Alzheimer Disease: Schönknecht P

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.

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.

Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frölich L, Schönknecht P, Ito K, Mielke R, Kalbe E, Zündorf G, Delbeuck X, Pelati O, Anchisi D, Fazio F, Kerrouche N, Desgranges B, Eustache F, Beuthien-Baumann B, Menzel C, Schröder J, Kato T, Arahata Y, Henze M, Heiss WD. · University Cologne, Neurological Clinic and Max-Planck-Institute for Neurological Research, 50931 Köln, Germany. · Neuroimage. · Pubmed #12482085 No free full text.

Abstract: A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimer's disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

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.

Toro P, Schönknecht P, Schröder J. · Section for Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany. · J Alzheimers Dis. · Pubmed #19387105 No free full text.

Abstract: Diabetes mellitus type 2 (T2DM) is considered to be an important risk factor for mild cognitive impairment (MCI) and subsequent Alzheimer's disease (AD). The majority of studies relating T2DM to MCI and AD were performed in North America. We investigated the potential impact of T2DM on the development of MCI and AD in the Interdisciplinary Longitudinal Study on Adult Development and Aging which involves a representative birth cohort of subjects born between 1930 and 1932 in Germany. Subjects received a thorough psycho-geriatric examination and neuropsychological testing; particular care was taken to exclude subjects with severe medical or neurological conditions sufficient to explain the cognitive deficits, or other major psychiatric disorders. When compared to healthy subjects (n=159), patients with MCI (n=108) or AD (n=26) showed a tendency towards increased prevalence rates for T2DM (17% vs. 23%; chi2=1.7, p=0.18). In both patients with MCI and controls, T2DM was associated with psychomotor slowing but not deficits in other cognitive domains typically involved in MCI. Our findings indicate that T2DM is involved in MCI and may aggravate the clinical picture as a concomitant factor.

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.

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.

Ewers M, Buerger K, Teipel SJ, Scheltens P, Schröder J, Zinkowski RP, Bouwman FH, Schönknecht P, Schoonenboom NS, Andreasen N, Wallin A, DeBernardis JF, Kerkman DJ, Heindl B, Blennow K, Hampel H. · Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Neurology. · Pubmed #18071141 No free full text.

Abstract: BACKGROUND: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. OBJECTIVE: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau(231)) for the prediction of conversion from MCI to AD during a short-term observation interval. METHODS: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. RESULTS: Levels of p-tau(231) were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori-defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). CONCLUSIONS: An a priori defined cutoff value of p-tau(231) yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau(231) for the prediction of Alzheimer disease.

Thomann PA, Dos Santos V, Toro P, Schönknecht P, Essig M, Schröder J. · Section of Geriatric Psychiatry, University of Heidelberg, Vossstr. 4, 69115 Heidelberg, Germany. philipp · Neurobiol Aging. · Pubmed #17875348 No free full text.

Abstract: Olfactory dysfunction has been reported to occur already in the early stages of Alzheimer's disease (AD) and to increase with disease severity. In neuropathological research, the deposition of neurofibrillary tangles and neuritic plaques in the olfactory bulb and tract (OBT) of AD patients has been consistently demonstrated. We used high-resolution magnetic resonance imaging (MRI) to determine the volume of the OBT in 21 patients with early AD and in 21 healthy comparison subjects. The OBT was manually traced on consecutive coronal slices. When compared to healthy controls, right, left and mean OBT volumes were significantly reduced in patients with AD (p<0.01). In AD patients, the mean OBT volume was significantly correlated with global cognitive performance as determined by the mini-mental state examination (r=0.605; p=0.004). Manual tracing on MRI images revealed OBT atrophy to be present early in the course of AD. Since the respective findings were associated with cognitive impairment, they may contribute to early recognition and diagnosis of the disease.

Hunt A, Schönknecht P, Henze M, Seidl U, Haberkorn U, Schröder J. · Section for Geriatric Psychiatry, Ruprecht-Karls-University Heidelberg, Voss-Strasse 4, D-69115 Heidelberg, Germany. · Psychiatry Res. · Pubmed #17524628 No free full text.

