Vulnerability of multiple large-scale brain networks in dementia with Lewy bodies.

Aberrations of large-scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large-scale resting-state networks' integrity and their interactions. We found both local and long-distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network-level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network-level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.

Distinct brain dysfunctions underlying visuo-constructive deficit in DLB and AD.

Visuo-constructive abilities are a multicomponential process that can be impaired in several neurodegenerative dementias. Among visuo-constructive tasks, the Rey-Osterrieth Complex Figure-copy (ROCF-c) is the most commonly used and it seems influenced by different skills mediated by specific brain regions. This task complexity allows exploring differential mechanisms of impairment in different neurodegenerative disorders. In this study we examined the neuroanatomical substrates of ROCF-c performance in patients with Dementia with Lewy Bodies (DLB) and patients with Alzheimer's disease (AD). We included forty-five patients with probable DLB, and thirty-four patients with probable typical-AD. To identify the ROCF-c scores neural correlates we performed a regression analysis with brain hypometabolism using the ROCF-c scores as independent variable. Then we evaluated the correlation between regional hypometabolism and ROCF-c scores in each group separately, throughout offline Pearson correlation analysis. The DLB and AD groups differed only in visuo-constructive and memory performances. DLB patients performed worse at the visuo-constructive test, while typical-AD patients performed worse at the verbal memory task. In DLB, worse performance at ROCF-c scores (more severe visuo-constructive impairment) correlated with occipital and temporo-parietal hypometabolism. In AD, worse performance at ROCF-c score was associated with brain hypometabolism in the temporo-parietal regions. The inability to correctly perform the ROCF-c derives from distinct brain dysfunctions in DLB and AD. The present results suggest alterations in visuoperceptual processes due to the severe occipital hypometabolism in DLB, and in visuospatial processes related to temporo-parietal hypometabolism in AD.

Two distinct pathological substrates associated with MMSE-pentagons item deficit in DLB and AD.

INTRODUCTION: Dementia with Lewy Bodies (DLB) is characterized by a prominent deficit in visuospatial abilities. Visuospatial impairment is also detectable in the course of Alzheimer's dementia (AD). However, visuospatial impairment presents some differences in these two conditions, suggesting pathological involvement of distinct brain circuits. Recent studies applied a new method to score the Mini Mental State Examination (MMSE) pentagon copy subtest, namely the Qualitative Scoring Pentagon Test (QSPT), which is a sensitive measure of visuospatial abilities. Using [18F]fluorodeoxy-glucose positron emission tomography (FDG-PET), we assessed the relationship between in vivo brain metabolic dysfunction and visuospatial deficits, in terms of QSPT total value, in DLB and AD. MATERIALS AND METHODS: Sixty Patients were diagnosed as DLB (n = 35) and AD (n = 25) dementia according with the standard research diagnostic criteria. Each patient underwent a FDG-PET scan as support for the final diagnosis. Patients underwent an extended neuropsychological evaluation, including MMSE, language, memory, executive functions and visuospatial abilities tests. The MMSE QSPT scoring was calculated following the methods by Caffarra et al. (2013). Offline voxel-wise correlation analysis between QSPT total scores and FDG-PET brain metabolism was then performed, correcting for MMSE, sex and disease duration. RESULTS: Both groups presented reduced visuospatial performances, as assessed by QSPT scores. DLB compared to AD showed a statistically significant difference in QSPT rotation parameter (p = 0.022). In DLB, worse performance at QSPT total score, i.e. more severe visuospatial impairment, correlated with brain occipital hypometabolism (i.e. lateral occipital cortex, calcarine cortex, fusiform and lingual gyri). In AD, worse performance at QSPT total score correlated with brain hypometabolism in the right parietal cortex (i.e. superior and inferior parietal cortex and angular gyrus). DISCUSSION: These findings reveal that visuospatial deficits may derive from distinct brain alterations in AD and DLB. We propose that the inabilities to perform correctly the QSPT task is related to altered visuoperceptual process in DLB, and visuospatial process in AD. This is consistent with our results showing hypometabolism in brain system related to visuoperceptual processing, namely the occipital cortex in DLB, and visuospatial processing, namely parietal cortex in AD.

