Alzheimer Disease: Pantel J

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.

Leuner K, Pantel J, Frey C, Schindowski K, Schulz K, Wegat T, Maurer K, Eckert A, Müller WE. · Zafes, Biocenter, Department of Pharmacology, University of Frankfurt, Frankfurt, Germany. · J Neural Transm Suppl. · Pubmed #17982897 No free full text.

Abstract: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative stress and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, a correct diagnosis in the early stage of AD is not only of importance considering that early drug treatment is more effective but also that the psychological burden of the patients and relatives could be decreased. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as biomarker for AD in a peripheral cell model, the lymphocytes.

Schröder J, Pantel J, Schönknecht P, Essig M. · Sektion Gerontopsychiatrie, Psychiatrische Universitätsklinik Heidelberg, · Radiologe. · Pubmed #12955213 No free full text.

Abstract: Dementing disorders belong to the most frequent neuropsychiatric diseases of the elderly population with prevalence rates of 5% in the 75 year old, but more than 10% in subjects older than 80 years. It is broadly accepted that the dementias are not caused by a single etiological factor but are attributed to a variety of different disease processes that affect the brain either directly or indirectly. According to pathoanatomic studies, two thirds of all dementias are caused by Alzheimer's disease (AD). Early recognition and differential diagnosis, which represent an important prerequisite for an optimized therapy, can be facilitated considerably by neuroimaging as well as by molecular biological findings. Therapeutic approaches include general medical management, psychosocial interventions as well as pharmacotherapy of cognitive and non-cognitive deficits. In general, early intervention using a combination of different therapeutic measures is recommended. In future, structural and functional neuroimaging might not only be used for diagnostic purposes but also to objectify and monitor the effect of treatment on relevant brain structures

Schönknecht P, Pantel J, Schröder J. · Psychiatrische Universitätsklinik Vossstrasse 4 69115 Heidelberg, Germany. · Z Gerontol Geriatr. · Pubmed #11393001 No free full text.

Abstract: Alzheimer's disease (AD) is a degenerative dementing disorder which is characterised by a progressive atrophy of several brain regions. This process may be visualised in vivo by the use of magnetic resonance imaging (MRI) in combination with appropriate volumetric post-processing techniques. Recent volumetric MRI studies in AD consistently found an extensive volume loss of the medial temporal lobe structures including amygdala and hippocampus which appeared already in the early clinical stages of the disorder. This finding is progressive during the clinical course of AD and is associated with other biological markers of the disease such as cerebrospinal fluid beta A 4 levels and apolipoprotein E genotype. With respect to the extent and the distribution of the structural changes, AD may be differentiated from other neuropsychiatric disorders which could facilitate the differential diagnosis in vivo.

Barth S, Schönknecht P, Pantel J, Schröder J. · Sektion Gerontopsychiatrie der Psychiatrischen Klinik der Universität Heidelberg. · Fortschr Neurol Psychiatr. · Pubmed #16217697 No free full text.

Abstract: To investigate the psychometric properties of the German version of the CERAD-NP, neuropsychological deficits were compared between 49 patients with mild cognitive impairment (MCI), 80 patients with Alzheimer's disease (AD), 36 with major depression (MD), and 26 elderly controls. All participants were outpatients of the memory clinic of the Section of Geriatric Psychiatry, Heidelberg University. Diagnoses were established based on clinical examination, laboratory testing, neuroimaging, and routine neuropsychological testing according to the criteria of aging-associated cognitive decline (AACD) for MCI, NINCDS-ADRDA for AD, and DSM-IV for MD, respectively. All CERAD-NP subtests discriminated between controls and AD patients with the latter showing significantly (p< or = 0.05) lower test scores. The subtests verbal fluency and constructive apraxia differed significantly between mildly and moderately AD, while the subtests assessing declarative (epsisodic) memory performance showed only minor, non-significant differences between the respective groups. The LKB patients took an intermediate position between controls and AD patients with significantly lower scores in verbal fluency and declarative memory performance than the controls. When compared with the AD patients, MCI patients were significantly impaired in all subtests except constructive apraxia. Relative to the controls, the patients with MD showed a decreased episodic memory performance but no evidence suggesting an impairment in other neuropsychological domains. Our results indicate that the CERAD-NP is a psychometric instrument which allows a sensitive discrimination between mild and moderate AD, MCI, MD and healthy controls. However, sensitivity of discrimination between different stages of dementia varies with respect to the different subtest. While the subtest for episodic memory showed floor effects already for mild dementia, subtests for verbal fluency and constructive apraxia were able to discriminate even between more advanced stages of the disease.

