Alzheimer Disease: Möller HJ

Padberg F, Hampel H, Möller HJ. · No affiliation provided · MMW Fortschr Med. · Pubmed #11824167 No free full text.

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Padberg F, Hampel H, Möller HJ. · No affiliation provided · Fortschr Med Orig. · Pubmed #11789127 No free full text.

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Hampel H, Mitchell A, Blennow K, Frank RA, Brettschneider S, Weller L, Möller HJ. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · J Neural Transm. · Pubmed #14991453 No free full text.

Abstract: Alzheimer's disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and beta-amyloid 1-42 (Abeta(1-42)), phosphorylated tau (p-tau) and beta-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Abeta(1-42) in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes.

Frölich L, Fox J, Padberg F, Maurer K, Möller HJ, Hampel H. · Klinik für Psychiatrie und Psychotherapie I Johann Wolfgang Goethe-Universität, Heinrich-Hoffmann-Str 10, 60528 Frankfurt am Main, Germany. · Curr Pharm Des. · Pubmed #14754383 No free full text.

Abstract: Diagnosis and therapy of dementia have made considerable progress in recent years. Drugs have been developed which improve cognitive performance, delay the loss of abilities of daily living and prevent early nursing home placement in a considerable number of patients. With the various pharmacological and non-pharmacological approaches, effective treatment options of AD are available at present and the therapeutic potential will even increase in future. Thus, the treatment of dementia should more focused and explicit in its goals for the doctor, the patient and the relatives. Therapeutic targets must be defined on the basis of the individual needs and deficits and with regard to different levels of the disease process. Ideally, treatment should always aim at an etiological and/or a pathophysiological level. At present, however, aiming at the neurotransmitter level, the core syndrome of cognitive deficits can be approached by treatment options. Further therapeutic targets can be defined on the level of activities of daily living, following a resource focused approach, as well as on the level of behavioral disturbances. Additional therapeutic targets should be seen under a humanitarian or palliative perspective. And finally, family members are also targets for therapy in dementia, even if such therapy is not directed towards the demented patient. All these treatment targets have to be evaluated and adapted under the perspective of time because prominent symptoms in AD change considerably with disease progression. Selection and adaptation of medication becomes easier if such targets are considered and if therapeutic effects are monitored target-specifically.

Fuchsberger T, Möller HJ, Hampel H. · Klinik und Poliklinik für Psychiatrie und Psychotherapie, LMU München. · MMW Fortschr Med. · Pubmed #14579485 No free full text.

Abstract: In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are being investigated in ongoing clinical and experimental studies. Presently available treatments should be initiated early on, and applied as long as needed, which requires the earliest possible clinical diagnosis by the primary-care physician. The results of initial studies reveal an effect of antidementia agents also in mixed Alzheimer's and vascular dementia, as well as vascular and lewy-body dementia. Efforts to obtain approval for these indications are underway.

Frölich L, Padberg F, Kratzsch T, Maurer K, Möller HJ, Hampel H. · Klinik für Psychiatrie und Psychotherapie der Univ. Frankfurt/M. · MMW Fortschr Med. · Pubmed #10920665 No free full text.

Abstract: In recent years, considerable progress has been made both in the diagnosis and treatment of dementia. Drugs have been developed which enhance cognitive performance in a large percentage of those afflicted, delay impairment of the ability to cope with the tasks of daily life, and avoid premature admission to a nursing home. In the practical medical care setting, however, these advantages are being utilized to only a limited extent, and this despite the fact that numerous therapeutic options are now available for the treatment of AD. New therapeutic approaches are aimed at inhibiting the pathological cleavage and extracellular and intracellular deposition of amyloid, preventing the toxic effects of amyloid accumulation around the neurons, and re-establishing intracellular transport deranged by the aggregation of neurofibrils. A further approach is the use of combinations of available substances with differing, possibly synergic, effects. Over and beyond this, treatment of AD in the "presymptomatic stage", or in the stage of only mild cognitive disturbance, is currently the subject of clinical trials.

Möller HJ. · Psychiatric Hospital of the Ludwig-Maximilian-University, Munich, Germany. · Eur Neuropsychopharmacol. · Pubmed #10332935 No free full text.

