Alzheimer Disease: Gertz HJ

Förstl H, Werheid K, Ulm K, Schönknecht P, Schmidt R, Pantel J, Hörr R, Gutzmann H, Gertz HJ, Frölich L, Bickel H. · Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München. · Dtsch Med Wochenschr. · Pubmed #19142839 No free full text.

Abstract: Long-term studies will be pivotal in order to examine the efficacy of preventive and early therapeutic interventions during the preclinical phase of dementia. Biomarkers will be of importance due to the large sample sizes and the necessary logistic efforts, high drop-out rates and slow clinical progression. The validity of functional and even structural imaging methods is currently investigated with early and promising results; it is presently unclear whether conventional csf-markers of Alzheimer's disease (beta-amyloid and tau-proteins) are sufficiently sensitive to monitor the effects of early interventions. It also remains doubtful whether modifications of these methods will ever be useful and available for practical purposes.

Leicht H, Gertz HJ. · Medizinische Fakultät, Universität Leipzig. · Psychiatr Prax. · Pubmed #18726844 No free full text.

Abstract: OBJECTIVE: Impaired insight (anosognosia) is frequently present in Alzheimer's disease. However, established instruments for diagnosing anosognosia are lacking. METHOD: This article reviews the literature on impaired insight in Alzheimer's disease with a focus on assessment methods that have been applied to its study. RESULTS: The primary methods for assessing anosognosia are clinical judgment, comparison of patient and caregiver reports, and comparison of patients' self-assessment and task performance. CONCLUSIONS: While simple approaches such as expert rating scales can be appropriate for clinical practice, more elaborate procedures in research may shed light on the cognitive mechanisms involved in anosognosia. Previous results have shown that unawareness of deficits affects cognitive and emotional domains as well as activities of daily living, thus any diagnostic instrument should capture these different aspects. However, methodological issues such as the objectivity of caregiver reports or patients' ability to assess their own performance need to be considered in order to obtain reliable data.

Roick C, Hinz A, Gertz HJ. · Universität Leipzig, Klinik und Poliklinik für Psychiatrie, Germany. · Psychiatr Prax. · Pubmed #17443451 No free full text.

Abstract: OBJECTIVE: The measurement of quality of life (QoL) in dementia is a methodological challenge because of the patients' cognitive impairment and anosognosia. This review gives an overview of the possibilities and methodological problems of QoL measurement in dementia patients. METHODS: With literature searches conducted in PubMed and Web of Science 12 dementia-specific QoL-measures were identified. RESULTS: Most authors agreed that patients with mild to moderate dementia themselves can validly and reliably estimate their QoL. But with increasing severity of the disease, patient ratings must mostly be replaced by proxy ratings. The latter are especially essential in longitudinal studies, but are not a satisfying substitute for the patients' perspective. Thus, the influence of depression and care-related burden on the proxies' QoL-ratings should be controlled. CONCLUSIONS: QoL-instruments, applicable to all stages of dementia should be preferred, because longitudinal QoL-measures are more meaningful than cross sectional analyses. The patients' perspective should be taken into consideration as long as possible, since proxies assess the QoL of dementia patients differently from the persons affected.

Frölich L, Schmitt B, Calabrese P, Diener H, Förstl H, Gertz HJ, Hallauer JF, Hampel H, Ihl R, Rieke K, Riepe M, Supprian T. · Zentralinstitut für Seelische Gesundheit Mannheim, Universität Heidelberg. · Dtsch Med Wochenschr. · Pubmed #15717252 No free full text.

This publication has no abstract.

Gertz HJ, Kiefer M. · University of Leipzig, Department of Psychiatry, Liebigstr 22, D 04103 Leipzig, Germany. · Curr Pharm Des. · Pubmed #14754386 No free full text.

Abstract: Ginkgo biloba extracts (EGb) are well-defined plant extracts. It has several indications as dementia, macula degeneration, tinnitus and winter depression. A review of the current and past literature about older people with Alzheimer's dementia or vascular dementia or age-associated memory impairment treated with Ginkgo biloba extract, reveals that EGb has reproducible effects on cognitive functions in Alzheimer's disease. The drug is well tolerated.

Wolf H, Jelic V, Gertz HJ, Nordberg A, Julin P, Wahlund LO. · Karolinska Institutet, Neurotec, Division of Geriatric Medicine, Huddinge University Hospital, Sweden. · Acta Neurol Scand Suppl. · Pubmed #12603252 No free full text.

