Entwicklung einer MRT-Messsequenz zur Charakterisierung des Pulmonalvenen-Flussprofils

Ziel der vorliegenden Dissertation ist die Entwicklung einer MRT-Aufnahmesequenz, deren gewählte zeitliche u. räumliche Auflösung, das pulmonalvenöse Flussprofil adäquat abbildet u. somit die Beurteilung der Diastolischen Funktion gewährleistet. Mit modifizierten Sequenzen hinsichtlich der zeitlichen u. räumlichen Auflösung erfolgten vergleichende Messungen an der Aorta u. der Pulmonalvene. Es wurden die charakteristischen Flussprofilpunkte der 4 Venen sowie das pulmonalvenöse mit dem transmitralen Flussprofil verglichen. An der Aorta zeigte sich kein signifikanter Unterschied bezüglich der Sequenzen. An der Pulmonalvene erzeugte eine höhere zeitliche Auflösung höhere Extrema. Der signifikante Unterschied der Absolutwerte der 4 Pulmonalvenen, konnte durch Normierung aufgehoben werden. Das transmitrale Flussprofil korrelierte gut mit dem pulmonalvenösen. Die Wahl einer hohen zeitlichen Auflösung sowie eine Normierung sind essenziell zur Charakterisierung des Pulmonalvenen-Flussprofils

Course of neuropsychological impairment during natalizumab-associated progressive multifocal leukoencephalopathy

$\textbf {Background and purpose}$ Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system from the John Cunningham virus (JCV), is a side effect of natalizumab (NTZ) treatment for relapsing–remitting multiple sclerosis (RRMS), potentially leading to a substantial increase of physical and mental disability. Nevertheless, data of neuropsychological impairment during the NTZ-PML disease course are missing. Our objective was to evaluate the neuropsychological disease course of NTZ-PML patients and to compare neuropsychological deficits of NTZ-PML patients with two different non-PML multiple sclerosis (MS) cohorts. $\bf Methods$ Neuropsychological examinations of 28 NTZ-PML patients performed during different phases of the disease ([i] at PML diagnosis, [ii] during immune reconstitution inflammatory syndrome [IRIS], and [iii] post-IRIS/PML) were retrospectively analyzed and compared to those of NTZ-treated RRMS or secondary progressive MS patients with and without immunotherapy. $\bf Results$ Compared to controls, NTZ-PML patients performed worse in neuropsychological examinations during all stages of disease, mainly affecting visuospatial ability and working memory. Furthermore, failure to eliminate the JCV from the central nervous system was associated with a progredient decline of cognition, especially working memory. $\bf Conclusions$ Working memory and visuospatial abilities are the core neuropsychological deficits of NTZ-PML patients in long-term follow-up. Our findings should be implemented in neurorehabilitation strategies

Cortical and subcortical grey and white matter atrophy in myotonic dystrophies type 1 and 2 is associated with cognitive impairment, depression and daytime sleepiness

$\textbf {Objectives:}$ Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). $\textbf {Methods:}$ 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. $\textbf {Results:}$ Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. $\textbf {Conclusion:}$ GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks

Insight into metabolic 1 ^{1}H-MRS changes in natalizumab induced progressive multifocal leukoencephalopathy brain lesions

$\textbf {Background:}$ Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing–remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. $\textbf {Objective:}$ To study metabolic profiles in natalizumab-associated PML lesions of MS patients by $^{1}$H magnetic resonance spectroscopy ($^{1}$H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). $\textbf {Methods:}$ 20 patients received $^{1}$H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of $^{1}$H-MRS. $\textbf {Results:}$ In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS ($\it p$ = 0.014) with a maximum in the PML–IRIS group ($\it p$ = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase ($\it p$ = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML ($\it p$ = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations $\it p$ = 0.481, $\it p$ = 0.018; $\it p$ = −0.505, $\it p$ = 0.014; and $\it p$ = −0.488, $\it p$ = 0.020). $\textbf {Conclusion:}$ $^{1}$H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease

Metabolic profiles by 1^{1}H-magnetic resonance spectroscopy in natalizumab-associated post-PML lesions of multiple sclerosis patients who survived progressive multifocal leukoencephalopathy (PML)

$\bf Purpose$ Early diagnosis and treatment of multiple sclerosis-related progressive multifocal leukoencephalopathy (PML) significantly improve clinical outcomes. However, there is a lack of information regarding the restart of immunomodulatory therapy in the post-PML setting, when multiple sclerosis activity reappears. We aimed at the examination of metabolic differences using $^{1}$H-magnetic resonance spectroscopy ($^{1}$H-MRS) in multiple sclerosis patients at various post-PML stages and at the exploration of differences according to their disease and JC virus (JCV) status. $\bf Methods$ $^{1}$H-MRS of PML lesions was carried out on 15 relapsing-remitting multiple sclerosis patients with natalizumab-associated PML. Patients were grouped according to their stage after PML infection as early post-PML, less than 19 months after PML onset ($\it n$ = 5), or late post-PML group, more than 23 months after PML onset ($\it n$ = 10). The latter group was further categorized according to persisting JCV load in the cerebrospinal fluid. $\bf Results$ Early post-PML patients showed significantly higher Lipid/Creatine ratios within PML lesions than late post-PML ($\it p$ = 0.036). Furthermore, N-Acetyl-Aspartate/Creatine and N-Acetyl-Aspartate/Choline were significantly reduced in early post-PML and late post-PML lesions relative to normal-appearing white matter. In late post-PML, virus-positive patients showed significantly higher ratios of Choline/Creatine ($\it p$ = 0.019) and consequently a reduced N-Acetyl-Aspartate/Choline ratio ($\it p$ = 0.010) in contrast to virus-negative patients. In late post-PML patients with persisting viral load, an elevated Choline/Creatine ratio correlated significantly with higher disability. $\bf Conclusions$ $^{1}$H-MRS may provide additional information related to underlying PML disease activity in various post-PML stages. In particular, Choline/Creatine levels, Lipid levels, and N-Acetyl-Aspartate/Choline are relevant markers in the post-PML setting, taking also the JCV status into account

Novel variants in a patient with late-onset hyperprolinemia type II

$\bf Background$ Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. $\bf Case presentation$ The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B$_6$ serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The $\it ALDH4A1$ gene sequencing confirmed two previously unknown compound heterozygous variants ($\it ALDH4A1$ gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and $\it ALDH4A1$ gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B$_6$ therapy no further seizures occurred. $\bf Conclusion$ We describe two novel $\it ALDH4A1$-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation

Quantification of individual remyelination during short-term disease course by synthetic magnetic resonance imaging

