Matthias J. Müller

Ultrastructural Hippocampal and White Matter Alterations in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Mild cognitive impairment (MCI) is considered to be a transitional stage between normal aging and dementia. In Alzheimer’s disease (AD), white matter structural pathology is due to Wallerian degeneration and central angiopathy. However, in MCI patients, the presence and extent of white matter alterations as a possible correlate of impaired memory function and as predictor of subsequent progression to AD is not clarified yet. Diffusion tensor imaging (DTI) reveals the ultrastructural integrity of cerebral white matter tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI. In our prospective study, conventional and diffusion tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in temporal, frontal, parietal and occipital white matter regions as well as in the corpus callosum (genu and splenium) and the hippocampus. MCI patients showed higher MD values in the left centrum semiovale (p = 0.013; right: p = 0.026), in the left temporal (p = 0.006), the right temporal (p = 0.014) and the left hippocampal (p = 0.002) region as compared to the control group. FA values of MCI patients and controls did not differ significantly in any region. Compared to controls, AD patients had increased MD values in the left centrum semiovale (p = 0.012), the left parietal (p = 0.001), the right parietal (p = 0.028), the left temporal (p = 0.018), the right temporal (p = 0.011) and the left hippocampal region (p = 0.002). Decreased FA values were measured in the left temporal area (p = 0.017) and in the left hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients. Elevated MD values indicating brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the left hippocampus. The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%). Therefore, the DTI technique validates the MCI concept, and diffusion tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Color-coded diffusion-tensor-imaging of posterior cingulate fiber tracts in mild cognitive impairment.

Different processes like microvascular dysfunction, free radical toxicity, beta-amyloid deposits, and Wallerian degeneration can cause functionally relevant disturbances of cerebral neuronal networks by myelin degeneration. Color-coded diffusion-tensor-imaging (ccDTI) allows the structural identification and quantification of myelinated fiber tracts. Particularly, posterior cingulate fiber tracts, which are regarded as important neuronal substrates of the network representing memory processing can be localized only imprecisely by conventional magnetic resonance imaging techniques. The posterior cingulate bundles were assessed by ccDTI in 17 patients with amnestic mild cognitive impairment (MCI), 25 patients with Alzheimers dementia (DAT), and 21 age-matched controls. Additionally, DTI values were correlated with memory performance in the delayed verbal recall test. Fractional anisotropy and mean diffusivity differed significantly between MCI and controls, as well as between DAT and controls. Performance in the delayed verbal recall test of the entire study group correlated significantly with posterior cingulate bundle anisotropy and diffusivity. Using ccDTI seems, hence, a favorable strategy to detect and quantify the structural integrity of posterior cingulate white matter in MCI. Alterations of DTI parameters substantiate the involvement of white matter pathology in the development of MCI. Moreover, ccDTI could serve as in vivo method to investigate age and disease-related myelin alterations as potential morphological substrates of cognitive dysfunction.

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

Background:  Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first‐line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O‐desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N‐desmethylvenlafaxine (NDV).

Functional implications of hippocampal volume and diffusivity in mild cognitive impairment

Hippocampal atrophy has been related to mild cognitive impairment (MCI) and early Alzheimer disease (AD), but the diagnostic significance of cross-sectionally determined hippocampal volumes is still ambiguous. Diffusion-Tensor-Imaging (DTI) in MCI patients revealed an association of microstructural changes in hippocampal areas with verbal memory decline. MRI volumetry and DTI were combined to investigate 18 MCI patients attending a memory clinic, and 18 carefully age- and gender-matched healthy controls. Neuropsychological testing, high resolution T1-weighted volume MRI scans, and DTI scans with regions-of-interest in hippocampal areas were applied. Left hippocampal volume was significantly lower (-11%, P = 0.02) in MCI patients than in control subjects. No significant differences were found for the right hippocampus (-4%). Mean diffusivity (MD) was significantly elevated in MCI patients vs. controls in left (+10%, P = 0.002) and right hippocampal areas (+13%, P = 0.02). Hippocampal volume and MD values were not significantly correlated. Combining left hippocampal volume and MD measures showed that lower left hippocampal volumes were associated with poor verbal memory performance particularly when co-occurring with high MD values. No comparable associations could be found regarding the right hippocampal formation and with respect to non-verbal memory function. The results demonstrate that microstructural abnormalities as revealed by DTI are very sensitive early indicators of hippocampal dysfunction. The combination of macro- and microstructural parameters in hippocampal areas could be promising in early detection of neurodegenerative processes.

CNS manifestations of Fabry's disease

BACKGROUND Fabrys disease is a rare hereditary lysosomal storage disease with multiorgan involvement. Deficiency of alpha-galactosidase A activity leads to accumulation of neutral glycosphingolipids, especially in vascular endothelial and smooth-muscle cells. Along with progressive renal and cardiac dysfunction, stroke is a major and often life-threatening burden of the disease. Cerebral vasculopathy, confirmed by neuropathological, neuroradiological, and functional studies, occurs commonly and leads to ischaemic cerebrovascular events at an early age. RECENT DEVELOPMENTS Fabrys disease is an X-linked disease and women have been regarded as only mildly affected carriers. However, research has shown a high prevalence of ischaemic stroke and transient ischaemic attacks, along with imaging evidence of CNS involvement, in female patients with the disease, which suggests that at least in a subgroup of clinically affected women the severity of CNS disease is comparable to that in men. Another study has shown a high prevalence of the disease in young patients of both sexes with cryptogenic stroke, emphasising the need for more clinical attention to be paid to this under-diagnosed disease. WHERE NEXT?: These new findings should be replicated in larger samples. Brain structural changes and CNS involvement in the disease need to be monitored carefully in follow-up studies to broaden our knowledge of the course of neurobiological changes and to identify potential effects of enzyme-replacement therapy, which is already showing some benefit in cardiac and renal dysfunction in the disease. Finally, a diagnosis of Fabrys disease should always be considered in young patients who have had a stroke.