Abstract: OBJECTIVE: In this paper, the current neuroimaging literature is reviewed with regard to characteristic findings in mild cognitive impairment (MCI). Particular attention is drawn to the possible value of neuroimaging modalities in the prediction and early diagnosis of Alzheimer's disease (AD). METHODS: First, the potential contribution of neuroimaging to an early, preclinical diagnosis of degenerative disorders is discussed at the background of our knowledge about the pathogenesis of AD. Second, relevant neuroimaging studies focusing on MCI are explored and summarized. Neuroimaging studies were found through Medline search and by systematically checking through the bibliographies of relevant articles. RESULTS: Structural volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET)/single photon emission tomography (SPECT) are currently the most commonly used neuroimaging modalities in studies focusing on MCI. There were considerable variations in demographical and clinical characteristics across studies. However, significant hippocampal and entorhinal cortex volume reductions were consistently found in subjects with MCI as compared with cognitively unimpaired controls. While hippocampal and entorhinal cortex atrophy in subjects with MCI are also well-established risk factors for the development of AD, these measures cannot be regarded as being of high predictive value in an individual case. Evidence for other typical neuroimaging changes in MCI is still scarce. In PET and SPECT studies, reduced blood flow and/or glucose metabolism in temporoparietal association areas, posterior cingulate and hippocampus were associated with a higher risk of progressive cognitive decline in MCI. In quantitative electroencephalogram (QEEG), low beta, high theta, low alpha and slowed mean frequency were associated with development of dementia. CONCLUSIONS: Existing studies suggest that neuroimaging measures have the potential to become valuable tools in the early diagnosis of AD. To establish their value in routine use, larger studies, preferably with long prospective follow-up are needed.

Hensel A, Ibach B, Muller U, Kruggel F, Kiefer M, Gertz HJ. · Department of Psychiatry, University of Regensburg, Regensburg, Germany. · Dement Geriatr Cogn Disord. · Pubmed #15084793 No free full text.

Abstract: The pattern of callosal atrophy might be useful for the differentiation between frontotemporal dementia (FTD) and Alzheimer's disease (AD) in advanced cases. However, it is unclear whether the pattern of callosal atrophy differs between patients with FTD and patients with AD in mild to moderate stages. Volumetric MR images were recorded from 48 probands (12 with FTD, 12 with late-onset AD, and 24 controls). All patients were in a mild or in a moderate stage. The corpus callosum was divided into five segments. A repeated-measures analysis of variance showed that there was no difference in the pattern of callosal atrophy between the groups. We provide evidence that patients with FTD and patients with late-onset AD do not differ in the pattern of callosal atrophy on condition that: (1) FTD patients and AD patients are in a mild to moderate stage and (2) FTD patients and AD patients differ in age.

Froelich L, Gertz HJ, Heun R, Heuser I, Jendroska K, Kornhuber J, Kurz A, Mueller-Thomsen T, Ries F, Waechtler C, Metz M, Goebel C. · Division of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, University of Heidelberg, Heidelberg, Germany. · Dement Geriatr Cogn Disord. · Pubmed #15084792 No free full text.

Abstract: This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.

van de Pol LA, Hensel A, Barkhof F, Gertz HJ, Scheltens P, van der Flier WM. · Department of Neurology, Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands. · Neurology. · Pubmed #16434661 No free full text.

Abstract: Hippocampal atrophy is a marker of Alzheimer disease (AD). It remains unclear whether this holds true for younger patients as well. Hippocampal volume was measured on MRI scans of 103 clinically diagnosed AD patients and 73 controls (aged 51 to 85 years). Aging and AD were independently associated with smaller hippocampal volume. Both young and old AD patients have hippocampal atrophy abnormal for age. Age-dependent criteria for hippocampal atrophy, suggestive of AD, are needed.

van de Pol LA, Hensel A, van der Flier WM, Visser PJ, Pijnenburg YA, Barkhof F, Gertz HJ, Scheltens P. · VUMC, Department of Neurology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16306153 links to  free full text

Abstract: BACKGROUND: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer's disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). OBJECTIVE: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer's disease, using volumetry and a visual rating scale. METHODS: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer's disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. RESULTS: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer's disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer's disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. CONCLUSIONS: Hippocampal atrophy is not only a characteristic of Alzheimer's disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.

Heinen-Kammerer T, Motzkat K, Daniel D, Gertz HJ, Koller M, Lorenz W, Pilartz H, Zimmer B, Habs M, von den Driesch V, Rychlik R. · Institut für Empirische Gesundheitsökonomie, Burscheid. · MMW Fortschr Med. · Pubmed #16261949 No free full text.

Abstract: BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined. PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society's perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted. RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis. RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.