Brain glucose metabolism in Lewy body dementia: implications for diagnostic criteria.

BACKGROUND: [18F]FDG-PET hypometabolism patterns are indicative of different neurodegenerative conditions, even from the earliest disease phase. This makes [18F]FDG-PET a valuable tool in the diagnostic workup of neurodegenerative diseases. The utility of [18F]FDG-PET in dementia with Lewy bodies (DLB) needs further validation by considering large samples of patients and disease comparisons and applying state-of-the-art statistical methods. Here, we aimed to provide an extensive validation of the [18F]FDG-PET metabolic signatures in supporting DLB diagnosis near the first clinical assessment, which is characterized by high diagnostic uncertainty, at the single-subject level. METHODS: In this retrospective study, we included N = 72 patients with heterogeneous clinical classification at entry (mild cognitive impairment, atypical parkinsonisms, possible DLB, probable DLB, and other dementias) and an established diagnosis of DLB at a later follow-up. We generated patterns of [18F]FDG-PET hypometabolism in single cases by using a validated voxel-wise analysis (p < 0.05, FWE-corrected). The hypometabolism patterns were independently classified by expert raters blinded to any clinical information. The final clinical diagnosis at follow-up (2.94 ± 1.39 [0.34-6.04] years) was considered as the diagnostic reference and compared with clinical classification at entry and with [18F]FDG-PET classification alone. In addition, we calculated the diagnostic accuracy of [18F]FDG-PET maps in the differential diagnosis of DLB with Alzheimer's disease dementia (ADD) (N = 60) and Parkinson's disease (PD) (N = 36). RESULTS: The single-subject [18F]FDG-PET hypometabolism pattern, showing temporo-parietal and occipital involvement, was highly consistent across DLB cases. Clinical classification at entry produced several misclassifications with an agreement of only 61.1% with the diagnostic reference. On the contrary, [18F]FDG-PET hypometabolism maps alone accurately predicted diagnosis of DLB at follow-up (88.9%). The high power of the [18F]FDG-PET hypometabolism signature in predicting the final clinical diagnosis allowed a ≈ 50% increase in accuracy compared to the first clinical assessment alone. Finally, [18F]FDG-PET hypometabolism maps yielded extremely high discriminative power, distinguishing DLB from ADD and PD conditions with an accuracy of > 90%. CONCLUSION: The present validation of the diagnostic and prognostic accuracy of the disease-specific brain metabolic signature in DLB at the single-subject level argues for the consideration of [18F]FDG-PET in the early phase of the DLB diagnostic flowchart. The assessment of the [18F]FDG-PET hypometabolism pattern at entry may shorten the diagnostic time, resulting in benefits for treatment options and management of patients.

The expression of the non-receptor tyrosine kinases Arg and c-abl is differently modulated in B lymphoid cells at different stages of differentiation.

The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases. Both genes are ubiquitously expressed. The interactions of these two similar protein kinases are still not well known, although it has been suggested that they could cooperate, with redundant actions, to provide intracellular signals in the cells. Lymphopenia occurs in mice with homozygous disruption of c-abl, indicating that in certain tissues Arg is unable to substitute c-abl functions. In B and T lymphoid cell lines at different stages of differentiation, we studied, by a reverse transcriptase-competitive polymerase chain reaction and Western blotting, Arg and c-abl in order to evaluate whether the expression pattern of the two genes could give insight as to why they do not exhibit overlapping roles in lymphocytes and whether the product levels of the two genes are related to lymphoid differentiation. The data showed that their expression is differently modified in lymphoid B cell lines. The highest Arg transcript and protein levels are in the mature B cells.