Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks.

AIM: Our aim was to describe the rearrangements of the brain activity related to genetic mutations in the SPAST gene. METHODS: Ten SPG4 patients and ten controls underwent a 5 min resting state magnetoencephalography recording and neurological examination. A beamformer algorithm reconstructed the activity of 90 brain areas. The phase lag index was used to estimate synchrony between brain areas. The minimum spanning tree was used to estimate topological metrics such as the leaf fraction (a measure of network integration) and the degree divergence (a measure of the resilience of the network against pathological events). The betweenness centrality (a measure to estimate the centrality of the brain areas) was used to estimate the centrality of each brain area. RESULTS: Our results showed topological rearrangements in the beta band. Specifically, the degree divergence was lower in patients as compared to controls and this parameter related to clinical disability. No differences appeared in leaf fraction nor in betweenness centrality. CONCLUSION: Mutations in the SPAST gene are related to a reorganization of the brain topology.

Amnestic Mild Cognitive Impairment Is Associated With Frequency-Specific Brain Network Alterations in Temporal Poles.

There is general agreement that the neuropathological processes leading to Alzheimer's disease (AD) begin decades before the clinical onset. In order to detect early topological changes, we applied functional connectivity and network analysis to magnetoencephalographic (MEG) data obtained from 16 patients with amnestic Mild Cognitive Impairment (aMCI), a prodromal stage of AD, and 16 matched healthy control (HCs). Significant differences between the two groups were found in the theta band, which is associated with memory processes, in both temporal poles (TPs). In aMCI, the degree and betweenness centrality (BC) were lower in the left superior TP, whereas in the right middle TP the BC was higher. A statistically significant negative linear correlation was found between the BC of the left superior TP and a delayed recall score, a sensitive marker of the "hippocampal memory" deficit in early AD. Our results suggest that the TPs, which are involved early in AD pathology and belong to the memory circuitry, have an altered role in the functional network in aMCI.

Brain functional networks become more connected as amyotrophic lateral sclerosis progresses: a source level magnetoencephalographic study.

This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as "early stage" or "advanced stage") and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas. In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients.

Mindfulness Meditation Is Related to Long-Lasting Changes in Hippocampal Functional Topology during Resting State: A Magnetoencephalography Study.

It has been suggested that the practice of meditation is associated to neuroplasticity phenomena, reducing age-related brain degeneration and improving cognitive functions. Neuroimaging studies have shown that the brain connectivity changes in meditators. In the present work, we aim to describe the possible long-term effects of meditation on the brain networks. To this aim, we used magnetoencephalography to study functional resting-state brain networks in Vipassana meditators. We observed topological modifications in the brain network in meditators compared to controls. More specifically, in the theta band, the meditators showed statistically significant (p corrected = 0.009) higher degree (a centrality index that represents the number of connections incident upon a given node) in the right hippocampus as compared to controls. Taking into account the role of the hippocampus in memory processes, and in the pathophysiology of Alzheimer's disease, meditation might have a potential role in a panel of preventive strategies.

Effects of Acetylcholine on ß-Amyloid-Induced cPLA2 Activation in the TB Neuroectodermal Cell Line: Implications for the Pathogenesis of Alzheimer's Disease.

The role of ß-amyloid (Aß) in the pathogenesis of Alzheimer's disease (AD) is still considered crucial. The state of Aß aggregation is critical in promoting neuronal loss and neuronal function impairment. Recently, we demonstrated that Acetylcholine (ACh) is neuroprotective against the toxic effects of Aß in the cholinergic LAN-2 cells. In biophysical experiments, ACh promotes the soluble Aß peptide conformation rather than the aggregation-prone ß-sheet conformation. In order to better understand the biological role of ACh in AD, we studied the effect of Aß on the phosphorylation of the cytosolic phospholipase A2 (cPLA2) in the TB neuroectodermal cell line, which differentiates toward a neuronal phenotype when cultured in the presence of retinoic acid (RA). We chose the phosphorylated form of cPLA2 (Ser505, Phospho-cPLA2) as a biomarker to test the influence of ACh on the effects of Aß in both undifferentiated and RA-differentiated TB cells. Our results show that TB cells are responsive to Aß. Moreover, in undifferentiated cells 1 h treatment with Aß induces a 2.5-fold increase of the Phospho-cPLA2 level compared to the control after 24 h in vitro, while no significant difference is observed between Aß-treated and non-treated cells after 4 and 7 days in vitro. The RA-differentiated cells are not sensitive to Aß. In TB cell line ACh is able to blunt the effects of Aß. The ability of ACh to protect non-cholinergic cells against Aß reinforces the hypothesis that, in addition to its role in cholinergic transmission, ACh could also act as a neuroprotective agent.

