Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

[Biomarker-based diagnostics of Alzheimer's disease : Concept of suspected non-Alzheimer pathology]. / Biomarker-basierte Diagnostik der Alzheimer-Krankheit : Konzept der "suspected non-Alzheimer pathology".

In the field of prodromal Alzheimer's disease biomarker-based diagnostics are becoming increasingly more important. Unclear biomarker constellations, such as suspected non-Alzheimer pathology (SNAP) can lead to diagnostic and prognostic uncertainty. The use of biomarker-based research criteria in the clinical routine is therefore not without problems. Despite sometimes contradictory findings it appears to be nearly certain that the biomarker constellation of SNAP indicates an increased risk of progression to dementia, at least in patients with mild cognitive deficits (MCI). This article discusses the prognostic implications of a SNAP result and the diagnostic and prognostic problems of biomarker-based diagnostic criteria are presented based on the SNAP.

Organic labeling influences food valuation and choice.

Everyday we choose between a variety of different food items trying to reach a decision that fits best our needs. These decisions are highly dependent on the context in which the alternatives are presented (e.g. labeling). We investigate the influence of cognition on food evaluation, using an fMRI experiment in which subjects saw and bid on different foods labeled with (or without) a widely known German emblem for organically produced food. Increased activity in the ventral striatum was found for foods labeled "organic" in comparison to conventionally labeled food. Between-subject differences in activity were related to actual everyday consumption behavior of organic food.

The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression.

BACKGROUND: The role of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of affective disorders such as depression has been controversial. Mounting evidence comes from structural imaging, that the functional BDNF Val66Met polymorphism influences the hippocampal volume with carriers of the 66Met allele (Val/Met and Met/Met group) having smaller hippocampi. Given that stress-induced atrophy of the hippocampus is associated with the pathogenesis of affective disorders, the functional BDNF Val66Met polymorphism could be an incremental risk factor. METHOD: Eighty-seven healthy Caucasian participants underwent structural imaging and were genotyped for the BDNF Val66Met polymorphism. Data were analysed by means of voxel-based morphometry (VBM). RESULTS: Region of interest (ROI) analyses revealed an association between the 66Met allele and smaller parahippocampal volumes and a smaller right amygdala. In addition, the whole-brain analysis showed that the thalamus, fusiformus gyrus and several parts of the frontal gyrus were smaller in 66Met allele carriers. CONCLUSIONS: This study demonstrates that the impact of the BDNF Val66Met polymorphism is not confined to the hippocampus but also extends to the parahippocampal gyrus and the amygdala.

Social comparison affects reward-related brain activity in the human ventral striatum.

Whether social comparison affects individual well-being is of central importance for understanding behavior in any social environment. Traditional economic theories focus on the role of absolute rewards, whereas behavioral evidence suggests that social comparisons influence well-being and decisions. We investigated the impact of social comparisons on reward-related brain activity using functional magnetic resonance imaging (fMRI). While being scanned in two adjacent MRI scanners, pairs of subjects had to simultaneously perform a simple estimation task that entailed monetary rewards for correct answers. We show that a variation in the comparison subject's payment affects blood oxygenation level-dependent responses in the ventral striatum. Our results provide neurophysiological evidence for the importance of social comparison on reward processing in the human brain.

[NeuroCogFX--a computer-based neuropsychological assessment battery for the follow-up examination of neurological patients]. / NeuroCogFX--eine computergestützte neuropsychologische Testbatterie für Verlaufsuntersuchungen bei neurologischen Erkrankungen.

Many neurological therapeutic trials require a longitudinal assessment of cognitive functions. An ideal instrument for that purpose should be in accordance to the criteria of classical testing theory and, furthermore, it should be repeatable and economic in administration and interpretation. We developed NeuroCogFX, a computerized assessment battery, according to these criteria. NeuroCogFX comprises subtests for short term memory, working memory, psychomotor speed, selective attention, verbal and figural memory and verbal fluency (mean duration: 25 minutes). Age-related normative data was obtained from 244 subjects without history of neurological or psychiatric disease (age range 16 - 75 years). Forty-two subjects were re-tested after an average of 8 weeks (range: 6 - 10 weeks) in order to assess retest reliability and training effects. Retest-reliabilities were middle-sized in all but one subtest, ranging from r (12) = 0.5 to r (12) = 0.7 (2-back Test: r (12) = 0.37). For construct validation NeuroCogFX was administered in addition to a comprehensive neuropsychological assessment battery in a group of 40 healthy subjects and in 42 patients with chronic epilepsy. The test allows a valid assessment of short-term memory, reaction speed, memory and verbal fluency. NeuroCogFX is an economic, sufficiently reliable and valid instrument for the neuropsychological follow-up examination in single patients and study groups which can be administered if a comprehensive neuropsychological assessment is unavailable.

The effect of word concreteness on recognition memory.

