Claude Alain Maurage

Biochemical Staging of Synucleinopathy and Amyloid Deposition in Dementia With Lewy Bodies

The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated &agr;-synuclein, tau, and A&bgr; species. All sporadic cases of DLB were associated with abundant deposits of A&bgr; x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and A&bgr; accumulation. The constant and abundant A&bgr; x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.

Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease

Objective: Vascular dementia (VaD) and Alzheimer disease with cerebrovascular disease (AD+CVD) are the leading causes of dementia after Alzheimer disease alone (AD). Little is known about the progression of either VaD or AD+CVD. The aim of this study was to compare demographic features, cognitive decline and survival of patients with VaD, AD+CVD and AD alone attending a memory clinic. Methods: This study included 970 patients who were followed at the Lille-Bailleul memory clinic, France. Cognitive functions were measured with the Mini Mental State Examination (MMSE) and the Dementia Rating Scale (DRS). Survival rate was analysed with a left-truncated Cox model. Analyses were adjusted for age, sex, education, hypertension, diabetes and baseline MMSE and DRS. Results: Of 970 patients, 141 had VaD, 663 AD alone and 166 AD+CVD. The latter were significantly older than AD or VaD patients at onset (71 (SD 7) vs 69 (9) and 68 (9) years, p = 0.01) and at first visit (75 (6) vs 73 (8) and 72 (8) years, p = 0.0002). Baseline MMSE and DRS evaluations were highest for VaD compared with AD alone or AD+CVD patients (p<0.006). Cognitive decline during follow-up was slowest for VaD, intermediate for AD+CVD and fastest for AD alone (p = 0.03). After adjustment, compared with AD patients, mortality risk was similar for those with VaD (relative mortality risk (RR) = 0.7 (0.5 to 1.1)) and tended to be lower for AD+CVD (RR = 0.7 (0.5 to 1.0)). The shorter the delay between first symptoms and first visit, the longer patients survived. Conclusion: This clinical cohort study shows that patients with VaD, AD+CVD and AD present different characteristics at baseline and during follow-up, and underlines the need to distinguish between them.

Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease

BackgroundThe accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer’s disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling.ResultsHerein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P.ConclusionsCollectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Patterns of response to crizotinib in recurrent glioblastoma according to ALK and MET molecular profile in two patients

Two patients with an unmethylated MGMT promoter and IDH1 (R132H) wild-type recurrent glioblastoma were treated with crizotinib. Prolonged stabilization of the disease (17 months) was achieved in the first case. Interestingly, anaplastic lymphoma kinase (ALK) expression and c-MET protein overexpression was observed. Conversely, no response to crizotinib was obtained in the second case with MET protein overexpression and c-MET amplification but no ALK expression or ALK gene amplification. These case studies suggest that novel targeted ALK inhibitors may provide relevant clinical benefit in selected cases in which driver mutations are demonstrable.

Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death

Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.

Glioblastoma occurring after the surgical resection of a craniopharyngioma

Abstract The authors report the case of a man who underwent cranial surgery for the removal of a craniopharyngioma using a right pterional approach. Three months later, he developed a right-sided temporal glioblastoma. The presentation is suggestive of a causal relationship between surgery and the development of a malignant glial tumor.