Vellas B, Cunha L, Gertz HJ, De Deyn PP, Wesnes K, Hammond G, Schwalen S, Anonymous00189. · Memory Research Resource Center for Alzheimer's Disease, Service de gériatrie, CHU Hôpital Lagrave Casselardit, Toulouse, France. · Curr Med Res Opin. · Pubmed #16197661 No free full text.

Abstract: INTRODUCTION: Exploratory pilot studies and knowledge of its mode of action suggested that galantamine, a cholinesterase inhibitor and modulator of nicotinic receptors, can improve attention. This study was designed to test the effects of galantamine on attention in patients with mild-to-moderate Alzheimer's disease (AD) and to see how changes in attention affected their caregivers. METHODS: This was an open-label, multicentre study. Patients received galantamine (up to 24 mg/day) for 12 weeks. Attention was assessed after 1, 4, 8 and 12 weeks using computerized tests including Choice Reaction Time (CRT), and caregiver, physician and patient ratings. RESULTS: Data were available from 373 patients (mean age 75 years, mean baseline MMSE score 21). Attention as measured by CRT improved significantly from baseline to study endpoint (p < 0.001), improvements were observed after 1 week and statistical significance was maintained from 8 weeks. Physicians rated 67% of patients as globally improved and 5% as worsened. Caregivers reported improved attention in 57% of patients and worsening in 6%; 62% of patients considered they had improved and 3% considered themselves to be worse. Caregiver stress, time spent caring for patients and patients' interactions with others all improved from baseline to endpoint. Galantamine was generally well tolerated; the most common adverse events were gastrointestinal. CONCLUSION: Previous controlled trials have demonstrated that galantamine has a positive effect on cognition, activities of daily living, behaviour and global condition, but this is the first study to suggest that galantamine may specifically improve attention (according to both objective and subjective measures) in patients with AD. These effects may be a consequence of galantamine's potentiating action at nicotinic receptors.

Hensel A, Wolf H, Dieterlen T, Riedel-Heller S, Arendt T, Gertz HJ. · Department of Psychiatry, University of Leipzig, Germany. · J Neurol Sci. · Pubmed #16112136 No free full text.

Abstract: The volume of the amygdala is reduced in advanced Alzheimer's disease (AD). However, there is controversy whether amygdala atrophy is present in mild AD and in the transitional phase between health and the onset of dementia. The aim of this prospective longitudinal study was to investigate whether amygdala atrophy is present in subjects with questionable dementia and mild dementia and whether amygdala volume is associated with the future rate of cognitive change, that is the annual change in the Mini Mental State Examination (MMSE). At baseline, volumes of the amygdala were measured in 97 participants aged 70-87 years (40 controls, 33 patients with questionable dementia, 24 patients with mild AD) using magnetic resonance imaging. Eighty-six participants were clinically re-examined after 2.3 years on average. At baseline, significant differences in mean amygdala volume were found between controls and participants with mild AD. There was no significant correlation between the longitudinal annual change in MMSE and the baseline amygdala volume in any of the three groups.

Wolf H, Hensel A, Arendt T, Kivipelto M, Winblad B, Gertz HJ. · Department of Psychiatry, University of Leipzig, Leipzig, Germany. · Ann Neurol. · Pubmed #15505826 No free full text.

Abstract: The association between hippocampal volume (as a presumed index of Alzheimer's disease pathology) with serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high-density lipoprotein cholesterol on hippocampal atrophy and Alzheimer's disease.

Wolf H, Julin P, Gertz HJ, Winblad B, Wahlund LO. · Department of Neurotec, Section of Clinical Geriatrics, Karolinska Institute, Huddinge University Hospital, S141 86 Huddinge, Sweden. · Int J Geriatr Psychiatry. · Pubmed #15449362 No free full text.

Abstract: OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.

Wolf H, Gertz HJ. · Klinik und Poliklinik für Psychiatrie der Universität Leipzig. · MMW Fortschr Med. · Pubmed #15366492 No free full text.

Abstract: Non-cognitive disorders and behavioral disturbances in dementia syndromes are the domain of antidepressants and neuroleptic agents. At the present time, neuroleptics are being prescribed too often and antidepressants too rarely. The choice of antidepressant depends upon whether a sedative effect is desired. Although caution is advised when increasing the dose, the target dose does not differ from that for young adults. Neuroleptics should always be administered in the lowest effective dose. In principle, the modern atypical substances should be preferred to the classical neuroleptics. Restraint should be exercised with the prescription of benzodiazepines in patients with dementia.

Kohler J, Riepe MW, Jendroska K, Pilartz H, Adler G, Berger FM, Calabrese P, Frölich L, Gertz HJ, Hampel H, Haupt M, Mielke R, Paulus HJ, Zedlick D. · Neurologische Universitätsklinik, Ulm. · Fortschr Med Orig. · Pubmed #12613271 No free full text.

Abstract: The efficacy of antidemential agents proven in comprehensive studies and by clinical experience, now justifies an active and positive approach by the general physician to the diagnosis and treatment of patients with dementia. The proposals on how to implement diagnostic and therapeutic measures in the doctor's office comply both with medical quality criteria and the requirements for appropriateness of treatment and considerations of economy stipulated by German law. They therefore provide the basis for a modern diagnostic work-up and treatment strategy, which will also meet economical demands.

Kohler J, Riepe MW, Jendroska K, Pilartz H, Adler G, Berger FM, Calabrese P, Frölich L, Gertz HJ, Hampel H, Haupt M, Mielke R, Paulus HJ, Zedlick D. · Arzt für Neurologie, Cornelia-Passage 8, D-79312 Emmendingen. · MMW Fortschr Med. · Pubmed #12532523 No free full text.

This publication has no abstract.

Hensel A, Wolf H, Kruggel F, Riedel-Heller SG, Nikolaus C, Arendt T, Gertz HJ. · Memory Clinic, Department of Psychiatry, University of Leipzig, Emilienstrasse 14, 04107 Leipzig, Germany. · J Neurol Neurosurg Psychiatry. · Pubmed #12082047 links to  free full text

Abstract: Previous studies have shown a reduction in corpus callosum area in advanced Alzheimer's disease, but it is unclear whether callosal atrophy is present in the transitional phase between health and the onset of dementia. The aim of this study was to investigate whether callosal atrophy is present in subjects with questionable and mild dementia and to assess the diagnostic value of callosal measures. In 83 subjects aged 72 to 85 years (33 normal controls, 27 patients with questionable dementia, 23 with mild Alzheimer's disease), magnetic resonance images were recorded and the mid-sagittal callosal area measured. Significant differences were found between normal controls and mild dementia. In subjects with questionable dementia callosal size was intermediate between normal controls and mild Alzheimer's disease. However, callosal measures were unsuitable for diagnostic differentiation between healthy subjects, subjects with questionable dementia, and subjects with mild Alzheimer's disease. The severity of white matter changes did not differ between the groups.

Gertz HJ, Wolf H, Arendt T. · Klinik und Poliklinik für Psychiatrie, Universität Leipzig, Liebigstrasse 22, 04103 Leipzig. · Nervenarzt. · Pubmed #12078017 No free full text.

Abstract: The term vascular dementia refers to dementia syndromes which are caused by hypoxic-ischaemic brain lesions. Lesions found in vascular dementia such as complete and incomplete infarctions, selective necroses, and others are nonspecific. The characteristics and severity of the clinical syndrome are determined by the size and topography of the ischaemic lesions. Among others, age and pre-existing brain atrophy are risk factors for the development of dementia based on vascular lesions. There is a high comorbidity of Alzheimer's disease and vascular dementia. It can be presumed that ischaemic lesions and Alzheimer-like pathological changes exert additive effects in the manifestation of the clinical dementia syndrome. The diagnostic process follows three steps: 1. presence of a dementia syndrome, 2. presence of cerebrovascular disease, 3. evidence for a relationship between 1 and 2. Present diagnostic criteria, such as "International Classification of Diseases" (ICD-10), "National Institute of Neurological Disorders," "Stroke-Associated Internationale pour la Reserche et l'Enseignement en Neurosciences" (NINDS-AIREN), and "Alzheimer's Disease Diagnostic and Treatment Centers" (ADDTC) describe differing constellations and show little congruence. Estimates of the prevalence depend highly on the set of criteria used. Hence, they differ considerably.

Grunwald M, Busse F, Hensel A, Riedel-Heller S, Kruggel F, Arendt T, Wolf H, Gertz HJ. · University of Leipzig, Department of Psychiatry, EEG-Research Laboratory and Memory Clinic, Leipzig, Germany. · Alzheimer Dis Assoc Disord. · Pubmed #11882748 No free full text.

Abstract: The aim of this study was to investigate spectral EEG theta-power during perceptive-cognitive demands in age-homogeneous groups of subjects with mild cognitive impairment (MCI), mild dementia (MDE), and a healthy control (CO) group. The present study includes 51 subjects (23 males, 28 females). We used the scales of the CDR (clinical dementia rating) to assign the subjects to the different groups. EEG data were collected during 10 minutes rest condition with eyes closed and during haptic perception test.The quality of the haptic reproductions differed significantly between CO and MCI, as well as between CO and MDE. The statistical comparison between EEG theta-power under rest condition and theta-power during haptic tasks revealed a significant decrease in theta-power during haptic tasks in all three groups over parieto-occipital regions. During haptic tasks, the theta-power was significantly different between CO and MDE over occipital regions and over parieto-temporal regions. A significant difference between CO and MCI was only revealed over right occipital regions (O2). Spectral theta-power during haptic tasks is a suitable measure to distinguish healthy subjects (CO) from patients with MCI respectively MDE. The results show that haptic tasks are sensitive to early perceptive-cognitive and functional deficits in patients with MCI.

Stieler JT, Lederer C, Brückner MK, Wolf H, Holzer M, Gertz HJ, Arendt T. · Department of Neuroanatomy, Paul Flechsig Institute of Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany. · Neuroreport. · Pubmed #11742221 No free full text.

Abstract: Cell-cycle dysregulation might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We now provide evidence for a dysfunction of the cell division cycle as a more general cellular phenomenon of the disease. Peripheral blood lymphocytes, stimulated with mitogenic compounds, were less able to express CD69, an early proliferation marker, in AD patients than in age-matched controls. Expression levels of CD69 of both T-cells and B-cells correlated inversely with the Mini-mental Scale. The results suggest that a systemic failure of cellular proliferation control might be of critical importance for the pathomechanism of AD.

Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA, Paykel ES, McGee M, Jakes R, Honer WG, Harrington CR, Wischik CM. · Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. · Am J Pathol. · Pubmed #10934165 links to  free full text

Abstract: We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.

Lüth HJ, Holzer M, Gertz HJ, Arendt T. · Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, University of Leipzig, Germany. · Brain Res. · Pubmed #10661494 No free full text.

Abstract: Aberrancies of growth and proliferation-regulating mechanisms might be critically involved in the processes of neurodegeneration in Alzheimer's disease (AD). Expression of p21ras and further downstream signalling elements involved in regulation of proliferation and differentiation as, for example, MEK, ERK1/2, cyclins, cyclin-dependent kinases and their inhibitors such as those of the p16INK4a family, are elevated early during the course of neurodegeneration. Activation of p21ras can also directly be triggered by nitric oxide (NO), synthesized in the brain by various isoforms of nitric oxide synthase (NOS) that might be differentially involved into the pathomechanism of AD. To study the potential link of NO and critical regulators of cellular proliferation and differentiation in the process of neurofibrillary degeneration, we analyzed the expression pattern of NOS-isoforms, p21ras and p16INK4a compared to neurofibrillary degeneration in AD. Additionally to its expression in a subtype of cortical interneurons that contain the nNOS-isoform also in normal brain, nNOS was detected in pyramidal neurons containing neurofibrillary tangles or were even unaffected by neurofibrillary degeneration. Expression of nNOS in these neurons was highly co-localized with p21ras and p16INK4a. Because endogenous NO can activate p21ras in the same cell which in turn leads to cellular activation and stimulation of NOS expression [H.M. Lander, J.S. Ogiste, S.F.A. Pearce, R. Levi, A. Novogrodsky, Nitric oxide-stimulated guanine nucleotide exchange on p21 ras, J. Biol. Chem. 270 (1995) 7017-7020], the high level of co-expression of NOS and p21ras in neurons vulnerable to neurofibrillary degeneration early in the course of AD thus provides the basis for an autocrine feedback mechanism that might exacerbate the progression of neurodegeneration in a self-propagating manner.

Arendt T, Holzer M, Gertz HJ, Brückner MK. · Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, University of Leipzig, Federal Republic of Germany. · J Neural Transm. · Pubmed #10443554 No free full text.

Abstract: To assess a potential relationship between cortical neurofibrillary degeneration and cortical cholinergic deafferentation, the load of PHF-tau was analysed in eight cortical regions and in the basal nucleus of Meynert in 12 cases with Alzheimer's disease by means of a sensitive ELISA employing the monoclonal antibody B5-2. The activity of choline acetyltransferase was determined on identical tissue samples. The results demonstrate a highly correlative relationship between the cortical distribution of the amount of PHF-tau, mainly present in neuropil threads, and cholinergic depletion early during the course of the disease. This relationship was less strong in more advanced stages. The results support the suggestion that the formation of PHF-tau in cholinergic axon terminals which might result in a loss of cholinergic synapses and a cholinergic dysconnection of the cortex, is an early event in AD. During the progression of the disease, formation of PHF-tau appears to spread over the cortex which results in a more even distribution of neuropil threads and a progressive involvement of non-cholinergic neurons.