Abstract: A number of observations support the hypothesis that a central deficit in acetylcholine (ACh) may be responsible for the initiation of Alzheimer's disease (AD). For example, cholinergic innervation in AD is reduced in areas of the brain important for processing information. Further, reduced concentrations of choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of ACh, correlate with the number of beta-amyloid senile plaques and cognitive dysfunction in AD patients. Consequently, several strategies to increase cholinergic neurotransmission have been developed, including ACh precursors, ACh release enhancers, cholinesterase (ChE) inhibitors and receptor agonists. Although ChE inhibitors appear to be the most promising, tacrine, the first ChE inhibitor to be registered and approved for the treatment of AD, has significant tolerability problems. Thus, ChE inhibitors with improved side-effect profiles have been developed and subsequently awarded marketing approval. However, in addition to the cholinergic system that is the most severely affected neurotransmitter system in AD, other neurotransmitter systems may be involved (e.g. serotonergic, noradrenergic and glutamatergic). Therefore, bifunctional compounds or combinations of drugs may provide additional therapeutic value.

Hampel H, Padberg F, Buch K, Unger J, Stübner S, Möller HJ. · Psychiatrische Klinik und Poliklinik, Ludwig-Maximilians-Universität München. · Dtsch Med Wochenschr. · Pubmed #10076553 No free full text.

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Teipel SJ, Drzezga A, Bartenstein P, Möller HJ, Schwaiger M, Hampel H. · Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr. 7, 80336 Munich, Germany. · Psychopharmacology (Berl). · Pubmed #16767418 No free full text.

Abstract: RATIONALE: Cholinergic enhancement is among the best established treatments of Alzheimer's disease (AD). The cognitive effects of treatment are thought to be mediated by improvement of neuronal transmission. Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) by measuring cortical metabolic response to activation assesses integrity of neuronal transmission in vivo. OBJECTIVE: To determine the effects of treatment with donepezil, a centrally selective acetylcholinesterase inhibitor, on cortical metabolism in AD using 18FDG-PET. METHODS: We enrolled 23 patients, 18 of which completed the study, with mild to moderate probable AD (mini-mental status exam scores of 15-28, inclusive) in a double-blind cross over trial of 8 weeks donepezil compared to 8 weeks placebo with repeated double 18FDG-PET examinations during passive audio-visual stimulation. Effects of treatment on cortical metabolic response to stimulation were determined with a linear model on a voxel level using Statistical Parametric Mapping (SPM 99, Wellcome Department of Imaging Neuroscience, London). RESULTS: Effects of treatment on cognitive measures were not different between donepezil and placebo. During passive audio-visual stimulation, patients showed activation in posterior visual and auditory areas and decreased activation in frontal cortex and basal ganglia. Resting state metabolism was increased with donepezil in left prefrontal cortex and decreased in right hippocampus. Cortical response to activation was increased in right hippocampus with donepezil compared to placebo. CONCLUSION: Donepezil treatment shows a spatially limited functional effect on right hippocampus and left prefrontal cortical metabolism, independently of clinical response to treatment.

Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. · Department of Neurology, Friedrich-Wilhelms-University, Sigmund-Freudstr. 25, 53105 Bonn, Germany. · J Neurol Neurosurg Psychiatry. · Pubmed #15377700 links to  free full text

Abstract: OBJECTIVE: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD. METHODS: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. RESULTS: Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. CONCLUSION: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.

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.

Hegerl U, Mergl R, Henkel V, Gallinat J, Kotter G, Müller-Siecheneder F, Pogarell O, Juckel G, Schröter A, Bahra R, Emir B, Laux G, Möller HJ. · No affiliation provided · J Clin Psychopharmacol. · Pubmed #12640228 No free full text.

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Frodl T, Hampel H, Juckel G, Bürger K, Padberg F, Engel RR, Möller HJ, Hegerl U. · Department of Psychiatry, Ludwig-Maximilians University Munich, Germany. · Psychophysiology. · Pubmed #12212666 No free full text.

Abstract: Accurate and early diagnosis of Alzheimer's Disease (AD) with reliable and noninvasive methods is of great importance for clinical practice as effective and specific antidementive therapies become available. The aim of the study was to evaluate the clinical relevance of event-related P300 in the early diagnosis of AD. Thirty patients with AD, 26 patients with mild cognitive impairment (MCI) from our Memory Clinic and 26 age-matched healthy controls (HC) were studied with event-related P300 potentials. Amplitudes of temporo-basal dipoles (TB-P300) were significantly diminished in AD compared to HC and MCI. Furthermore, latencies of temporo-superior dipoles (TS-P300) were significantly prolonged in AD compared with HC. Sensitivity was 90.0% for the differentiation of patients with AD from HC (specificity 79.1%) using reduced TB-P300 amplitudes and prolonged TS-P300 latencies. Similar results were found using Pz amplitudes as well as Fz latencies. Our data suggest that TB-P300 amplitudes and TS-P300 latencies may be an accurate clinically available, nonexpensive, noninvasive, and reliable marker for AD.

Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K, DeBernardis J, Kerkman D, McCulloch C, Kohnken R, Padberg F, Pirttilä T, Schapiro MB, Rapoport SI, Möller HJ, Davies P, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center, Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Arch Neurol. · Pubmed #12164722 links to  free full text

Abstract: BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.

Hampel H, Teipel SJ, Bayer W, Alexander GE, Schwarz R, Schapiro MB, Rapoport SI, Möller HJ. · Dementia Research and Neuroimaging Section, Memory Clinic, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr.7, 80336, Munich, Germany. · J Neurol Sci. · Pubmed #11809161 No free full text.

Abstract: OBJECTIVE: The specificity of magnetic resonance imaging (MRI)-based hippocampal measurements in detecting Alzheimer's disease (AD) pathology is reduced by an age-related reduction of the hippocampus volume. We propose an adjustment for this age effect to increase the diagnostic accuracy of hippocampal volumes in AD. METHOD: Using an orthogonal rotational transformation of the coordinate system, values of MRI-determined volumes of hippocampus-amygdala formation (HAF) were transformed according to the age effect in 27 AD patients and 28 age- and sex-matched healthy control subjects. RESULTS: The age transformation increased the diagnostic accuracy of HAF volumes in the study sample and in an independent sample from the literature. The age-transformed HAF volume predicted AD in a subject with mild cognitive impairment (MCI) with later biopsy-confirmed AD. CONCLUSION: Age transformation may provide an easily applicable method to increase the clinical diagnostic accuracy of hippocampal measurements by considering the effect of aging on hippocampus volume.

Zill P, Bürger K, Behrens S, Hampel H, Padberg F, Boetsch T, Möller HJ, Ackenheil M, Bondy B. · Psychiatric Hospital of the Ludwig-Maximilians-University, Munich, Nussbaumstrasse 7, D-80336, Munich, Germany. · Neurosci Lett. · Pubmed #11058789 No free full text.

Abstract: Recent reports have suggested that genetic polymorphisms in the alpha-2 macroglobulin (A2M) gene are associated with an increased risk for Alzheimer's disease. In the present study we tested two polymorphisms in the alpha-2 macroglobulin gene, a 5 bp deletion at the 5' splice site of exon 18 and a G/A point mutation (V1000I) in exon 24, in a sample of 118 healthy, non demented controls and 238 consecutively recruited gerontopsychiatric patients, diagnosed as: Alzheimer's disease (N=88), mild cognitive impairment (N=32), subjective cognitive complaints (N=54) and depression/other psychiatric disorders (N=64). The aim of this study was to test whether the investigated polymorphisms has a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders or to differentiate genetically AD from other forms of dementia, respectively. Also a possible relation to the APOE varepsilon4 polymorphism was examined. Our study failed to show an association between the two investigated polymorphisms in the alpha-2 macroglobulin gene and any of the four different psychogeriatric patient subgroups, either alone or in combination with the APOE varepsilon4 genotype.

Kahle PJ, Jakowec M, Teipel SJ, Hampel H, Petzinger GM, Di Monte DA, Silverberg GD, Möller HJ, Yesavage JA, Tinklenberg JR, Shooter EM, Murphy GM. · Departments of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA. · Neurology. · Pubmed #10751266 No free full text.

Abstract: OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Möller HJ, Rogers SL, Friedhoff LT. · Withington Hospital, Manchester, UK. · Dement Geriatr Cogn Disord. · Pubmed #10325453 No free full text.

Abstract: Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD.

Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. · Trinity Center for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin 24, Ireland. · J Clin Psychiatry. · Pubmed #19573486 No free full text.

Abstract: OBJECTIVE: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease. METHOD: A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. RESULTS: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. CONCLUSIONS: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population. TRIAL REGISTRATION: (Controlled-Trials.com) Identifier: ISRCTN72046462.

Bokde AL, Karmann M, Teipel SJ, Born C, Lieb M, Reiser MF, Möller HJ, Hampel H. · Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · J Clin Psychopharmacol. · Pubmed #19512976 No free full text.