Abstract: While significantly reduced glucose metabolism in fronto-temporo-parietal and cingulate cortices has been demonstrated in Alzheimer's disease (AD) compared with controls, cerebral glucose metabolism in patients with mild cognitive impairment who subsequently develop AD is less well-defined. In the present study we measured cerebral glucose metabolism by positron emission tomography (PET) with (18)F-2-fluoro-2-deoxy-D-glucose in 14 patients with aging-associated cognitive decline (AACD), 44 patients with AD, and 14 healthy control subjects at baseline. The AACD patients were clinically followed up, and conversion to AD was determined. Compared with controls, AACD patients had significantly reduced glucose metabolism in the right precuneus, posterior cingulate, right angular gyrus, and bilateral middle temporal cortices, while the respective deficits were more pronounced in AD patients and also involved the frontal cortices. AACD patients who subsequently converted to AD (AACD-converters) showed more extended metabolic changes which also involved the frontal and temporal cortices, right cingulate gyrus, right thalamus, and bilateral precuneus.

Kaiser E, Schönknecht P, Thomann PA, Hunt A, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Germany. · Neurosci Lett. · Pubmed #17408854 No free full text.

Abstract: It is generally accepted that cerebrospinal fluid (CSF) biomarkers such as tau protein, phosphorylated tau protein (threonine 181) and beta-amyloid (1-42) can facilitate early and differential diagnosis of Alzheimer's disease (AD). Since the respective concentrations can only be measured in a number of specialized centers, time to CSF specimen work-up has been considered as crucial for the stability of the respective biomarkers. When shipping of CSF samples is needed for biomarker measurement and immediate freezing of samples is not available, an overnight delay of up to 24h frequently occurs. Therefore, we investigated the potential impact of a 24h delayed freezing on CSF biomarker concentrations and compared it to 2h storage (room temperature, 20 degrees C) and an immediate freezing. First, storage at room temperature for 2h had only marginal, non-significant effects on the concentrations of CSF total tau protein and phospho-tau protein (181) compared to immediate freezing. Second, storage at room temperature for 24h did not significantly affect total tau protein or phospho-tau protein but beta-amyloid (1-42) concentrations which increased significantly compared to the samples frozen immediately. These results indicate that CSF samples for the evaluation of total tau and phospho-tau protein may be kept at room temperature for up to 24h whereas CSF samples for beta-amyloid (1-42) need to be frozen immediately.

Lewczuk P, Kornhuber J, Vanderstichele H, Vanmechelen E, Esselmann H, Bibl M, Wolf S, Otto M, Reulbach U, Kölsch H, Jessen F, Schröder J, Schönknecht P, Hampel H, Peters O, Weimer E, Perneczky R, Jahn H, Luckhaus C, Lamla U, Supprian T, Maler JM, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Neurobiol Aging. · Pubmed #17239996 No free full text.

Abstract: In this report we evaluated the clinical performance of APOE genotyping and three protein biomarkers (total tau, beta-amyloid(1-42), and tau phosphorylated at threonine 181) in a prospective multicenter study using the INNO-BIA AlzBio3 assay applied on Luminex platform. Concentration of biomarkers of Alzheimer's disease in cerebrospinal fluid (CSF) was measured with multiplexing technology (n=223), and compared to the results of ELISA assays in patients with early dementias or mild cognitive impairment (MCI) collected at 12 gerontopsychiatric university departments, and APOE genotyping was performed. Concentrations of Abeta(1-42) were statistically significantly lower in MCI-AD subjects compared to MCI-O, and significantly lower in D-AD patients compared to MCI-O. P-tau(181P) concentrations were significantly higher in MCI-AD patients compared to MCI-O, and significantly higher in D-AD patients compared to MCI-O. The total tau concentrations in MCI-AD patients were significantly higher compared to MCI-O, and higher in D-AD compared to MCI-O, moreover, the concentration of total tau was significantly higher in D-AD compared to MCI-AD patients. For the differential diagnosis between D-AD and D-O, the optimal cutoff concentration of Abeta(1-42) was 197.7 pg/mL, and that for P-tau(181P) was 47.9 pg/mL. These cutoff values were also applied to discriminate between MCI-AD and MCI-O subjects. Simultaneous measurement of the biomarkers significantly improves management of the samples and quality control of the assays' performance.

Lewczuk P, Beck G, Ganslandt O, Esselmann H, Deisenhammer F, Regeniter A, Petereit HF, Tumani H, Gerritzen A, Oschmann P, Schröder J, Schönknecht P, Zimmermann K, Hampel H, Bürger K, Otto M, Haustein S, Herzog K, Dannenberg R, Wurster U, Bibl M, Maler JM, Reubach U, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Neurosci Lett. · Pubmed #17045397 No free full text.

