Preoperative factors associated with shunt responsiveness in patients with idiopathic normal-pressure hydrocephalus.

OBJECTIVE: We aimed to evaluate a possible association between preoperative factors (disease duration and vascular risk factors) and shunt responsiveness in patients with idiopathic normal-pressure hydrocephalus (iNPH). METHODS: We conducted a retrospective observational study in a high-volume center for iNPH treatment in Japan and reviewed the clinical data of 107 consecutive patients with probable iNPH who underwent shunt surgery between January 1, 2018, and August 31, 2019, and were followed up for at least 12 months after surgery. Preoperatively, these patients underwent the timed up-and-go test (TUG) and Mini-Mental State Examination (MMSE); moreover, follow-up evaluations were performed 12 months postoperatively, at which TUG and MMSE scores were used as metrics for shunt responsiveness assessment. The degree of shunt responsiveness was regressed to several preoperative factors, including preoperative TUG and MMSE scores, vascular risk factors, and duration from iNPH onset to shunt surgery, to evaluate which preoperative factors may be predictive of shunt responsiveness. RESULTS: In multivariate regression analysis, there was no statistically significant association between the presence of preoperative vascular risk factors and the postoperative TUG or MMSE score 12 months after shunt surgery. Meanwhile, preoperative history of ischemic stroke and a longer duration from iNPH onset to surgery were significantly associated with poorer shunt responsiveness in terms of MMSE and TUG scores. CONCLUSIONS: The current study suggested the potential involvement of stroke history and disease duration with the 1-year prognosis of iNPH after shunt surgery, of which validity needs to be corroborated in further studies.

Chronic cerebral hypoperfusion shifts the equilibrium of amyloid ß oligomers to aggregation-prone species with higher molecular weight.

Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer's disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid ß oligomers respond to hypoperfusion. BCAS accelerated amyloid ß (Aß) convergence to the aggregation seed, facilitating the growth of Aß plaques, but without changing the total Aß amount in the brain. Furthermore, Aß oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aß is in an equilibrium among monomeric, oligomeric, and aggregation forms, our data suggest that cerebral hypoperfusion after BCAS shifted this equilibrium to a state where a greater number of Aß molecules participate in Aß assemblies to form aggregation-prone Aß oligomers with high molecular weight. The reduced blood flow in the cerebral arteries due to BCAS attenuated the dynamics of the interstitial fluid leading to congestion, which may have facilitated Aß aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aß to become aggregation-prone.

Methylation changes and aberrant expression of FGFR3 in Lewy body disease neurons.

Lewy body disease (LBD) is characterized by accumulation of aggregated α-synuclein in the central nervous system as eosinophilic cytoplasmic inclusions called Lewy bodies. According to their distribution pattern, it is classified into brainstem LBD, limbic LBD and diffuse neocortical LBD. It has been reported that α-synuclein affects various points in the MAPK cascade but its relationship with FGF receptors, which are the most upstream of the pathway, has not been previously investigated. We discovered that among the four FGFRs, FGFR3 showed neuronal upregulation in LBD brains histopathologically. Further examination using neuron-specific methylome analysis revealed that the gene body of FGFR3 was hypermethylated in LBD, suggesting its increased transcription. Altered methylation was not observed in the non-neuronal genome. Altered methylation status was associated with the severity of α-synuclein pathology.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aß. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aß burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Recurrent cerebral aneurysm formation and rupture within a short period due to invasive aspergillosis of the nasal sinus; pathological analysis of the catastrophic clinical course.

Destructive infiltration of invasive fungal sinusitis can easily occur into the central nervous system (CNS). Cerebral aneurysms associated with fungal infection are highly vulnerable to rupture, and can frequently and rapidly take a serious clinical course. We experienced a patient who twice developed cerebral aneurysm followed by rupture due to invasive fugal sinusitis. This 77-year-old man was admitted for progressive bilateral visual disturbance, which was initially treated as idiopathic hypertrophic pachymeningitis. The patient subsequently suffered subarachnoid hemorrhage (SAH) twice in only 12 days. Both SAH originated from different newly formed cerebral aneurysms. Trapping was performed for both ruptured aneurysms. Pathological examination of the resected aneurysms indicated the presence of fungi determined to be Aspergillus. This Aspergillus infection was also discovered inside the frontal sinus by endoscopic biopsy, so a regimen of antifungal agents was instituted. Prolonged antifungal therapy caused renal impairment, which ultimately led to the patient's death. Autopsy detected no mycotic infiltration of the major cerebral arteries, except for the 2 ruptured cerebral aneurysms. However, prolonged mycosis of the CNS, such as in the deep part in the falx cerebri and in the small veins proximal to the tentorium cerebelli, was observed, indicating that mycosis invading the cranium is refractory even to long-term administration of antifungal agents. The present case strongly suggests that urgent and proactive definitive diagnosis is essential to successfully treat invasive paranasal sinus aspergillosis. If infiltration of the CNS is suspected, early surgical resection and antifungal therapy must be initiated immediately.