Abstract: Visual perception has been shown to be altered in Alzheimer disease (AD) patients, and it is associated with decreased cognitive function. Galantamine is an active cholinergic agent, which has been shown to lead to improved cognition in mild to moderate AD patients. This study examined brain activation in a group of mild AD patients after a 3-month open-label treatment with galantamine. The objective was to examine the changes in brain activation due to treatment. There were 2 tasks to visual perception. The first task was a face-matching task to test the activation along the ventral visual pathway, and the second task was a location-matching task to test neuronal function along the dorsal pathway. Brain activation was measured using functional magnetic resonance imaging. There were 5 mild AD patients in the study. There were no differences in the task performance and in the cognitive scores of the Consortium to Establish a Registry for Alzheimer's Disease battery before and after treatment. In the location-matching task, we found a statistically significant decrease in activation along the dorsal visual pathway after galantamine treatment. A previous study found that AD patients had higher activation in the location-matching task compared with healthy controls. There were no differences in activation for the face-matching task after treatment. Our data indicate that treatment with galantamine leads to more efficient visual processing of stimuli or changes the compensatory mechanism in the AD patients. A visual perception task recruiting the dorsal visual system may be useful as a biomarker of treatment effects.

Möller T, Born C, Reiser MF, Möller HJ, Hampel H, Teipel SJ. · Alzheimer Gedächtniszentrum, Psychiatrische Klinik der Ludwig-Maximilians Universität, München, Deutschland. · Nervenarzt. · Pubmed #18810380 No free full text.

Abstract: BACKGROUND: Measurement of regional atrophy of the corpus callosum and cortical grey matter may differentiate between primary loss of intracortical projecting neurons and primary fibre degeneration in Alzheimer's disease (AD) and vascular dementia (VD). METHODS: The regional corpus callosum area and cortical grey matter volumes were measured in 30 patients with the clinical diagnosis of probable AD, 20 patients with the clinical diagnosis of probable VD and 24 healthy elderly control subjects using MRI in two centers in Munich and Amsterdam. RESULTS: Patients with AD showed significantly reduced volumes of cortical grey matter in all cerebral lobes and atrophy of anterior and posterior corpus callosum areas. In VD patients only occipital lobe grey matter volume and anterior corpus callosum area were significantly reduced. In AD patients reduction of cortical grey matter volumes was significantly correlated with regional reductions of corpus callosum areas, but not in VD patients or controls. CONCLUSION: These findings support the notion that measurement of the corpus callosum and cortical grey matter atrophy may identify the underlying causes of cortical disconnection in AD and VD and may be helpful to differentiate between both conditions.

Bokde AL, Lopez-Bayo P, Born C, Dong W, Meindl T, Leinsinger G, Teipel SJ, Faltraco F, Reiser M, Möller HJ, Hampel H. · Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Psychiatry Res. · Pubmed #18672352 No free full text.

Abstract: Subjects with mild cognitive impairment (MCI) have a higher risk of developing Alzheimer's disease compared with healthy controls (HC). Sensory impairment can contribute to the severity of cognitive impairment. We measured the activation changes in the visual system between MCI and HC subjects. There were 16 MCI subjects with either amnestic MCI or multiple-domain+amnestic MCI and an HC group of 19 subjects. There were two tasks: (a) a face matching and (b) a location matching task. Brain activation was measured using functional magnetic resonance imaging. There were no differences in task performance. The HC group selectively activated the ventral and dorsal pathways during the face and location matching tasks, respectively, while the MCI group did not. The MCI group had greater activation than the HC group in the left frontal lobe during the location matching task. There were no areas of increased activation in the HC group compared with the MCI group. The MCI group, as a compensatory mechanism, activated both visual pathways and increased activation in the left frontal lobe during the location matching task compared with the healthy controls. To our knowledge, this is the first study that has examined visual processing in MCI.

Teipel SJ, Mitchell AJ, Möller HJ, Hampel H. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · J Neural Transm Suppl. · Pubmed #17982900 No free full text.