Spatio-temporal and kinematic gait analysis in patients with Frontotemporal dementia and Alzheimer's disease through 3D motion capture.

Alzheimer's disease (AD) and behavioral variant of Frontotemporal Dementia (bvFTD) are characterized respectively by atrophy in the medial temporal lobe with memory loss and prefrontal and anterior temporal degeneration with dysexecutive syndrome. In this study, we hypothesized that specific gait patterns are induced by either frontal or temporal degeneration. To test this hypothesis, we studied the gait pattern in bvFTD (23) and AD (22) patients in single and dual task ("motor" and "cognitive") conditions. To detect subtle alterations, we performed motion analysis estimating both spatio-temporal parameters and joint excursions. In the single task condition, the bvFTD group was more unstable and slower compared to healthy subjects, while only two stability parameters were compromised in the AD group. During the motor dual task, both velocity and stability parameters worsened further in the bvFTD group. In the same experimental conditions, AD patients showed a significantly lower speed and stride length than healthy subjects. During the cognitive dual task, a further impairment of velocity and stability parameters was observed in the bvFTD group. Interestingly, during the cognitive dual task, the gait performance of the AD group markedly deteriorated, as documented by the impairment of more indices of velocity and stability. Finally, the kinematic data of thigh, knee, and ankle were more helpful in revealing gait impairment than the spatio-temporal parameters alone. In conclusion, our data showed that the dysexecutive syndrome induces specific gait alterations. Furthermore, our results suggest that the gait worsens in the AD patients when the cognitive resources are stressed.

The dark sides of amyloid in Alzheimer's disease pathogenesis.

Although widely explored, the pathogenesis of Alzheimer's disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of ß-amyloid (Aß) remain to be elucidated. Many evidences are starting to cast doubt on Aß as the primary causative factor in AD. For instance, Aß is deposited in the brain following many different kinds of injury. Also, concentration of Aß needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid-independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival.

Partial recovery after severe immune reconstitution inflammatory syndrome in a multiple sclerosis patient with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in patients with multiple sclerosis and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension, with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication.

A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.

Vanishing white matter (VWM; OMIM # 603896) is one of the most prevalent inherited childhood leukoencephalopathies. It has, however, become evident that VWM has a wider clinical spectrum, with age at onset inversely related to clinical severity. Many affected women experience a combination of leukoencephalopathy and primary amenorrhea or premature ovarian failure, a condition named ovarioleukodystrophy. Mutations in any of the genes encoding the 5 subunits of the Eukaryotic Initiation Factor 2B gene (EIF2B1, 2, 3, 4, and 5) can independently cause VWM.(1).

Early onset behavioral variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations.

A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration with or without concomitant motor neuron disease phenotype and TDP-43 based pathology. Here, we report on three cases carrying the hexanucleotide repeat expansion with an atypical presentation consisting in the development of psychiatric symptoms. Patient #1, a 53 year old man with positive family history for dementia, presented with mood deflection, characterized by apathy, social withdraw, and irritability in the last two years. He was diagnosed with "mild cognitive impairment due to depressive syndrome" six months later and subsequently with Alzheimer's disease. Patient #2, a woman with positive family history for dementia, developed behavioral disturbances, aggressiveness, and swearing at 57 years of age. Patient #3 presented, in the absence of brain atrophy, with mystical delirium with auditory hallucinations at 44 years of age, and did not present neurological symptoms over a 7-year follow up. The description of these cases underlines that the hexanucleotide repeat expansion in chromosome 9 could be associated with early onset psychiatric presentations.

A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia.

A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain CT scan showed mild diffuse cortical atrophy, ventricles' asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-ß42, tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules.