Alzheimer Disease: Zetterberg H

Zetterberg H. · No affiliation provided · Eur J Neurol. · Pubmed #18973609 No free full text.

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Zetterberg H, Andreasen N, Blennow K. · Sahlgrenska Universitetssjukhuset Mölndal. · Lakartidningen. · Pubmed #19585836 No free full text.

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Zetterberg H. · Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at Goteborg University, Molndal, Sweden. · Scand J Clin Lab Invest. · Pubmed #19199126 No free full text.

Abstract: Amyloid-beta (Abeta) is either directly involved in the pathogenesis of Alzheimer's disease (AD) or tightly correlated with other primary pathogenic factors. It is produced from amyloid precursor protein (APP) by proteolytic processing dependent on the beta-site APP-cleaving enzyme 1 (BACE1) and gamma-secretase, and is degraded by a broad range of proteases. This update summarizes the currently available studies that have determined the usefulness of BACE1 and secreted fragments of APP and Abeta as cerebrospinal fluid biomarkers for AD.

Wasling P, Daborg J, Riebe I, Andersson M, Portelius E, Blennow K, Hanse E, Zetterberg H. · Department of Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. · J Alzheimers Dis. · Pubmed #19158416 No free full text.

Abstract: Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-beta (Abeta) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Abeta is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Abeta, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Abeta and its precursor protein AbetaPP during development with special focus on electrophysiological findings.

Hampel H, Bürger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. · School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital, Dublin, Ireland. · Alzheimers Dement. · Pubmed #18631949 No free full text.

Abstract: BACKGROUND: In the earliest clinical stages of Alzheimer's disease (AD) when symptoms are mild, clinical diagnosis can be difficult. AD pathology most likely precedes symptoms. Biomarkers can serve as early diagnostic indicators or as markers of preclinical pathologic change. Candidate biomarkers derived from structural and functional neuroimaging and those measured in cerebrospinal fluid (CSF) and plasma show the greatest promise. Unbiased exploratory approaches, eg, proteomics or cortical thickness analysis, could yield novel biomarkers. The objective of this article was to review recent progress in selected imaging and neurochemical biomarkers for early diagnosis, classification, progression, and prediction of AD. METHODS: We performed a survey of recent research, focusing on core biomarker candidates in AD. RESULTS: A number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy, hold promise as biomarkers. These neurobiologic measures appear to relate closely to pathophysiologic, neuropathologic, and clinical data, such as hyperphosphorylation of tau, amyloid beta (Abeta) metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. Current advances in the neuroimaging of mediotemporal, neocortical, and subcortical areas of the brain of mild cognitive impairment (MCI) and AD subjects are presented. CSF levels of Abeta42, tau, and hyperphosphorylated tau protein (p-tau) can distinguish subjects with MCI who are likely to progress to AD. They also show preclinical alterations that predict later development of early AD symptoms. Studies on plasma Abeta are not entirely consistent, but recent findings suggest that decreased plasma Abeta42 relative to Abeta40 might increase the risk of AD. Increased production of Abeta in aging is suggested by elevation of BACE1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and p-tau are increased in MCI as well and show predictive value. Other biomarkers might indicate components of a cascade initiated by Abeta, such as oxidative stress or inflammation. These merit further study in MCI and earlier. CONCLUSIONS: A number of neuroimaging candidate markers are promising, such as hippocampus and entorhinal cortex volumes, basal forebrain nuclei, cortical thickness, deformation-based and voxel-based morphometry, structural and effective connectivity by using diffusion tensor imaging, tractography, and functional magnetic resonance imaging. CSF Abeta42, BACE1, total tau, and p-tau are substantially altered in MCI and clinical AD. Other interesting novel marker candidates derived from blood are being currently proposed (phase I). Biomarker discovery through proteomic approaches requires further research. Large-scale international controlled multicenter trials (such as the U.S., European, Australian, and Japanese Alzheimer's Disease Neuroimaging Initiative and the German Dementia Network) are engaged in phase III development of the core feasible imaging and CSF biomarker candidates in AD. Biomarkers are in the process of implementation as primary outcome variables into regulatory guideline documents regarding study design and approval for compounds claiming disease modification.

