Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders

Anatomical correlates of early mutism in progressive nonfluent aphasia

Patients with progressive nonfluent aphasia (PNFA) can become mute early in the course of the disease. Voxel-based morphometry showed that PNFA is associated with left anterior insula and inferior frontal atrophy. In PNFA with early mutism, volume loss was more prominent in the pars opercularis and extended into the left basal ganglia. Damage to the network of brain regions involved in both coordination and execution of speech causes mutism in PNFA

Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimer's Disease Spectrum

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer's disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum. Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups. Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed. Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer's disease. The presence of an informant also seems necessary given its accuracy as a source of information

Deformation-based shape analysis of the hippocampus in the semantic variant of primary progressive aphasia and Alzheimer’s disease

Background Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer’s disease (AD). Methods We measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit. Results Comparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus. Discussion Our study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA

Test-Retest Reliability of Diffusion Measures Extracted Along White Matter Language Fiber Bundles Using HARDI-Based Tractography

High angular resolution diffusion imaging (HARDI)-based tractography has been increasingly used in longitudinal studies on white matter macro- and micro-structural changes in the language network during language acquisition and in language impairments. However, test-retest reliability measurements are essential to ascertain that the longitudinal variations observed are not related to data processing. The aims of this study were to determine the reproducibility of the reconstruction of major white matter fiber bundles of the language network using anatomically constrained probabilistic tractography with constrained spherical deconvolution based on HARDI data, as well as to assess the test-retest reliability of diffusion measures extracted along them. Eighteen right-handed participants were scanned twice, one week apart. The arcuate, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculi were reconstructed in the left and right hemispheres and the following diffusion measures were extracted along each tract: fractional anisotropy, mean, axial, and radial diffusivity, number of fiber orientations, mean length of streamlines, and volume. All fiber bundles showed good morphological overlap between the two scanning timepoints and the test-retest reliability of all diffusion measures in most fiber bundles was good to excellent. We thus propose a fairly simple, but robust, HARDI-based tractography pipeline reliable for the longitudinal study of white matter language fiber bundles, which increases its potential applicability to research on the neurobiological mechanisms supporting language

Dormant origins and fork protection mechanisms rescue sister forks arrested by transcription

The yeast RNA/DNA helicase Sen1, Senataxin in human, preserves the integrity of replication forks encountering transcription by removing RNA-DNA hybrids. Here we show that, in sen1 mutants, when a replication fork clashes head-on with transcription is arrested and, as a consequence, the progression of the sister fork moving in the opposite direction within the same replicon is also impaired. Therefore, sister forks remain coupled when one of the two forks is arrested by transcription, a fate different from that experienced by forks encountering Double Strand Breaks. We also show that dormant origins of replication are activated to ensure DNA synthesis in the proximity to the forks arrested by transcription. Dormant origin firing is not inhibited by the replication checkpoint, rather dormant origins are fired if they cannot be timely inactivated by passive replication. In sen1 mutants, the Mre11 and Mrc1-Ctf4 complexes protect the forks arrested by transcription from processing mediated by the Exo1 nuclease. Thus, a harmless head-on replication-transcription clash resolution requires the fine-tuning of origin firing and coordination among Sen1, Exo1, Mre11 and Mrc1-Ctf4 complexes

Aging and Language: Maintenance of Morphological Representations in Older Adults

Studies employing primed lexical decision tasks have revealed morphological facilitation effects in children and young adults. It is unknown if this effect is preserved or diminished in older adults. In fact, only few studies have investigated age-related changes in morphological processing and results are inconsistent across studies. To address this issue, we investigated inflection morphology compared to orthographic and semantic processing in young and older adults. Twenty-six adults aged 60–85 and 22 younger adults aged 19–28 participated. We probed verb recognition using a sandwich-masked primed lexical decision paradigm. We investigated lexical decision using different prime presentation times (PPTs) (33, 66, and 150 ms), and prime types with priming conditions involving orthographic (e.g., cassis—CASSE ‘blackcurrant—break’), regular inflection morphological (cassait—CASSE ‘broke—break’), and semantic primes (brise—CASSE ‘break—break’) and their controls, while measuring response accuracy and reaction times. Response accuracy analyses revealed that older participants performed at ceiling on the lexical decision task, and that accuracy levels were higher compared to young adults. Reaction-time data revealed effects of age group, priming condition, and an interaction of age group and morphological priming, but no PPT effects. Both young and older adults presented a significant facilitation effect (reduced reaction times) in the orthographic and morphological priming conditions. No semantic effects were observed in either group. Younger adults also showed a significantly stronger morphological priming effect, while older adults showed no difference between orthographic and morphological priming when comparing priming magnitudes. These findings suggest (1) that regular inflectional morphological processing benefits lexical access in younger French adults, confirming studies in other languages, and (2) that this advantage is reduced at older ages