Schonknecht P, Pantel J, Werle E, Hartmann T, Essig M, Baudendistel K, Beyreuther K, Schroder J. · Sektion Gerontopsychiatrie, Psychiatrische Klinik der Universitat Heidelberg. · Fortschr Neurol Psychiatr. · Pubmed #11103680 No free full text.

Abstract: Tau protein concentration in cerebrospinal fluid was determined in 55 patients with Alzheimer's disease (AD), 18 patients with vascular dementia (VD), 19 patients with dementia caused by other disorders and 14 patients with major depression. Significantly (p < 0.05) elevated protein tau concentrations were found in AD patients (564.5 +/- 275.5 pg/ml) compared to all other patient groups (VD: 406.5 +/- 263.9 pg/ml; other dementia: 275.0 +/- 135.4 pg/ml; depression: 212.9 +/- 115.6 pg/ml). However, tau levels in AD patients covered a broad range (163.2 pg/ml-1200 pg/ml). AD patients with tau levels below the 25%-percentile of the distribution (among them a high percentage of patients with presenile onset) showed tau levels similar to those of the patients with late life depression. No significant correlations between tau levels and clinical variables such as severity of dementia, age, age of onset, duration of illness, and cerebral changes as assessed by volumetric magnetic resonance imaging could be demonstrated. Similarly, we could not find an influence of either APO-E genotype or psychotropic medication on the tau levels in AD patients. In accordance with other studies our results confirm elevated tau levels in AD compared to elderly not demented control subjects. Comparing groups, this finding applies as well with respect to VD and other dementing disorders. However, elevated tau levels cannot be detected in a subgroup of AD patients. This finding needs to be further investigated in future studies.

Hampel H, Broich K, Hoessler Y, Pantel J. · Department of Psychiatry, Ludwig-Maximilian University Munich, Alzheimer Memorial Center, Munich, Germany. · Dialogues Clin Neurosci. · Pubmed #19585950 No free full text.

Abstract: The introduction of biological markers in the clinical management of Alzheimer's disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.

Thomann PA, Kaiser E, Schönknecht P, Pantel J, Essig M, Schröder J. · Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany. · J Psychiatry Neurosci. · Pubmed #19270764 links to  free full text

Abstract: BACKGROUND: We sought to examine the association of levels of total tau (t-tau) and phosphorylated tau 181 (p-tau181) protein with brain morphology in mild cognitive impairment, as defined by the concept of aging-associated cognitive decline (AACD) and Alzheimer disease. METHODS: Twenty-three participants with AACD, 16 with Alzheimer disease and 15 healthy controls underwent magnetic resonance imaging and lumbar puncture. We performed voxel-based morphometry to investigate the association between tau levels in cerebrospinal fluid (CSF) and cerebral grey matter density throughout the entire brain. RESULTS: Voxel-based morphometry revealed that both elevated t-tau and p-tau181 concentrations were associated with reduced grey matter density in temporal, parietal and frontal regions. Among participants with AACD, elevated levels of p-tau181 (but not t-tau) in CSF were correlated with a pronounced atrophy in the right hippocampus. LIMITATIONS: Our study was limited by the small sample, especially with respect to the analysis comprising the AACD subgroups. Moreover, we did not correct our voxel-based morphometry analyses for multiple dependent comparisons, therefore they harbour a risk of false-positive results. CONCLUSION: Elevated levels of t-tau and p-tau181 in CSF reflect degenerative processes in the cortical regions typically affected in Alzheimer disease. Our findings in participants with AACD support the hypothesis that p-tau181 might be more specifically related to neurodegenerative changes in early Alzheimer disease.