Zetterberg H. · Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital/Mölndal, S-431 80 Mölndal, Sweden. · Recent Pat CNS Drug Discov. · Pubmed #18537770 No free full text.

Abstract: Over the past decade, a tremendous amount of consistent data have accumulated showing reduced levels of the 42 amino acid isoform of amyloid-beta (Abeta(42)) in cerebrospinal fluid (CSF) from patients with mature as well as incipient Alzheimer's disease (AD). However, as CSF analyses necessitate a spinal tap, which some consider hard to implement in the clinical routine and in clinical trials, there is a strong interest in the possible association of Abeta levels in plasma with AD. This review provides an update on the current status of research on plasma Abeta as a biomarker for AD in the context of recent patents in the field.

Portelius E, Zetterberg H, Gobom J, Andreasson U, Blennow K. · Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, The Sahlgrenska Academy at Göteborg University, Mölndal, Sweden. · Expert Rev Proteomics. · Pubmed #18466053 No free full text.

Abstract: Diagnosis and monitoring of sporadic Alzheimer's disease (AD) have long depended on clinical examination of individuals with end-stage disease. However, upcoming anti-AD therapies are optimally initiated when individuals show very mild signs of neurodegeneration. There is a developing consensus for cerebrospinal fluid amyloid-beta (Abeta) as a core biomarker for the mild cognitive impairment stage of AD. Abeta is directly involved in the pathogenesis of AD or tightly correlated with other primary pathogenic factors. It is produced from amyloid precursor protein (APP) by proteolytic processing that depends on the beta-site APP-cleaving enzyme 1 and the gamma-secretase complex, and is degraded by a broad range of proteases. This review summarizes targeted proteomic studies of Abeta in biological fluids and identifies clinically useful markers of disrupted Abeta homeostasis in AD. The next 5 years will see a range of novel assays developed on the basis of these results. From a longer perspective, establishment of the most effective combinations of different biomarkers and other diagnostic modalities may be foreseen.

Andreasen N, Zetterberg H. · Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Sweden. · Curr Med Chem. · Pubmed #18393845 No free full text.

Abstract: Alzheimer's disease (AD) is an age-related disorder that causes brain damage resulting in progressive cognitive impairment and death. Three decades of progress have given us a detailed understanding of the underlying molecular mechanisms. Over the past 10 years, this knowledge has translated into a range of targets for therapy, the most promising of which is amyloid beta (Abeta). An imbalance between the production and clearance of Abeta is thought by many to represent the earliest event in the pathogenesis of AD. Abeta is known to be subject to oligomerisation, a process that increases its synaptotoxicity. The oligomers may aggregate further to proto-fibrils and fibrils, eventually forming senile plaques, the neuropathological hallmark of AD. In this article we review the key aspects of Abeta as a biomarker for AD, including its pathogenicity, the diagnostic performance of different Abeta assays in different settings, and the potential usefulness of Abeta as a surrogate marker for treatment efficacy in clinical trials of novel Abeta-targeting drugs.

Blennow K, de Leon MJ, Zetterberg H. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Sweden. · Lancet. · Pubmed #16876668 No free full text.

Abstract: Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, Zetterberg H, Galasko D, Praticò D, Griffin S, Schenk D, Siemers E. · University of California San Diego, Department of Neurosciences, La Jolla, California, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493230 links to  free full text

Abstract: Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.

Blennow K, Popa C, Rasulzada A, Minthon L, Wallin A, Zetterberg H. · Institutionen för klinisk neurovetenskap, Sahlgrenska Universitetssjukhuset/Mölndal, Sweden. · Lakartidningen. · Pubmed #16196432 No free full text.

Abstract: The clinical symptomatology and pathogenic mechanisms of chronic traumatic brain injury associated with boxing (CTBI-B) is reviewed. This syndrome is also known as punch drunk syndrome or dementia pugilistica. Since even milder forms of CTBI-B are rare among amateur boxers, we make a distinction between amateur and professional boxing throughout the review. Focus is also set on the interesting similarities in neurochemical changes and pathogenic mechanisms between CTBI-B, acute traumatic brain injury (e.g. road traffic accidents) and Alzheimer's disease.

Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW, Anonymous00416. · Department of Public Health and Geriatrics, Uppsala University Hospital, Uppsala, Sweden. · Lancet Neurol. · Pubmed #18672400 No free full text.

Abstract: BACKGROUND: PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu2(+)-mediated and Zn2(+)-mediated toxic oligomerisation of Abeta seen in Alzheimer's disease (AD). Strong preclinical efficacy data and the completion of early, clinical safety studies have preceded this phase IIa study, the aim of which was to assess the effects of PBT2 on safety, efficacy, and biomarkers of AD. METHODS: Between December 6, 2006, and September 21, 2007, community-dwelling patients over age 55 years were recruited to this 12-week, double-blind, randomised trial of PBT2. Patients were randomly allocated to receive 50 mg PBT2, 250 mg PBT2, or placebo. Inclusion criteria were early AD (mini-mental state examination [MMSE] score between 20 and 26 points or Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) score between 10 and 25 points), taking a stable dose of acetylcholinesterase inhibitor (donepezil, galantamine, or rivastigmine) for at least 4 months, a modified Hachinski score of 4 points or less, and CT or MRI results that were consistent with AD. The principal outcomes were safety and tolerability. Secondary outcomes were plasma and CSF biomarkers and cognition. Analysis was intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00471211. FINDINGS: 78 patients were randomly assigned (29 to placebo, 20 to PBT2 50 mg, and 29 to PBT2 250 mg) and 74 (95%) completed the study. 42 (54%) patients had at least one treatment emergent adverse event (10 [50%] on PBT2 50 mg, 18 [62%] on PBT2 250 mg, and 14 [48%] on placebo). No serious adverse events were reported by patients on PBT2. Patients treated with PBT2 250 mg had a dose-dependent (p=0.023) and significant reduction in CSF Abeta(42) concentration compared with those treated with placebo (difference in least squares mean change from baseline was -56.0 pg/mL, 95% CI -101.5 to -11.0; p=0.006). PBT2 had no effect on plasma biomarkers of AD or serum Zn(2+) and Cu(2+) concentrations. Cognition testing included ADAS-cog, MMSE, and a neuropsychological test battery (NTB). Of these tests, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group: category fluency test (2.8 words, 0.1 to 5.4; p=0.041) and trail making part B (-48.0 s, -83.0 to -13.0; p=0.009). INTERPRETATION: The safety profile is favourable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma is suggestive of a central effect of the drug on Abeta metabolism. Cognitive efficacy was restricted to two measures of executive function. Future trials that are larger and longer will establish if the effects of PBT2 on biomarkers and cognition that are reported here translate into clinical effectiveness.

Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. · Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. · JAMA. · Pubmed #19622817 No free full text.

Abstract: CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Kondziella D, Göthlin M, Fu M, Zetterberg H, Wallin A. · Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. · Neuroreport. · Pubmed #19424098 No free full text.

Abstract: High levels of B-type natriuretic peptide (BNP), a serum marker of congestive heart failure, are associated with an increased risk for cognitive decline. However, no study has yet assessed this marker in different subtypes of dementia. We tested the hypothesis that BNP has a more significant association with vascular dementia than Alzheimer disease. Plasma BNP was measured in 15 patients with subcortical vascular dementia, in 19 Alzheimer patients without evidence of vascular comorbidity, and in age-matched controls. Compared with controls (28+/-7 ng/l), BNP was elevated in subcortical vascular dementia (63+/-17 ng/l; P=0.03), but not in Alzheimer disease (36+/-5 ng/l). In conclusion, subcortical vascular dementia is indeed associated with moderately elevated BNP levels, whereas this could not be shown for Alzheimer disease. This probably reflects the larger cardiovascular burden in patients with subcortical vascular dementia.

