Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer's Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models.

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus-a complex brain structure with a pivotal role in learning and memory-is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice-a model of AD-and to determine the impact of Aß40 and Aß42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood-brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aß40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aß42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease.

Effect of lithium in pyramidal neurons of Cornu Ammonis in an animal model.

Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was to evaluate, at a cellular level, the size of both cell body and nucleus of pyramidal neurons located throughout the Cornu Ammonis (CA1 to CA4 regions). To perform this duty, we used 16 rats that were randomized into two groups: control and dietary lithium-treated. After one month, they were sacrificed and their brains removed for histopathological analysis. Serial photos of the entire Cornu Ammonis were taken and, after dividing them into 4 regions of interest, we measured the cell body and nucleus on each pyramidal neuron belonging to the first 5 photos of each region of interest. As a result of this histological analysis, cell body area and nuclear area were significantly larger in the experimental group in a specific area of the Cornu Ammonis that could correspond to CA2 or the transition between CA1 and CA2. These results suggest that the effect of lithium is not homogeneous throughout the hippocampus and allows directing future studies to a specific area of this structure.

Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations.

Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody-drug conjugates (ADCs) ado-trastuzumab-emtansine and trastuzumab-deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.

Branching enzyme deficiency/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular genetic studies.

The fatal infantile neuromuscular presentation of branching enzyme deficiency (glycogen storage disease type IV) due to mutations in the gene encoding the glycogen branching enzyme, is a rare but probably underdiagnosed cause of congenital hypotonia. We report an infant girl with severe generalized hypotonia, born at 33 weeks gestation who required ventilatory assistance since birth. She had bilateral ptosis, mild knee and foot contractures and echocardiographic evidence of cardiomyopathy. A muscle biopsy at 1 month of age showed typical polyglucosan storage. The autopsy at 3.5 months of age showed frontal cortex polymicrogyria and polyglucosan bodies in neurons of basal ganglia, thalamus, substantia innominata, brain stem, and myenteric plexus, as well as liver involvement. Glycogen branching enzyme activity in muscle was virtually undetectable. Sequencing of the GBE1 gene revealed a homozygous 28 base pair deletion and a single base insertion at the same site in exon 5. This case confirms previous observations that GBE deficiency ought to be included in the differential diagnosis of congenital hypotonia and that the phenotype correlates with the 'molecular severity' of the mutation.

Neuropathology of the brain and spinal cord in human West Nile virus infection.

OBJECTIVE: To describe the histopathology of the brain and spinal cord in human West Nile virus (WNV) infection. MATERIALS AND METHODS: Single case report, including premortem clinical and laboratory findings, and autopsy. RESULTS: An 83-year-old female presented with acute confusion, high fevers, dysarthria and generalized subjective weakness, with decreased deep tendon reflexes and weakness on physical examination. Electromyography showed evidence of a sensorimotor axonal polyneuropathy of the right-sided extremities. She became ventilator-dependent and died after a 2-week ICU stay, following withdrawal of life support. WNV infection was confirmed premortem by detection of IgM antibodies from serum and CSF and postmortem by RT-PCR from brain tissue. Examination of the brain parenchyma showed scattered microglial aggregates accompanied by perivascular chronic inflammation. The leptomeninges showed focal lymphocytic infiltrates. Examination of the spinal cord showed lymphocytic infiltrates in nerve roots and within the cord proper, with focal microglial nodules and neuronophagia in the ventral horns. Special stains were negative for a demyelinating process. General autopsy revealed only emphysema and atelectasis. CONCLUSIONS: The findings in this case suggest direct viral infection of the spinal cord and nerve roots as the mechanism of the flaccid paralysis often observed in patients infected with WNV. Findings are reviewed in comparison with other reports of neuropathologic findings in human WNV infection.