The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val108/158Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMTVAL/VAL and COMTVAL/MET genotype carriers showed a better response than COMTMET/MET-bearing patients in the mirtazapine group. Moreover, carriers of the COMTVAL/VAL or COMTVAL/MET genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMTMET/MET homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.

ObjectiveThis evaluation focuses on polymorphisms of the cytochrome-P450 (CYP) isoenzymes 2C9, 2C19 and 2D6 and their association with plasma concentrations within a typical clinical setting. Side effects and treatment response were analysed in an exploratory approach in poor and ultra-rapid metabolisers.Patients and methodsWe analysed 136 Caucasian depressed inpatients treated with amitriptyline, citalopram, clomipramine, doxepin, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine, who underwent weekly plasma concentration measurements, assessment of the severity of illness and side effects during their stay in the hospital. Patients were genotyped with respect to CYP2C9 alleles *1 and *2, the CYP2C19 alleles *1, *2 and *3 and the CYP2D6 alleles *1 to *9 and CYP2D6 gene duplication.ResultsCYP2D6 poor metaboliser genotype and co-medication with inhibitors of CYP2D6 were associated with higher plasma concentrations than the drug-specific median plasma concentration when normalised to dose; plasma concentrations of CYP2C19 extensive metabolisers and smokers were significantly lower than the drug-specific median. Five of the six CYP2D6 poor metabolisers experienced side effects. Response was not associated with plasma concentrations above or below the lower limit of a presumed therapeutic range.ConclusionThese data indicate a significant influence of the CYP2D6 genotype, minor influence of the CYP2C19 genotype and no influence of the CYP2C9 genotype on plasma concentrations of patients taking mainly second-generation antidepressants. Because of the good tolerability of the latter and the flat dose–response relationship, genotyping should only be considered in cases of suspected side effects.

Differentiating moderate and severe depression using the Montgomery–Åsberg depression rating scale (MADRS)

BACKGROUND MADRS cut-off scores for moderate and severe depression were estimated in relation to the Hamilton Depression Rating Scale (HAMD(17)) and the Clinical Global Impressions Scale (CGI). METHOD HAMD(17), MADRS, and CGI ratings from patients with major depression (DSM-IV) were analyzed (N=85). Receiver operating characteristics (ROC) curves were applied. RESULTS Mean age was 51.4+/-14.5 years, 69% were female. Mean MADRS scores were 23.4+/-13.2, HAMD(17), MADRS, and CGI scores were highly correlated (r>0.85; P<0.0001). Best separation between moderate and severe depression according to CGI criteria was achieved with a MADRS score of 31 (sensitivity 93.5%, specificity 83.3%). LIMITATIONS Studies to validate severity gradations including DSM-IV or ICD-10 diagnostic severity categories are recommended. CONCLUSIONS Empirically based MADRS cut-off scores to separate moderate from severe depression on the basis of HAMD(17) and CGI severity ratings in patients with major depression were yielded.

Diagnostic utility of hippocampal size and mean diffusivity in amnestic MCI

Hippocampus atrophy is a frequent finding in mild cognitive impairment (MCI), whereas diffusion-tensor-imaging (DTI) has demonstrated its value to detect subtle brain tissue changes in several neuropsychiatric diseases including MCI. To compare the diagnostic accuracy of both methods, high resolution MRI scans for hippocampus volumetry, and co-registered DTI-scans for ROI-based mean diffusivity (MD) and fractional anisotropy (FA) were carried out in 18 patients with amnestic MCI (7 females, age 67.3+/-8.7 years, MMSE 25.2+/-2.2) and 18 controls (age 66.9+/-9.0 years, MMSE 28.7+/-1.0). Diagnostic properties of normalized hippocampus volume (HV) and DTI measures with regard to MCI status were estimated by receiver operating characteristics (ROC) analyses and logistic regression. Parameters of the left hippocampus showed superior predictive power when compared to the right. At a specificity set to 80%, left HV had low sensitivity (50%); left hippocampal MD values revealed superior sensitivity (89%), similar to left hippocampal FA (78%). The results demonstrate higher sensitivity of DTI-derived left hippocampal parameters than volume measures in detecting subtle hippocampal abnormalities related to MCI.

The benefit from whole body acupuncture in major depression

BACKGROUND In a single-blind placebo-controlled study design we investigated the efficacy of acupuncture additionally applied to drug treatment in major depression. METHODS We randomly included 70 inpatients with a major depressive episode in three different treatment groups: verum acupuncture, placebo acupuncture and a control group. All three groups were pharmacologically treated with the antidepressant mianserin. The verum group received acupuncture at specific points considered effective in the treatment of depression. The placebo group was treated with acupuncture at non-specific locations and the control group received pharmacological treatment plus clinical management. Acupuncture was applied three times a week over a period of 4 weeks. Psychopathology was rated by judges blind to verum/placebo conditions twice a week over 8 weeks. RESULTS Patients who experienced acupuncture improved slightly more than patients treated with mianserin alone. CONCLUSIONS Additionally applied acupuncture improved the course of depression more than pharmacological treatment with mianserin alone. However, we could not detect any differences between placebo and verum acupuncture.