Uhlhaas PJ, Pantel J, Lanfermann H, Prvulovic D, Haenschel C, Maurer K, Linden DE. · Department of Neurophysiology, Max-Planck Institute for Brain Research, Department of Psychiatry, Frankfurt am Main, Germany. · Dement Geriatr Cogn Disord. · Pubmed #18408365 No free full text.

Abstract: BACKGROUND: Deficits in visual processing are a prominent feature of Alzheimer's disease (AD), yet the cognitive and neuropathological mechanisms underlying these deficits are poorly understood. In the current study, we examined the hypothesis that perceptual organization is specifically impaired in AD compared to other dementias. METHODS: We examined perceptual organization with a psychophysically well-controlled measure of contour integration in patients with AD (n = 17), vascular dementia (n = 5), frontotemporal dementia (n = 5) and mild cognitive impairment (n = 10) and 11 age-matched healthy controls. RESULTS: Patients with AD differed significantly in their ability to detect contours comprised of Gabor elements as detection relied increasingly on long-range spatial interactions. Impairments in contour integration were particularly pronounced in AD patients with atrophy and gliosis of white matter in the occipital lobe. Deficits in perceptual organization were not found in patients with other dementias and participants with mild cognitive impairment. CONCLUSIONS: These results suggest that a subgroup of AD patients is characterized by a specific deficit in visual perceptual organization, which might reflect the impaired functional integrity of occipital cortico-cortical pathways.

Schröder J, Kaiser E, Schönknecht P, Hunt A, Thomann PA, Pantel J, Schröder J. · Sektion Gerontopsychiatrie, Psychiatrische Universitätsklinik, Vossstrasse 4, 69115, Heidelberg, Germany. · Z Gerontol Geriatr. · Pubmed #18327693 No free full text.

Abstract: In recent studies, patients diagnosed with Alzheimer's disease (AD) showed significantly elevated CSF levels of tau protein. Tau protein was therefore regarded as a putative molecular marker for AD. Since early diagnosis of AD is warranted for appropriate therapeutic intervention, investigation of total tau protein levels in patients with Aging Associated Cognitive Decline (AACD) and AD are reasonable. In our study the CSF concentrations of total tau protein were measured by ELISA in 132 patients with AD, 29 patients with AACD and 24 healthy controls. CSF concentrations were compared between the subgroups of mild, moderate and severe AD, AACD and the control group and were correlated with age and severeness of the illness. The concentration of total tau protein was increased significantly in patients with severe and moderate AD compared to all other groups. Within the group of AD patients, total tau protein correlated significantly with the severity of the dementia but not with age. Although the range of the measured tau protein concentrations is wide and overlapping between the diagnostic groups our data indicate that from a clinical point of view significantly increased tau protein levels confirm the clinical diagnosis of AD while normal values do not exclude it.

Giesel FL, Thomann PA, Hahn HK, Politi M, Stieltjes B, Weber MA, Pantel J, Wilkinson ID, Griffiths PD, Schröder J, Essig M. · Department of Radiology, German Cancer Research Center, Heidelberg, Germany. · Eur J Radiol. · Pubmed #17643890 No free full text.