MRI is an important diagnostic tool for evaluation of myelin content in multiple sclerosis and other CNS diseases, being especially relevant for studies investigating remyelinating pharmacotherapies. In this study, we evaluated a new synthetic MRI–based myelin estimation in methylenetetrahydrofolate reductase deficiency as a treatable primary demyelinating disorder and compared this method with established diffusion tensor imaging in both methylenetetrahydrofolate reductase deficiency patients and healthy controls. This is the first synthetic MRI–based $\textit {in vivo}$ evaluation of treatment-associated remyelination. 1.5 T synthetic MRI and 3 T diffusion MRI were obtained from three methylenetetrahydrofolate reductase deficiency patients at baseline and 6 months after therapy initiation, as well as from age-matched healthy controls (diffusion tensor imaging: $\it n$ = 14, synthetic MRI: $\it n$ = 9). Global and regional synthetic MRI parameters (myelin volume fraction, proton density, and relaxation rates) were compared with diffusion metrics (fractional anisotropy, mean/radial/axial diffusivity) and related to healthy controls by calculating z-scores and z-deviation maps. Whole-brain myelin (% of intracranial volume) of the index patient was reduced to 6 versus 10% in healthy controls, which recovered to a nonetheless subnormal level of 6.6% following initiation of high-dosage betaine. Radial diffusivity was higher at baseline compared with healthy controls (1.34 versus $(0.79 × 10^{−3} mm^{2}/s)$, recovering at follow-up $(1.19 × 10^{−3} mm^{2}/s)$. The index patient’s lesion volume diminished by 58% under treatment. Regional analysis within lesion area and atlas-based regions revealed lower mean myelin volume fraction $(12.7_{Baseline}/14.71_{Follow-up}$ and relaxation rates, higher proton density, as well as lower fractional anisotropy and higher radial diffusivity $(1.08 × 10^{−3}_{Baseline}/0.94 × 10^{−3}_{Follow-up}$) compared with healthy controls. The highest z-scores were observed for myelin volume fraction in the posterior thalamic radiation, with greater deviation from controls at baseline and reduced deviation at follow-up. Z-deviations of diffusion metrics were less pronounced for radial and mean diffusivity than for myelin volume fraction. Z-maps for myelin volume fraction of the index patient demonstrated high deviation within and beyond lesion areas, among others in the precentral and postcentral gyrus, as well as in the cerebellum, and partial remission of these alterations at follow-up, while radial diffusivity demonstrated more widespread deviations in supra- and infratentorial regions. Concordant changes of myelin volume fraction and radial diffusivity after treatment initiation, accompanied by dramatic clinical and paraclinical improvement, indicate the consistency of the methods, while myelin volume fraction seems to characterize remyelinated regions more specifically. Synthetic MRI–based myelin volume fraction provides myelin estimation consistent with changes of diffusion metrics to monitor short-term myelin changes on individual patient level

Temporal dynamics of diffusion metrics in early multiple sclerosis and clinically isolated syndrome

$\bf Background:$ Tract-based spatial statistics (TBSS) is suitable for the assessment of voxel-wise changes in fiber integrity in WM tracts in the entire brain. Longitudinal TBSS analyses of early multiple sclerosis (MS) using 3 Tesla magnetic resonance imaging (MRI) are not common. $\bf Objective:$ To characterize microstructural WM alterations at initial diagnosis in clinically isolated syndrome (CIS) and early MS at baseline and longitudinally over 2 years. $\bf Methods:$ DTI (Diffusion tensor imaging) at 3 Tesla was used to evaluate 106 therapy-naive patients with CIS or definite MS at baseline and at 1-year ($\it N$ = 83) and 2-year ($\it N$ = 43) follow-up compared to healthy controls (HC, $\it N$ = 49). TBSS was used for voxel-wise analyses of the DTI indices of fractional anisotropy (FA) and radial, mean, and axial diffusivity (RD, MD, AD) for cross-sectional and longitudinal comparisons. Mean values of FA, RD, and cluster voxel numbers were extracted from significant clusters using an atlas-based approach. Correlations with disability (EDSS) were calculated for FA and RD changes related to affected brain regions. $\bf Results:$ Reductions in FA compared to HC were found at baseline in patients with CIS and RRMS and involved most supra- and infratentorial WM tracts. In the cerebellum and cerebral peduncles, these changes negatively correlated with EDSS after 2 years. FA changes in patients with CIS and RRMS evolved in the second year, particularly in the descending projection pathways and the cerebellum, and were significantly associated with EDSS. RD alterations compared to HC were undetectable in patients at baseline but were observed after 1 year and were exacerbated during the second year in all major supratentorial WM tracts, the corpus callosum, and the cerebellum. FA did not change between baseline and year 1 follow-up, but longitudinal investigation between the first and second year revealed combined dynamic FA and RD changes in the corpus callosum and corona radiata. $\bf Conclusion:$ TBSS of diffusion metrics at initial diagnosis and at 2-year follow-up showed microstructural WM pathology and associations between FA reduction and future disability, respectively. Combined longitudinal changes in FA and RD occurred in specific structures, where RD increases likely reflected progressing axonal degeneration. The distinct temporal dynamics of FA and RD, implying constancy during the first year, supports early therapeutic intervention for CIS and RRMS