Abstract: BACKGROUND: High variability of estimates of cognitive decline in patients with Alzheimer's disease (AD) derived from unbalanced longitudinal designs may result as much from the applied statistical model as from true biological variability. OBJECTIVE: To compare the accuracy of two statistical models, serial subtraction score (SSA) and mixed-effects regression analysis (MEM), to estimate rates of cognitive decline in patients with amnestic mild cognitive impairment (MCI), a group at risk for AD. METHODS: We recorded serial mini mental state examination (MMSE) scores from 78 MCI patients. Additionally, we derived simulated trajectories of cognitive decline with unequally spaced observation intervals. Rates of change were assessed from clinical and simulated data using SSA and MEM models. RESULTS: MEM reduced variability of rates of change significantly compared to SSA. In a polynomial model, overall length of observation time explained a significant amount of variance of SSA, but not of MEM estimates. For simulated data, MEM was significantly more accurate in predicting true rates of change compared to SSA (p < 0.001). CONCLUSION: MEM yields more accurate estimates of cognitive decline from unbalanced longitudinal data. Simulation studies may be useful to select the appropriate statistical model for a given set of clinical data.

Teipel SJ, Born C, Ewers M, Bokde AL, Reiser MF, Möller HJ, Hampel H. · Alzheimer Memorial Center, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr 7, 80336, Munich, Germany. · Neuroimage. · Pubmed #17827035 No free full text.

Abstract: Automated deformation-based analysis of MRI scans can be used to detect specific pattern of brain atrophy in Alzheimer's disease (AD), but it still lacks an established model to derive the individual risk of AD in at-risk subjects, such as patients with mild cognitive impairment (MCI). We applied principal component analysis to deformation maps derived from MRI scans of 32 AD patients, 18 elderly healthy controls and 24 MCI patients. Principal component scores were used to discriminate between AD patients and controls and between MCI converters and MCI non-converters. We found a significant regional pattern of atrophy (p<0.001) in medial temporal lobes, neocortical association areas, thalamus and basal ganglia and corresponding widening of cerebrospinal fluid (CSF) spaces (p<0.001) in AD patients compared to controls. Accuracy was 81% for CSF- and 83% for brain-based deformation maps to separate AD patients from controls. Nine out of 24 MCI patients converted to AD during clinical follow-up. Discrimination between MCI converters and non-converters reached 80% accuracy based on CSF maps and 73% accuracy based on brain maps. In a logistic regression model, principal component scores based on CSF maps predicted clinical outcome in MCI patients even after controlling for age, gender, MMSE score and time of follow-up. Our findings indicate that multivariate network analysis of deformation maps detects typical features of AD pathology and provides a powerful tool to predict conversion into AD in non-demented at risk patients.

Teipel SJ, Bokde AL, Born C, Meindl T, Reiser M, Möller HJ, Hampel H. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Brain. · Pubmed #17566054 links to  free full text

Abstract: Functional MRI during face matching shows activation of the ventral visual stream, including the ventral temporal lobes and fusiform gyrus. In contrast, a location-matching task activates the dorsal visual stream, compromising parietal lobe areas. The morphological basis of the functional coupling between brain regions may be related to the distribution of neuron numbers and neuropil density, but has not yet been demonstrated in the living human brain. Regional neuron density can indirectly be assessed in vivo using structural MRI. The progression of Alzheimer's disease pathology along specific functional systems provides an in vivo lesion model to determine the interaction between reduced neuron numbers and reduced neuronal activation. In this study, we determined correlations between activation of the fusiform gyrus in fMRI during face matching and cortical grey matter density derived from structural MRI in 17 healthy elderly subjects (mean age = 67.5 years, SD = 4.5 years, 10 women) and 16 patients with amnestic mild cognitive impairment (MCI) (mean age = 69.9 years, SD = 8.0 years, 8 women), a predementia stage of Alzheimer's disease. Independently of diagnosis, stronger activation of the fusiform gyrus was correlated with larger grey matter density in the fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and dorsolateral prefrontal cortex. In contrast, smaller activation of the fusiform gyrus was associated with larger grey matter density in the inferior parietal lobule, post-central gyrus and dorsolateral prefrontal cortex. Compared to controls, MCI patients had more pronounced positive correlations in the ventral temporal lobes and more pronounced negative correlations in the parietal lobes. Our data suggest that fusiform activation is positively correlated with cortical grey matter density of brain areas belonging to the ventral visual stream and negatively correlated with grey matter density of brain areas belonging to the dorsal visual stream and that, these effects are more pronounced in MCI patients than in controls. These findings support the notion that the functional segregation within the visual system is based on the distribution of cortical grey matter volumes, possibly reflecting the spatial distribution of neuron density.