Abstract: PURPOSE: Objective quantification of brain structure can aid diagnosis and therapeutic monitoring in several neuropsychiatric disorders. In this study, we aimed to compare direct and indirect quantification approaches for hippocampal formation changes in patients with mild cognitive impairment and Alzheimer's disease (AD). METHODS AND MATERIALS: Twenty-one healthy volunteers (mean age: 66.2), 21 patients with mild cognitive impairment (mean age: 66.6), and 10 patients with AD (mean age: 65.1) were enrolled. All subjects underwent extensive neuropsychological testing and were imaged at 1.5T (Vision, Siemens, Germany; T1w coronal TR=4 ms, Flip=13 degrees , FOV=250 mm, Matrix=256 x 256, 128 contiguous slices, 1.8mm). Direct measurement of the hippocampal formation was performed on coronal slices using a standardized protocol, while indirect temporal horn volume (THV) was calculated using a watershed algorithm-based software package (MeVis, Germany). Manual tracing took about 30 min, semi-automated measurement less than 3 min time. RESULTS: Successful direct and indirect quantification was performed in all subjects. A significant volume difference was found between controls and AD patients (p<0.001) with both the manual and the semi-automated approach. Group analysis showed a slight but not significant decrease of hippocampal volume and increase in temporal horn volume (THV) for subjects with mild cognitive impairment compared to volunteers (p<0.07). A significant correlation (p<0.001) of direct and indirect measurement was found. CONCLUSION: The presented indirect approach for hippocampus volumetry is equivalent to the direct approach and offers the advantages of observer independency, time reduction and thus usefulness for clinical routine.

Giesel FL, Hahn HK, Thomann PA, Widjaja E, Wignall E, von Tengg-Kobligk H, Pantel J, Griffiths PD, Peitgen HO, Schroder J, Essig M. · Department of Radiology, German Cancer Research Center, 69120 Heidelberg, Germany. · AJNR Am J Neuroradiol. · Pubmed #16908557 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Quantitative markers of Alzheimer disease (AD), particularly in the early stages, are needed for clinical assessment and monitoring. We have evaluated a novel method to segment and visualize the ventricular system and obtain volumetric measures thereof. The temporal horn volume (THV) and index in patients with mild cognitive impairment (MCI) and in those with AD were evaluated. METHODS: High-resolution T1-weighted volume imaging was performed in 52 subjects (21 patients with MCI, 10 with AD, and 21 healthy control subjects). An interactive watershed transformation and semiautomated histogram analysis were implemented to produce segmented THV and temporal horn indices (THI) (ratio of THV to lateral ventricular volume). RESULTS: Cerebral ventricular and temporal horn size could be semiautomatically quantified from all 52 datasets. The method was fast and rater-independent. Qualitative ventricular inspections using surface rendering shading could uncover atrophic process with enlargement of the whole and especially temporal horn volume. Both THV and THI of patients with AD were significantly larger than those of patients with MCI or control subjects (P < .005). There was no significant difference in THV and THI between patients with MCI or control subjects (P > .05). There was a significant correlation between the neuropsychologic performance and both THI and THV across groups (P < .01). CONCLUSION: THV and THI could be used as markers of AD in the clinical environment and are expected to be helpful in monitoring therapeutic intervention.

Thomann PA, Wustenberg T, Pantel J, Essig M, Schroder J. · Section of Geriatric Psychiatry, University of Heidelberg, Germany. · Dement Geriatr Cogn Disord. · Pubmed #16415572 No free full text.

Abstract: BACKGROUND: Although previous studies demonstrate significant atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD), CC alterations in mild cognitive impairment have not been investigated yet. METHODS: 21 subjects with mild cognitive impairment, 10 with AD and 21 healthy controls were investigated using magnetic resonance imaging. In the mid-sagittal slice the CC was traced manually. Additionally, voxel-based morphometry (VBM) was performed. RESULTS: The CC was significantly smaller in patients with AD compared to healthy controls in both manual tracing and VBM. The atrophy was prominent in rostral parts of the CC. In subjects with mild cognitive impairment, the two rostral CC segments were smaller compared to controls when manually traced. In contrast, VBM revealed no significant difference between subjects with mild cognitive impairment and controls. CONCLUSION: Manual tracing was more sensitive in detecting discrete structural CC changes than VBM. Alterations of the CC in mild cognitive impairment rank in between normal aging and AD, supporting the hypothesis that mild cognitive impairment most often represents a preclinical stage of AD.