Abstract: Currently, neurochemical dementia diagnostics (NDD) are increasingly entering routine clinical neurochemistry, offering improved early and differential diagnosis of dementias. However, there is an obvious lack of standardization in pre-analytical sample handling and systematic quality surveys. Therefore, in this study, 14 laboratories in Germany, Austria, and Switzerland were given aliquots of a human cerebrospinal fluid (CSF) sample, and were asked to measure Alzheimer's disease (AD) biomarkers (amyloid beta (Abeta) peptides, total Tau protein, and phosphorylated Tau protein (P-tau(181P))) according to their routine protocols. Results: The inter-laboratory coefficients of variation of the results obtained by the laboratories participating in this study were in the range of 20-30%. Although the results of this quality control survey are promising, the quality of measurements has to be further optimized.

Buerger K, Otto M, Teipel SJ, Zinkowski R, Blennow K, DeBernardis J, Kerkman D, Schröder J, Schönknecht P, Cepek L, McCulloch C, Möller HJ, Wiltfang J, Kretzschmar H, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Neurobiol Aging. · Pubmed #16298235 No free full text.

Abstract: To study the potential diagnostic value of abnormally phosphorylated tau protein in Creutzfeldt-Jakob disease (CJD) compared to Alzheimer's disease (AD), we determined levels of tau phosphorylated at threonine 231 (p-tau231) and of total tau (t-tau) in cerebrospinal fluid (CSF) of CJD patients, AD patients, and healthy controls (HC). CJD patients showed excessively high t-tau levels but relatively low p-tau(231) concentrations compared to the AD group. t-tau alone yielded the best diagnostic accuracy to differentiate between CJD and AD patients, when compared to p-tau231 and the p-tau231/t-tau ratio (97, 78, and 95% correctly allocated cases, respectively). Our findings indicate a dissociation in the direction of change in CSF levels of t-tau and p-tau231 in CJD when compared to 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, Henze M, Hunt A, Klinga K, Haberkorn U, Schröder J. · Section of Geriatric Psychiatry, Department of Psychiatry, University of Heidelberg, Voss-Str. 4, D-69115 Heidelberg, Germany. · Psychiatry Res. · Pubmed #14561431 No free full text.

Abstract: Animal studies indicate that estrogens, such as 17beta-estradiol (E(2)), may enhance hippocampal metabolism and function. In postmenopausal Alzheimer's disease (AD) patients, cerebrospinal fluid (CSF) E(2) levels were significantly lower than in non-demented controls. This finding was inversely correlated with CSF beta-amyloid levels. To address the potential impact of this finding, E(2) levels in CSF were correlated with regional cerebral [18F]2-fluoro-2-deoxy-D-glucose (FDG) uptake as measured using positron emission tomography (PET) in six postmenopausal AD patients. CSF E(2) levels were determined using an electro-chemiluminescence-immunoassay on the Roche Elecsys 2010 immunoassay analyzer. Basic image processing was done by MEDx, using SPM routines for spatial normalization and statistics. CSF E(2) levels were significantly correlated with cerebral glucose metabolism in the left hippocampus. This is the first clinical study indicating an association between CSF E(2) concentration and hippocampal glucose metabolism in postmenopausal women with AD.

Giesel FL, Hempel A, Schönknecht P, Wüstenberg T, Weber MA, Schröder J, Essig M. · Abteilung für onkologische Diagnostik und Therapie, Deutsches Krebsforschungszentrum (dkfz) Heidelberg. · Radiologe. · Pubmed #12955219 No free full text.

Abstract: Currently, different cerebral neuroimaging methods are being applied to varying questions in the diagnosis of dementia. In patients with manifest Alzheimer's disease a reduction of cortical perfusion and metabolism in temporal and temporoparietal regions has been demonstrated when compared to healthy controls on a diversity of memory tasks. Since differing levels of performance and varying degrees of cortical atrophy may influence functional results considerably, an understanding of the processes associated with normal ageing is perceived as prerequisite for studies applying functional neuroimaging. The integration of knowledge concerning neuropsychological and neurobiological alterations associated with healthy ageing allows hypotheses for the differentiation of pathological ageing processes to be phrased. In this connection non-invasive methods such as fMRI and ASL are of increasing importance.

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.

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.