, Wattmo C, Minthon L. · Department of Psychiatry, Neuropsychiatric Clinic, Malmö University Hospital, Malmö, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #15211076 No free full text.

Abstract: Fifty consecutive outpatients with Alzheimer's disease (AD) received treatment with the cholinesterase inhibitor tacrine in an open longitudinal study. Assessments using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale - cognitive subscale, and a global rating were made at baseline and at 6, 12, 24, 36, 48 and 60 months. Three outcome groups were characterized: responders, unchanged and deteriorated. Additional outcome measures were time until nursing home placement, and mortality rate. At 6 months -75%, at 12 months -42%, at 24 months -20%, and after that 10% of the patients still on medication had improved or remained stable. The mortality rate did not differ between the outcome groups. Response to tacrine treatment at 6 or 12 months was found to predict a prolonged time until nursing home placement. No predictors for a positive treatment response could be identified at baseline.

Sjögren M, Englund E. · Department of Neuropsychiatry, Sahlgrenska University Hospital, Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #15178951 No free full text.

Abstract: We investigated the immunohistochemical stainability of phosphorylated tau and the light (NFL), intermediate (NFM), and heavy (NFH) neurofilament proteins in postmortem brain tissue from 8 patients with frontotemporal dementia (FTD), for comparison with 6 patients with Alzheimer's disease (AD), and 6 normal controls. In the FTD group, the neuropathological diagnosis was pure frontal-lobe degeneration of non-Alzheimer type (FLD) in 6 cases and in the remaining 2 cases mixed FLD-AD and frontal AD, respectively. The staining for tau was negative in 5 of the FLD cases and faintly positive in 1, but positive in all AD cases. The antibodies against NFM and NFH stained positive in FLD, AD, and controls, whereas the staining for NFL was negative in all FLD cases and positive in 1 AD case and in the controls. These findings regarding NFL and tau staining may be useful in the differential diagnosis of FLD and AD.

Wallin A, Sjögren M, Blennow K, Davidsson P. · Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #14512714 No free full text.

Abstract: The main objective was to investigate the acetylcholinesterase E (AChE) activity in the cerebrospinal fluid (CSF) of patients with three common dementia disorders. We also wanted to investigate the influence of apolipoprotein E (ApoE) epsilon4 allele possession and CSF-tau level on the CSF-AChE activity in these patients. The study included 17 consecutive patients with subcortical vascular dementia (SVD), 39 with Alzheimer's disease (AD), 14 with frontotemporal dementia (FTD) and 12 controls. CSF was obtained by lumbar puncture and CSF-AChE activity was measured by an enzyme antigen immunoassay. CSF-AchE activity was significantly decreased compared to controls only in the SVD group (p = 0.010). The CSF-tau level was increased in the AD group compared to the control (p < 0.01) and FTD groups (p < 0.05). No influence of ApoE epsilon4 allele possession on CSF-AChE activity was found. It is suggested that abnormal CSF-AChE activity in patients with SVD reflects a disturbance in the cholinergic system.

Sáez-Valero J, Fodero LR, Sjögren M, Andreasen N, Amici S, Gallai V, Vanderstichele H, Vanmechelen E, Parnetti L, Blennow K, Small DH. · Department of Pathology, University of Melbourne, Victoria, Australia. · J Neurosci Res. · Pubmed #12704813 No free full text.

Abstract: The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.

Johansson A, Hampel H, Faltraco F, Buerger K, Minthon L, Bogdanovic N, Sjögren M, Zetterberg H, Forsell L, Lilius L, Wahlund LO, Rymo L, Prince JA, Blennow K. · Department of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. · Neurosci Lett. · Pubmed #12648761 No free full text.

Abstract: Recent studies show linkage between Alzheimer's disease (AD) and two loci on chromosome 10. The cell division cycle 2 (cdc2) gene is located close to one of the chromosome 10 markers, and is a candidate gene for AD since it is involved in the pathogenesis of AD. We sequenced coding exons and flanking intronic sequences and the promoter region on the cdc2 gene and found three new single nucleotide polymorphisms (SNPs). We analyzed 272 Caucasian AD cases, 160 controls and 70 cases with frontotemporal dementia (FTD) for these SNPs. Homozygosity for one of the SNPs (Ex6+7I/D) was more frequent in both AD and FTD cases than in controls. In the combined tauopathy (AD and FTD) group the odds ratio (OR) was 1.77 (95% CI 1.19-2.63) for the Ex6+7II genotype. Our findings suggest that the Ex6+7I allele is associated with tauopathies, both AD and FTD.

Sáez-Valero J, Costell M, Sjögren M, Andreasen N, Blennow K, Luque JM. · Instituto de Neurociencias, UMH/CSIC, Campus de San Juan, San Juan, Alicante, Spain. · J Neurosci Res. · Pubmed #12645087 No free full text.

Abstract: Reelin is an essential glycoprotein for correct cytoarchitectonic organization during CNS development. Its function in the adult brain is far less well understood, but altered brain and blood reelin levels have been reported in some psychiatric disorders, and the possibility has been considered of an involvement of the reelin signaling pathway in neurodegeneration. Here we report, for the first time, the presence of detectable levels of reelin in rat and human cerebrospinal fluid (CSF) and show evidence for the involvement of a 180-kDa reelin fragment in two neurodegenerative disorders. This fragment was analyzed by Western blotting in CSF samples from 13 healthy control individuals and 14 frontotemporal dementia (FTD) and 20 Alzheimer's disease (AD) patients. Increased CSF 180-kDa reelin was found in FTD (161.7 +/- 6.7 arbitrary units; a.u.) and AD (151.4 +/- 3.8 a.u.) compared with control individuals (141.4 +/- 1.2 a.u., P < 0.05). Our results strongly suggest the involvement of reelin signaling in neurodegenerative pathologies.

Sjögren M, Wikkelsö C, Ostling S, Wallin A, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12411761 No free full text.

Abstract: We considered it possible that the differences in clinical symptoms between two suggested subgroups of Alzheimer's disease (AD), AD type I and AD type II, have biological correlates, for instance different metabolic profiles. Therefore, we performed regional cerebral blood flow (rCBF) measurements and investigated the cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid (HVA), 5-HIAA, and HMPG in 15 patients with AD type I, in 36 patients with AD type II, in a control group and in a contrast group consisting of 16 patients with frontotemporal dementia. The results suggest that there are underlying biological correlates of the phenomenological discrepancies between AD type I and AD type II. For instance, a decreased CSF level of HVA (p < 0.001) was specific to AD type I and decreased rCBF (p < 0.05 to <0.001) in three particular regions was specific to AD type II.