Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Diffusion Tensor Imaging of the Superior Thalamic Radiation and Cerebrospinal Fluid Distribution in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data. METHODS: Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH-patients. Ventricular and sulcal CSF volumes in the three groups were compared. RESULTS: Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age-matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls. CONCLUSIONS: Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly.

Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment.

BACKGROUND AND PURPOSE: In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI). METHODS: We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load. RESULTS: We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant. CONCLUSIONS: Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

Revealing the cerebello-ponto-hypothalamic pathway in the human brain.

The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain.

Diffusion tensor tractography of the mammillothalamic tract in the human brain using a high spatial resolution DTI technique.

The mammillary bodies as part of the hypothalamic nuclei are in the central limbic circuitry of the human brain. The mammillary bodies are shown to be directly or indirectly connected to the amygdala, hippocampus, and thalami as the major gray matter structures of the human limbic system. Although it is not primarily considered as part of the human limbic system, the thalamus is shown to be involved in many limbic functions of the human brain. The major direct connection of the thalami with the hypothalamic nuclei is known to be through the mammillothalamic tract. Given the crucial role of the mammillothalamic tracts in memory functions, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the mammillothalamic tract in the human brain. Fifteen healthy adults were studied after obtaining written informed consent. We used high spatial resolution diffusion tensor imaging data at 3.0 T. We delineated, for the first time, the detailed trajectory of the mammillothalamic tract of the human brain using deterministic diffusion tensor tractography.