Schönknecht P, Pantel J, Kruse A, Schröder J. · Section for Geriatric Psychiatry, Ruprecht-Karls University Heidelberg, Voss-Str. 4, D-69115 Heidelberg, Germany. · Am J Psychiatry. · Pubmed #16263846 links to  free full text

Abstract: OBJECTIVE: "Mild cognitive impairment" refers to cognitive deficits in older age that exceed age-related cognitive decline but do not fulfill criteria for dementia. Affected subjects are assumed to be at higher risk for the development of dementia, such as Alzheimer's disease. However, little is known about the group of young-old subjects with respect to the prevalence and natural course of cognitive decline. METHOD: Within the population-based Interdisciplinary Longitudinal Study on Adult Development and Aging, neuropsychological functioning was assessed in 500 community-dwelling young-old subjects of two German urban regions who were born during 1930-1932. The participants were carefully screened for physical and mental health and reexamined 4 years later. The concept of "aging-associated cognitive decline" was applied. RESULTS: At baseline, 13.4% of the subjects fulfilled criteria for aging-associated cognitive decline. Four years later, the prevalence rates for rose to 23.6%; 52.3% of the subjects initially classified as having aging-associated cognitive decline retained the diagnosis at follow-up. Although subjects with aging-associated cognitive decline showed a reduced performance in all neuropsychological domains addressed, a significant decline was confined to delayed verbal memory test performance during the 4-year follow-up period in relation to comparison subjects. Aging-associated cognitive decline did not predict conversion to dementia during the follow-up interval. CONCLUSIONS: In young-old community-dwelling individuals, aging-associated cognitive decline is a frequent condition with a high temporal stability. During a 4-year follow-up, subjects with aging-associated cognitive decline deteriorated specifically in measures of episodic memory, underscoring the value of the respective deficits in characterizing "mild cognitive impairment."

Pantel J, Schönknecht P, Essig M, Schröder J. · Section of Geriatric Psychiatry, University of Heidelberg, Vossstrasse 4, 69115 Heidelberg, Germany. · Neurosci Lett. · Pubmed #15135882 No free full text.

Abstract: Neuropsychological deficits were investigated with respect to regional distribution of cerebral atrophy as assessed by volumetric magnetic resonance imaging (MRI) in 50 patients with Alzheimer's dementia (AD; NINCDS-ADRDA criteria) and 20 healthy volunteers. When compared between groups, test performance of all investigated neuropsychological domains including declarative memory, language, praxia, psychomotor speed, as well as attention and concentration was significantly impaired. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex correlated with declarative memory performance, whereas volumes of the left temporo-parietal regions correlated with performance in naming and praxia. Furthermore, left frontal lobe atrophy was associated with verbal fluency. Our data confirm the central role that medial temporal atrophy plays for declarative memory deficits in AD and indicate that additional changes in the parietal, temporal and frontal lobes are responsible for further neuropsychological deficits characteristic of this disorder.

Pantel J, Schönknecht P, Essig M, Schröder J. · Sektion Gerontopsychiatrie, Psychiatrische Universitätsklinik Heidelberg. · Fortschr Neurol Psychiatr. · Pubmed #15095176 No free full text.