Portelius E, Brinkmalm G, Tran AJ, Zetterberg H, Westman-Brinkmalm A, Blennow K. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden. · Neurodegener Dis. · Pubmed #19229112 No free full text.

Abstract: BACKGROUND: Aggregation of beta-amyloid (Abeta) into oligomers and plaques is the central pathogenic mechanism in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein (APP) by beta- and gamma-secretases, whereas, in the nonamyloidogenic pathway, alpha-secretase cleaves within the Abeta sequence, and thus precludes Abeta formation. A lot of research has focused on Abeta production and the neurotoxic 42-amino-acid form of Abeta (Abeta1-42), while less is known about the nonamyloidogenic pathway and how Abeta is degraded. OBJECTIVE: To study the Abeta metabolism in man by searching for novel Abeta peptides in cerebrospinal fluid (CSF). METHODS: Immunoprecipitation, using an anti-Abeta antibody, 6E10, was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. RESULTS: We identified 12 truncated APP/Abeta peptides in the CSF, all of which end at amino acid 15 in the Abeta sequence, i.e. 1 amino acid before the proposed alpha-secretase site. Of these 12 APP/Abeta peptides, 11 are novel peptides and start N-terminally of the beta-secretase site. The most abundant APP/Abeta peptide starts 25 amino acids before the beta-secretase site, APP/Abeta (-25 to 15), and had a concentration of approximately 80 pg/ml. The identity of all the APP/Abeta peptides was verified in a cohort of AD patients and controls. A first pilot study also showed that the intensity of several APP/Abeta peaks in CSF was higher in AD cases than in controls. CONCLUSION: These data suggest an enzymatic activity that cleaves the precursor protein in a specific manner that may reflect a novel metabolic pathway for APP and Abeta.

Hansson SF, Andréasson U, Wall M, Skoog I, Andreasen N, Wallin A, Zetterberg H, Blennow K. · Neurochemical Laboratory, Department of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, The Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden. · J Alzheimers Dis. · Pubmed #19221428 No free full text.

Abstract: Amyloid-beta(Abeta) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Abeta can take part in the aggregation process. Therefore, endogenous Abeta-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Abeta-binding capacity in CSF is a specific feature of AD. A panel of known Abeta-binding CSF proteins, including beta-trace/prostaglandin D2 synthase (beta-trace), transthyretin (TTR), cystatin C (CysC) and alpha(1)-antitrypsin (AAT), were quantified and related to diagnosis and CSF levels of Abeta(1-38), Abeta(1-40) and Abeta(1-42). AD patients displayed a mild reduction in the CSF levels of beta-trace (p=0.020), CysC (p=0.017), AAT (p=0.019) and TTR (p=0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of beta-trace and CysC were also reduced in FTD. As expected, CSF Abeta(1-42) was reduced in AD compared with controls (p=0.00005) and with FTD patients (p=0.015). Positive correlations between Abeta(1-42) and beta-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Abeta-binding capacity in CSF may contribute to the amyloidogenic process in AD.

Brys M, Glodzik L, Mosconi L, Switalski R, De Santi S, Pirraglia E, Rich K, Kim BC, Mehta P, Zinkowski R, Pratico D, Wallin A, Zetterberg H, Tsui WH, Rusinek H, Blennow K, de Leon MJ. · New York University School of Medicine, Center for Brain Health, NY 10016, USA. · J Alzheimers Dis. · Pubmed #19221425 No free full text.

Abstract: Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

Marklund N, Blennow K, Zetterberg H, Ronne-Engström E, Enblad P, Hillered L. · Department of Neuroscience, Neurosurgery, Uppsala University Hospital, Uppsala, Gothenburg, Sweden. · J Neurosurg. · Pubmed #19216653 No free full text.

Abstract: OBJECT: Damage to axons contributes to postinjury disabilities and is commonly observed following traumatic brain injury (TBI). Traumatic brain injury is an important environmental risk factor for the development of Alzheimer disease (AD). In the present feasibility study, the aim was to use intracerebral microdialysis catheters with a high molecular cutoff membrane (100 kD) to harvest interstitial total tau (T-tau) and amyloid beta 1-42 (Abeta42) proteins, which are important biomarkers for axonal injury and for AD, following moderate-to-severe TBI.METHODS: Eight patients (5 men and 3 women) were included in the study; 5 of the patients had a focal/mixed TBI and 3 had a diffuse axonal injury (DAI). Following the bedside analysis of the routinely measured energy metabolic markers (that is, glucose, lactate/pyruvate ratio, glycerol, and glutamate), the remaining dialysate was pooled and two 12-hour samples per day were used to analyze T-tau and Abeta42 by enzyme-linked immunosorbent assay from Day 1 up to 8 days postinjury.RESULTS: The results show high levels of interstitial T-tau and Abeta42 postinjury. Patients with a predominantly focal lesion had higher interstitial T-tau levels than in the DAI group from Days 1 to 3 postinjury (p < 0.05). In contrast, patients with DAI had consistently higher Abeta42 levels when compared with patients with focal injury.CONCLUSIONS: These results suggest that monitoring of interstitial T-tau and Abeta42 by using microdialysis may be an important tool when evaluating the presence and role of axonal injury following TBI.

Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, Blennow K, Zetterberg H. · Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. · Neurosci Lett. · Pubmed #19022350 No free full text.

Abstract: The association of alpha-synuclein (alpha-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based alpha-syn biomarkers for these types of diseases. Recent studies show that alpha-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of alpha-syn in CSF down to 50pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF alpha-syn levels. AD patients had significantly lower alpha-syn levels than controls (median [inter-quartile range] 296 [234-372] and 395 [298-452], respectively, p<0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower alpha-syn than AD patients with MMSE scores of 20 or higher (p=0.02). There was also a tendency towards a negative correlation between alpha-syn levels and disease duration in the AD group (r=-0.247, p=0.06). Altogether, our results speak against CSF alpha-syn as a reliable biomarker for PD and DLB. The lower alpha-syn levels in AD, as well as the association of alpha-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.

Buchhave P, Janciauskiene S, Zetterberg H, Blennow K, Minthon L, Hansson O. · Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden. · Neurosci Lett. · Pubmed #18996438 No free full text.

Abstract: CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.

Zetterberg H, Andreasson U, Hansson O, Wu G, Sankaranarayanan S, Andersson ME, Buchhave P, Londos E, Umek RM, Minthon L, Simon AJ, Blennow K. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Göteborg University, Mölndal, Sweden. · Arch Neurol. · Pubmed #18695061 links to  free full text

Abstract: BACKGROUND: We used a sensitive and specific beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) assay to determine the relationship between BACE1 activity in cerebrospinal fluid (CSF) and markers of APP metabolism and axonal degeneration in early and late stages of Alzheimer disease (AD). OBJECTIVE: To assess CSF BACE1 activity in AD. DESIGN: Case-control and longitudinal follow-up study. SETTING: Specialized memory clinic. Patients Eighty-seven subjects with AD, 33 cognitively normal control subjects, and 113 subjects with mild cognitive impairment (MCI), who were followed up for 3 to 6 years. MAIN OUTCOME MEASURES: Cerebrospinal fluid BACE1 activity in relation to diagnosis and CSF levels of secreted APP and amyloid beta protein (Abeta) isoforms and the axonal degeneration marker total tau. RESULTS: Subjects with AD had higher CSF BACE1 activity (median, 30 pM [range, 11-96 pM]) than controls (median, 23 pM [range, 8-43 pM]) (P =.02). Subjects with MCI who progressed to AD during the follow-up period had higher baseline BACE1 activity (median, 35 pM [range, 18-71 pM]) than subjects with MCI who remained stable (median, 29 pM [range, 14-83 pM]) (P < .001) and subjects with MCI who developed other forms of dementia (median, 20 pM [range, 10-56 pM]) (P <.001). BACE1 activity correlated positively with CSF levels of secreted APP isoforms and Abeta(40) in the AD and control groups and in all MCI subgroups (P < .05) except the MCI subgroup that developed AD. Strong positive correlations were found between CSF BACE1 activity and total tau levels in all MCI subgroups (r >or= 0.57, P <or= .009). CONCLUSION: Elevated BACE1 activity may contribute to the amyloidogenic process in sporadic AD and is associated with the intensity of axonal degeneration.

