Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment.

BACKGROUND: Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previous evidence has been mixed, and the underlying mechanisms remain unclear. OBJECTIVE: We determined whether serum VitB12 concentrations within the normal range were linked to memory functions and related neuronal structures in patients with mild cognitive impairment (MCI). DESIGN: In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high-normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n= 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure. RESULTS: MCI patients with low-normal VitB12 showed a significantly poorer learning ability (P= 0.014) and recognition performance (P= 0.008) than did patients with high-normal VitB12. Also, the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and dentate gyrus region (P= 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects. CONCLUSIONS: Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural integrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency. This trial was registered at clinicaltrials.gov as NCT01219244.

Auditory verbal hallucinations and the interhemispheric auditory pathway in chronic schizophrenia.

OBJECTIVES: The interhemispheric auditory pathway has been shown to play a crucial role in the processing of acoustic stimuli, and alterations of structural and functional connectivity between bilateral auditory areas are likely relevant to the pathogenesis of auditory verbal hallucinations (AVHs). The aim of this study was to examine this pathway in patients with chronic schizophrenia regarding their lifetime history of AVHs. METHODS: DTI scans were acquired from 33 healthy controls (HC), 24 schizophrenia patients with a history of AVHs (LT-AVH) and nine schizophrenia patients without any lifetime hallucinations (N-LT-AVH). The interhemispheric auditory fibre bundles were extracted using streamline tractography. Subsequently, diffusivity indices, namely Fractional Anisotropy (FA), Trace, Mode, Axial and Radial diffusivity, were calculated. RESULTS: FA was decreased over the entire pathway in LT-AVH compared with N-LT-AVH. Moreover, LT-AVH displayed decreased FA and Mode as well as increased radial diffusivity in the midsagittal section of the fibre tract. CONCLUSIONS: These findings indicate complex microstructural changes in the interhemispheric auditory pathway of schizophrenia patients with a history of AVHs. Alterations appear to be absent in patients who have never hallucinated.

Creatine protects against excitoxicity in an in vitro model of neurodegeneration.

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H(2)O(2). In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H(2)O(2)-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.

The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia.

Alterations of the early auditory evoked gamma-band response in first-degree relatives of patients with schizophrenia: hints to a new intermediate phenotype.

BACKGROUND: There is growing evidence of abnormalities of high-frequency oscillations in the gamma-range of the electroencephalography in schizophrenia. The generation of neural activity in the gamma-band was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. Recently, a reduction of the early auditory evoked gamma-band response (eGBR) in schizophrenic patients was reported. In order to investigate the possible applicability of this neurophysiological marker as an intermediate phenotype for schizophrenia, this is the main question of our investigation: Is the early eGBR decreased regarding evoked power and phase locking in first-degree relatives of patients with schizophrenia? METHODS: We investigated the early eGBR in 17 unaffected first-degree relatives of patients with schizophrenia and in age-, gender- and education-matched groups of schizophrenic patients and healthy controls using an auditory reaction task. RESULTS: First-degree relatives of patients with schizophrenia and schizophrenic patients showed a significant reduction of evoked power and phase locking of the early eGBR compared to healthy controls. CONCLUSION: This study shows significantly reduced evoked power and phase locking of the early auditory eGBR in first-degree relatives of patients with schizophrenia pointing to the applicability of this marker as a heritable intermediate phenotype for schizophrenia. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses.

Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene.

OBJECTIVES: The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene. METHODS: Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed. RESULTS: Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz). CONCLUSION: Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.

Reduced early auditory evoked gamma-band response in patients with schizophrenia.

BACKGROUND: There is growing evidence for abnormalities of certain gamma-aminobutyric acid (GABA)-ergic interneurons and their interaction with glutamatergic pyramidal cells in schizophrenia. These interneurons are critically involved in generating neural activity in the gamma-band (30-100 Hz) of the electroencephalogram. One example of such gamma oscillations is the early auditory evoked gamma-band response (GBR). Although auditory processing is obviously disturbed in schizophrenia, there is no direct evidence providing a reduced early auditory evoked GBR so far. We addressed two questions: 1) Is the early auditory evoked GBR decreased regarding power and phase-locking in schizophrenic patients?; and 2) Is this possible decrease a result of reduced activity in the auditory cortex and/or the anterior cingulate cortex (ACC), which were identified as sources of the GBR previously? METHODS: We investigated the early auditory evoked GBR and its sources in the ACC and the auditory cortex in 90 medicated patients with schizophrenia and in age-, gender-, and education-matched healthy control subjects with an auditory reaction task. RESULTS: Patients with schizophrenia showed a significant reduction of power and phase-locking of the early auditory evoked GBR. This effect was due to a reduced activity in the auditory cortex and the ACC/medial frontal gyrus region (low-resolution brain electromagnetic tomography analysis). CONCLUSIONS: Generally, these findings are in line with earlier reports on the impaired ability of schizophrenic patients in generating gamma activity. In addition, this is the first study to demonstrate disturbance of gamma activity in auditory processing as assessed by the early auditory GBR power.

A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

Association of functional polymorphisms in NOS1 and NOS3 with loudness dependence of auditory evoked potentials.

Nitric oxide (NO) is a gaseous molecule with neurotransmitter properties that is involved in numerous functions in the central nervous system (CNS), the vascular system and also in macrophages. Haplotypes of NOS1 and NOS3 genes have been shown to be associated with different psychiatric disorders such as schizophrenia and bipolar disorder. Therefore, the detection of other characteristics of nitrinergic transmission is desirable. Because nitrinergic functioning influences serotonergic transmission, a functional marker of the serotonergic transmission, the loudness dependence of auditory evoked potentials (LDAEP), can be assumed to be influenced by nitrinergic changes as well. In order to clarify the relationship between nitrinergic transmission and LDAEP, 95 healthy subjects (41 males, 54 females) underwent electrophysiological recording and blood drawing for genotyping of single nucleotide polymorphisms (SNPs) and haplotypes of the NOS1 and NOS3 genes. Interestingly, two functional SNPs in both NOS1 (G-84A_exon 1c promoter polymorphism) and NOS3 (Glu298Asp) were associated with lower LDAEP. Further studies are needed to fully clarify the relationship between nitrinergic transmission, LDAEP and complex disorders such as schizophrenia and affective disorders.

A Ser9Gly polymorphism in the dopamine D3 receptor gene (DRD3) and event-related P300 potentials.

An important reason for the interest in P300 event-related potentials are findings in patients with psychiatric disorders like schizophrenia or alcoholism in which attenuations of the P300 amplitude are common findings. The P300 wave has been suggested to be a promising endophenotype for genetic research since attenuations of the amplitude and latency can be observed not only in patients but also in relatives. In parallel, the search for genes involved in the pathogenesis of psychiatric disorders has revealed for both, schizophrenia and alcoholism an association with a DRD3 Ser9Gly polymorphism in a number of studies. In the present study, we have investigated 124 unrelated healthy subjects of German descent and have found diminished parietal and increased frontal P300 amplitudes in Gly9 homozygotes in comparison to Ser9 carriers. This finding suggests a possible role of the DRD3 receptor gene in the interindividual variation of P300 amplitudes. Further studies should address the direct role of the DRD3 Ser9Gly polymorphism in attenuated P300 amplitudes in psychiatric disorders like schizophrenia or alcoholism.