Abstract: This study aims to systematically analyze the relationship between neuropsychological deficits and regional cerebral atrophic changes in Alzheimer's dementia (AD). As an extension of previous studies we not only investigated substructures of the medial temporal lobe but also included other relevant cerebral regions such as frontal, temporal, and parietal lobes. This approach was based on the assumption that morphological correlates of global and specific cognitive dysfunction might reflect to a certain degree the neuronal basis of the respective function. Accordingly, the functional role assigned to a certain cerebral structure or region can be further elucidated which might lead to a better understanding of the clinical and neuropsychological heterogeneity of AD. Fifty patients with AD (NINCDS-ADRDA criteria) and 20 healthy elderly control subjects were included. All patients and controls were examined on a standardized neuropsychological test battery. In addition, magnetic resonance imaging (MRI) of the brain was performed. Volumes of the whole brain, CSF-spaces, amygdala-hippocampus complex, frontal lobes, temporal lobes, and parietal lobes were measured using a standardized protocol. AD-patients were characterized by neuropsychological deficits with respect to memory, language, praxia, cognitive speed as well as attention and concentration. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex were correlated with declarative memory performance in the non-verbal visual domain. Furthermore, an association between left temporo-parietal regions and aspects of semantic memory, as well as verbal recall and left frontal regions could be established. The validity of our results is supported by recent findings from neuropathological and functional neuroimaging studies. In conclusion, our data indicate that MRI-based volumetry can be successfully used to detect morphological correlates of neuropsychological heterogeneity in AD and that this methodological approach allows to fruitfully study the neuronal basis of cognitive functions.

Schönknecht P, Pantel J, Hartmann T, Werle E, Volkmann M, Essig M, Amann M, Zanabili N, Bardenheuer H, Hunt A, Schröder J. · Department of Psychiatry, Section of Geriatric Psychiatry, University of Heidelberg, Voss-Street 4, Heidelberg D-69115, Germany. · Psychiatry Res. · Pubmed #14561434 No free full text.

Abstract: Increased tau levels are a well-established finding in Alzheimer's disease (AD). In contrast, the potential value of tau levels in the differential diagnosis of AD, vascular dementia (VD) and major depression warrants further investigation. The potential impact of psychotropic medication also needs to be established. We investigated cerebrospinal fluid (CSF) tau protein concentrations in 88 patients with AD, 23 patients with VD, 25 patients with major depression and 17 age-paralleled controls without cognitive impairment with respect to important clinical variables, type and dosage of psychotropic medication and cerebral changes as assessed by magnetic resonance imaging (MRI). The AD patients showed significantly elevated tau levels compared with patients with VD or major depression and controls. Tau levels obtained in the VD group were intermediate, with significant differences from both AD patients and patients with major depression and controls. Within the AD group, no significant correlation between tau levels, severity of dementia, age, duration of disease, type and dosage of psychotropic medication or MRI volumetric changes arose. A subgroup of AD patients without increased tau levels was characterized by a significantly larger percentage of patients with presenile onset.

Schönknecht P, Pantel J, Hunt A, Volkmann M, Buerger K, Hampel H, Schröder J. · Department of Psychiatry, University of Heidelberg, Voss-Strasse 4, D-69115, Heidelberg, Germany. · Neurosci Lett. · Pubmed #12614922 No free full text.

Abstract: Cerebrospinal fluid tau protein levels are considered to be a promising marker for Alzheimer's disease (AD) and may facilitate early detection. Using the newly developed INNOTEST Phospho-Tau((181P)) kit examination of total tau and tau protein phosphorylated at threonine 181 (phospho-tau 181) revealed significantly (P<0.05) higher values in both patients with incipient and manifest AD than in controls. In patients with vascular dementia, phospho-tau 181 levels were not different from controls but were significantly lower than in patients with manifest AD. These findings suggest that total and phosphorylated tau protein may facilitate early detection and differential diagnosis of AD.

Pantel J, Kratz B, Essig M, Schröder J. · University of Heidelberg, Germany. · Am J Psychiatry. · Pubmed #12562591 links to  free full text

Abstract: OBJECTIVE: Neuropathological evidence suggests that the earliest changes in Alzheimer's disease selectively affect the parahippocampal regions of the brain. This study was conducted to determine if otherwise healthy elderly subjects with mild cognitive impairment had structural volume deficits affecting the parahippocampal gyrus. METHOD: Magnetic resonance imaging (MRI) was used to compare global and regional brain volumes in 21 subjects with mild cognitive deficits defined according to the criteria for aging-associated cognitive decline, 22 cognitively intact comparison subjects, and 12 patients with Alzheimer's disease. RESULTS: Compared with the cognitively intact subjects, the subjects with aging-associated cognitive decline had a significantly smaller mean volume of the right parahippocampal gyrus. The subjects with aging-associated cognitive decline had a mean parahippocampal volume that was intermediate between that of the Alzheimer's disease patients and that of the cognitively intact subjects. CONCLUSIONS: Parahippocampal atrophy underlies the observed cognitive deficits in aging-associated cognitive decline. These findings support the hypothesis that aging-associated cognitive decline represents a preclinical stage of Alzheimer's disease.

Pantel J, Hüger DR, Kratz B, Minnemann E, Martin M, Schad LR, Essig M, Schröder J. · Sektion Gerontopsychiatrie, Psychiatrische Universitätsklinik Heidelberg, Germany. · Nervenarzt. · Pubmed #12215875 No free full text.

Abstract: The aim of the present study was to investigate the morphological changes in subjects with mild cognitive impairment (MCI) revealed by quantitative magnetic resonance imaging (MRI). Twenty-one subjects with cognitive impairment and 22 healthy controls were compared with 12 patients suffering from mild Alzheimer's disease (AD). The volumes of the following brain structures were assessed: total intracranial compartment, cerebrospinal fluid compartment, whole brain, and medial temporal substructures (hippocampus and parahippocampal gyrus). Subjects with mild cognitive impairment showed a significantly reduced volume of the right parahippocampal gyrus over healthy controls. Volumes of the other regions and structures did not differ between the MCI group and controls. The volumetric and neuropsychological findings of the present study support the hypothesis that mild cognitive impairment - at least in some of the affected individuals - can be seen as a preclinical stage of AD and that atrophy of the parahippocampal gyrus might be useful as an early marker of AD.

Schönknecht P, Lütjohann D, Pantel J, Bardenheuer H, Hartmann T, von Bergmann K, Beyreuther K, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Voss-Strasse 4, 69115, Germany. · Neurosci Lett. · Pubmed #11983301 No free full text.

Abstract: Experiments in cell cultures indicate that accumulation of cholesterol in hippocampal neurons results in an accelerated cleavage of amyloid precursor protein into amyloidogenic components. To be eliminated from the brain, cholesterol is converted to 24S-hydroxycholesterol which may reflect cerebral cholesterol turnover. We investigated cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol in a group of 14 Alzheimer's disease (AD) patients and ten healthy controls without any cognitive deficits or psychiatric or neurological disorders. To exclude potential effects of circulating plasma cholesterol on CSF 24S-hydroxycholesterol levels, only patients and controls with cholesterol levels in the normal range of 150-230 mg/dl were included. We found significantly elevated 24S-hydroxycholesterol CSF but not plasma levels in AD patients compared with healthy controls. Our results demonstrate that CSF 24S-hydroxycholesterol is increased in AD. This effect does not seem to be triggered by plasma cholesterol levels since the latter did not significantly differ between groups.

Schönknecht P, Pantel J, Klinga K, Jensen M, Hartmann T, Salbach B, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Voss-Strasse 4, D-69115, Heidelberg, Germany. · Neurosci Lett. · Pubmed #11427315 No free full text.

Abstract: Recent in-vitro studies indicate that estrogens such as 17beta-estradiol (E2) may decrease the production of beta-amyloid 1-42 (Abeta42), a peptide central for the formation of senile plaques in Alzheimer's disease (AD). To test this hypothesis in a clinical study, cerebrospinal fluid levels of E2 were compared between 30 female AD patients and 11 female patients with non-dementing diseases such as major depression and investigated with respect to beta-amyloid 1-40 and Abeta42 levels. E2 levels were significantly (P<0.05) lower in the AD group than in controls; within the AD group E2 levels were inversely correlated with Abeta42 concentrations (r=-0.36, P=0.05). This is the first clinical study providing evidence for an influence of E2 on Abeta42 metabolism in vivo. This observation corresponds to the putative beneficial effects of estrogen replacement therapy on the development and course of AD.