Zetterberg H, Jacobsson J, Rosengren L, Blennow K, Andersen PM. · Department of Neurochemistry and Psychiatry, Sahlgrenska University Hospital, Göteborg University, Sweden. · J Neurol Sci. · Pubmed #18656208 No free full text.

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome with familial and sporadic forms. We conducted a study including 60 sporadic and 19 familial ALS patients, 206 reference patients with other neurological disorders and 1265 neurologically healthy controls to assess the Alzheimer-associated apolipoprotein E (APOE) epsilon4 gene variant as a possible risk factor for ALS. While no major influence of APOE epsilon4 on disease risk was detected, a gene dose-dependent effect with lower age at onset of sporadic ALS in epsilon4 carriers was found (p=0.027). These data support APOE epsilon4 as a subordinate contributing factor in ALS.

Klyubin I, Betts V, Welzel AT, Blennow K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Peng Y, Wisniewski T, Selkoe DJ, Anwyl R, Walsh DM, Rowan MJ. · Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland. · J Neurosci. · Pubmed #18417702 links to  free full text

Abstract: The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.

Portelius E, Hansson SF, Tran AJ, Zetterberg H, Grognet P, Vanmechelen E, Höglund K, Brinkmalm G, Westman-Brinkmalm A, Nordhoff E, Blennow K, Gobom J. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden. · J Proteome Res. · Pubmed #18351740 No free full text.

Abstract: The neurodegenerative disorder Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The presence of neurofibrillary tangles, consisting of hyperphosphorylated tau protein, is one of the major neuropathologic characteristics of the disease, making this protein an attractive biomarker for AD and a possible target for therapy. Here, we describe an optimized immunoprecipitation mass spectrometry method that enables, for the first time, detailed characterization of tau in human cerebrospinal fluid. The identities of putative tau fragments were confirmed using nanoflow liquid chromatography and tandem mass spectrometry. Nineteen tryptic fragments of tau were detected, of which 16 are found in all tau isoforms while 3 represented unique tau isoforms. These results pave the way for clinical CSF studies on the tauopathies.

Höglund K, Hansson O, Buchhave P, Zetterberg H, Lewczuk P, Londos E, Blennow K, Minthon L, Wiltfang J. · Neurochemistry Lab, Department of Neuroscience and Physiology, Göteborg University, Molndal, Sweden. · Neurodegener Dis. · Pubmed #18309230 No free full text.

Abstract: BACKGROUND: Identifying individuals at high risk of developing Alzheimer's disease (AD) is important for future therapeutic strategies, and there is a clinical need for diagnostic biomarkers to identify incipient AD. OBJECTIVE: The aim of the present study was to investigate if the AD-associated Abeta peptide pattern recently found in cerebrospinal fluid (CSF) could discriminate between patients with incipient AD and those with stable mild cognitive impairment (MCI) by analyzing CSF from patients with MCI at baseline. METHODS: The levels of Abeta(1-37, -38, -39, -40, -42) were analyzed by Abeta-SDS-PAGE/immunoblot in CSF from 19 healthy controls, 25 patients with stable MCI and from 25 patients with MCI who later developed AD during 4- to 6-year follow-up. RESULTS: All healthy controls and 20 out of 22 patients who developed AD were correctly classified by their baseline Abeta peptide pattern. In 9 out of 25 stable MCI patients, the pattern indicated incipient AD in spite of clinical nonconversion. Interestingly, these individuals had apolipoprotein E genotypes and CSF levels of tau and phospho-tau that are known to be associated with high risk of AD. CONCLUSION: Altogether, our study reveals the novel finding that the Abeta peptide pattern is able to predict AD in patients with MCI with a sensitivity of 91% and specificity of 64%. The specificity would increase to 94% if the high-risk patients in the stable MCI cohort developed AD during extended follow-up.