Concrete words that are readily imagined are better remembered than abstract words. Theoretical explanations for this effect either claim a dual coding of concrete words in the form of both a verbal and a sensory code (dual-coding theory), or a more accessible semantic network for concrete words than for abstract words (context-availability theory). However, the neural mechanisms of improved memory for concrete versus abstract words are poorly understood. Here, we investigated the processing of concrete and abstract words during encoding and retrieval in a recognition memory task using event-related functional magnetic resonance imaging (fMRI). As predicted, memory performance was significantly better for concrete words than for abstract words. Abstract words elicited stronger activations of the left inferior frontal cortex both during encoding and recognition than did concrete words. Stronger activation of this area was also associated with successful encoding for both abstract and concrete words. Concrete words elicited stronger activations bilaterally in the posterior inferior parietal lobe during recognition. The left parietal activation was associated with correct identification of old stimuli. The anterior precuneus, left cerebellar hemisphere and the posterior and anterior cingulate cortex showed activations both for successful recognition of concrete words and for online processing of concrete words during encoding. Additionally, we observed a correlation across subjects between brain activity in the left anterior fusiform gyrus and hippocampus during recognition of learned words and the strength of the concreteness effect. These findings support the idea of specific brain processes for concrete words, which are reactivated during successful recognition.

[Staging of prostate cancer: value of the combined information of endorectal MRI, biopsy Gleason score, and preoperative PSA level]. / Staging des Prostatakarzinoms: Wertigkeit der kombinierten Information aus endorektaler MRT, bioptischem Gleason Score und präoperativem PSA-Wert.

PURPOSE: To evaluate the predictive value of MR imaging criteria, the biopsy Gleason score, and preoperative PSA levels for differentiating between T2 and T3 prostate carcinomas. MATERIALS AND METHODS: Endorectal MR images of 81 patients (median age: 65 years, range: 48 to 81 years) who had biopsy-proven prostate cancer and underwent a radical prostatectomy were analyzed retrospectively. The existence of different imaging features were recorded for each patient. A radiological analysis comprising all used imaging criteria was also performed for every patient. Optimal cut-off levels for the biopsy Gleason score and preoperative PSA levels were obtained using ROC analyses. Subsequently, a logistic regression analysis was performed to identify features which make a significant contribution to the prediction of the tumor stage. RESULTS: Histological examination showed that 24 patients (29.6 %) had a T3 tumor and 57 patients (70.4 %) had a T2 tumor. The mean preoperative PSA level was 9.4 ng/ml (+/- 7 ng/ml), and the median Gleason score was 6 with a range of 4 to 8. The radiological judgment comprising all imaging criteria led to a sensitivity of 54.2 % and specificity of 79 % for the detection of a T3 tumor. The obliteration of the rectoprostatic angle (regression coefficient B = 2.30; standard error (se) = 0.80; p = 0.002) and the biopsy Gleason score (B = 1.16; se = 0.3; p = 0.001) were the parameters with the highest independent predictive value for the diagnosis of an extracapsular tumor spread. The other radiological criteria and the preoperative PSA level were not statistically significant. A combination of the parameters "obliteration of the rectoprostatic angle" and "biopsy Gleason score" led to a sensitivity and specificity of 75 % and 79 %, respectively (existence of one parameter sufficient). The optimal cut-off value was a Gleason score of 7 for the differentiation between T2 and T3 prostate carcinomas. CONCLUSION: In our study, only the criteria "obliteration of the rectoprostatic angle" and "biopsy Gleason score" were of predictive value for the diagnosis of a T3 prostate carcinoma. The other MR imaging criteria and the preoperative PSA levels had no additional benefit.

Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy.

A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.

Neuropsychological outcome after chemotherapy for primary CNS lymphoma: a prospective study.

BACKGROUND: Combined radio- and chemotherapy for primary CNS lymphoma (PCNSL) is associated with a considerable risk of long-term neurotoxicity. The impact of high-dose methotrexate (MTX)-based chemotherapy alone on cognition and quality of life (QOL) is controversial. OBJECTIVE: To assess the impact of the tumor itself and its treatment with high-dose MTX-based chemotherapy on long-term cognition and QOL in patients with PCNSL. METHODS: Prospective neuropsychological examinations and MRI were performed in patients with PCNSL who were in complete remission for more than 12 months after completion of chemotherapy. A QOL assessment was performed at long-term follow-up. RESULTS: Twenty-three patients were eligible. The median follow-up period was 44 months after diagnosis. In long-term follow-up, 22 (95%) of 23 patients showed either preserved or improved cognitive functions as compared with pretreatment and immediate posttreatment baseline assessment. One patient showed an isolated decline in psychomotor speed. Eleven (48%) of 23 patients displayed at least mild cognitive deficits at long-term follow-up not related to therapy. Nineteen (83%) of 23 patients reported a good QOL. MRI revealed confluent white matter abnormalities in eight patients that were not associated with cognitive decline. CONCLUSION: In patients with primary CNS lymphoma (PCNSL) treated with a methotrexate (MTX)-based chemotherapy, no gross cognitive decline has to be expected as a long-term treatment effect. MTX-induced white matter changes apparent on MRI are not inevitably associated with cognitive impairment. Nevertheless, a substantial fraction of patients with PCNSL retain cognitive deficits as a residual symptom of the tumor.

MTX-induced white matter changes are associated with polymorphisms of methionine metabolism.

Methotrexate (MTX) is a folate antagonist inhibiting nucleic acid and methionine synthesis. Methionine is necessary for CNS myelination. In 42 patients with primary CNS lymphoma (PCNSL) treated with a systemic and intraventricular high-dose MTX-based polychemotherapy, the presence of a risk haplotype defined by polymorphisms influencing methionine metabolism referred a relative risk for CNS white matter changes of 4.7 (p = 0.001). The authors conclude that methionine metabolism influences MTX neurotoxicity.

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI(95%): 0.09-0.74; P=0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.

Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study.

The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70 years.