Bickel C, Pantel J, Eysenbach K, Schröder J. · Section of Geriatric Psychiatry, University of Heidelberg, Germany. · Brain Lang. · Pubmed #10716871 No free full text.

Abstract: Syntactic comprehension of German patients with dementia of the Alzheimer type was investigated and compared to healthy controls matched with respect to age, sex, and education. Special attention was directed at syntactic structures, which, in contrast to a language like English, are feasible in a grammatically rich language like German. In a sentence picture matching paradigm, only semantically reversible sentences were used. Syntactic complexity ranged from simple active voice sentences to more complex sentences like center-embedded object relative sentences. In comparison to their controls, patients showed a deficit in nearly all categories. Their performance was not influenced by age, but was heavily influenced by the degree of cognitive impairment. Patients with mild cognitive impairment, as defined by a MMSE score of 20 or higher, showed only slight difficulties in syntactic processing, whereas patients with moderate to severe impairment (MMSE < 20) did not perform above chance limits in most syntactic categories. It appears as though syntactic comprehension is only mildly affected in the early stages of Alzheimer's disease and is rather severely impaired in more advanced stages. In the present report, results are discussed in terms of working memory demands for syntactic processing.

Pantel J, Schröder J, Jauss M, Essig M, Minakaran R, Schönknecht P, Schneider G, Schad LR, Knopp MV. · Department of Psychiatry, Section of Geriatric Psychiatry, University of Heidelberg, Germany. · Psychiatry Res. · Pubmed #10466737 No free full text.

Abstract: It has been suggested that regional corpus callosum atrophy in Alzheimer's disease (AD) may serve as an in vivo index of neuronal loss in the neocortex. In this study total and regional size of the corpus callosum was evaluated with respect to the volumes of the frontal, temporal, and parietal lobes in 38 patients with AD (NINCDS-ADRDA criteria) using quantitative magnetic resonance imaging. Twenty healthy subjects matched for age and gender served as a control group. All quantitative measurements were performed by manual tracing using personal computer-based software. Both total size and the five measured regional subsections were significantly smaller in AD when compared to the control subjects. The severity of dementia was significantly correlated with the size of the middle sections of the corpus callosum (rostral body and midbody). Within the AD group, the rostral body of the corpus callosum was significantly correlated with the frontal lobe volumes, the midbody was correlated with the temporal lobe volumes, and size of the splenium was correlated with the parietal lobe volumes. We conclude that callosal atrophy in AD reflects the severity and pattern of cortical neuronal damage. Correlations between regional callosal atrophy and severity of dementia indicate that interhemispheric cortico-cortical disconnection may contribute to the dementia syndrome.

Jensen M, Schröder J, Blomberg M, Engvall B, Pantel J, Ida N, Basun H, Wahlund LO, Werle E, Jauss M, Beyreuther K, Lannfelt L, Hartmann T. · Karolinska Institutet, Department of Clinical Neuroscience and Family Medicine, Huddinge, Sweden. · Ann Neurol. · Pubmed #10211475 No free full text.

Abstract: All mutations known to cause familial Alzheimer's disease (AD) act by increasing the levels of soluble beta-amyloid peptide (A beta), especially the longer form, A beta42. However, in vivo elevation of soluble A beta in sporadic AD has so far not been shown. In the present study, we used enzyme-linked immunosorbent assays specific for A beta42 and A beta40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of A beta42 and A beta40 during disease progression. We also evaluated three other groups--one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that A beta42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, A beta40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of A beta42 than the healthy control group, implying that A beta42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of A beta42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics.