STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain.

AIMS: Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high-resolution imaging approaches is a current challenge in neuroscience. METHODS: To this end, we used a recent super-resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases. RESULTS: This approach allowed us to perform 2D-, 3D- and two-colour-STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto-temporal lobar degeneration. Aggregated Aß branches appeared reticulated and cross-linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP-43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α-synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy. CONCLUSIONS: STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super-resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.

Guidelines for clinical pharmacological practices in Huntington's disease.

OBJECTIVE: Evidence-based medicine is a difficult goal to achieve in rare diseases where randomized controlled trials are lacking. This report provides guidelines that capitalize on both the literature and expertise of the French National Huntington Disease Reference Centre to optimalize pharmacological therapeutic interventions for Huntington's disease (HD). MATERIAL AND METHODS: HD experts conducted a systematic analysis of the literature from 1965 to 2013, using a scoring procedure established by the French National Authority for Health. These experts offered their views when evidence was missing to set up provisional guidelines for care in HD. These guidelines were then scored and amended through two subsequent online questionnaires (using SurveyMonkey® scoring), and one face-to-face meeting with an external multidisciplinary working group as a step towards validation. RESULTS: Except for the beneficial effects of tetrabenazine in chorea, none of the published recommendations were grounded on established scientific evidence. Second-generation antipsychotics are nevertheless the first choice for patients with psychiatric manifestations (low level of evidence). All other guidelines are based on low-level evidence and little professional agreement. CONCLUSION: Patients' care has greatly improved over the last few years despite the lack of high-level evidence standards. Guidelines are based on the expertise of trained specialists from the French National Plan for Rare Diseases. This strategy should now be extended internationally to promote future studies and to harmonize worldwide care of HD.

Retinopathy, nephropathy, peripheral neuropathy and geriatric scale scores in elderly people with Type 2 diabetes.

AIMS: To analyse the relationships between retinopathy, nephropathy, peripheral neuropathy and geriatric scale scores in elderly people with Type 2 diabetes. METHODS: GERODIAB is the first French multi-centre, prospective, observational study designed to assess the influence of glycaemic control on mortality and morbidity through a 5-year follow-up study in people with Type 2 diabetes aged 70 years and older. In this report the relationships at baseline between retinopathy, nephropathy and peripheral neuropathy, and five geriatric scale scores in 987 people, using bivariate and multivariate analyses are analysed. RESULTS: Retinopathy (26%) was significantly associated with impaired scores on the Mini Geriatric Depression Scale, the Mini Nutritional Assessment and the Instrumental Activities of Daily Living scale. Logistic regression showed that the duration of diabetes, BMI, Mini Geriatric Depression Scale, hypoglycaemia and HbA1c were associated with retinopathy (concordance 69.1%; P < 0.001). Nephropathy (47.4%, including 34.8% with Modification of Diet in Renal Disease < 60 ml/min) was significantly associated with impaired Activities of Daily Living and Instrumental Activities of Daily Living scale scores. Using the logistic model, the most significant factors were age, duration of diabetes, triglycerides, HDL cholesterol, hypoglycaemia, hypertension and BMI (concordance 66.3%; P < 0.001). Peripheral neuropathy (28.2%) was associated with impaired scores on the Mini Mental State Examination, Activities of Daily Living, Instrumental Activities of Daily Living and Mini Geriatric Depression Scales. In the logistic model, diastolic blood pressure, duration of diabetes and the Instrumental Activities of Daily Living, Mini Geriatric Depression Scale and Mini Mental State Examination scales were included (concordance 69.8%; P < 0.001). CONCLUSION: In this specific sample, classical microvascular complications of diabetes were found to be associated with impaired geriatric scale scores. This highlights the benefits of systematic assessment in elderly people with Type 2 diabetes.

Mitochondrial dysfunction affecting visual pathways.

Mitochondrial dysfunction leads to cellular energetic impairment, which may affect the visual pathways, from the retina to retrochiasmal structures. The most common mitochondrial optic neuropathies include Leber's hereditary optic neuropathy and autosomal dominant optic atrophy, but the optic nerve can be affected in other syndromic conditions, such as Wolfram syndrome and Friedreich's ataxia. These disorders may result from mutations in either the mitochondrial DNA or in the nuclear genes encoding mitochondrial proteins. Despite the inconstant genotype-phenotype correlations, a clinical classification of mitochondrial disorders may be made on the basis of distinct neuro-ophthalmic presentations such as optic neuropathy, pigmentary retinopathy and retrochiasmal visual loss. Although no curative treatments are available at present, recent advances throw new light on the pathophysiology of mitochondrial disorders. Current research raises hopes for novel treatment of hereditary optic neuropathies, particularly through the use of new drugs and mitochondrial gene therapy.

Executive functions in clinical and preclinical Alzheimer's disease.

Executive functions is an umbrella term describing a wide range of higher order processes that allow the flexible modification of thought and behaviour in response to changing cognitive or environmental contexts. Impairment of executive functions is common in neurodegenerative disorders such as Alzheimer's disease. These deficits negatively affect everyday activities and hamper the ability to cope with other cognitive or behavioural disorders. In this paper, we propose a synthesis of the knowledge on executive impairments in clinical and preclinical Alzheimer's disease, mostly leaning on the current studies made in this domain. We made some propositions for neuropsychological assessment of executive functions in preclinical and clinical phases of Alzheimer's disease. We hope that this overview will provide a useful insight into an area that is still insufficiently explored in the field of the neuropsychology of Alzheimer's disease.

[Hereditary optic neuropathies]. / Neuropathies optiques héréditaires.

Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated neurological signs are increasingly recognized.

[Hereditary optic atrophies]. / Les atrophies optiques héréditaires.

INTRODUCTION: Hereditary optic neuropathies, resulting from retinal ganglion cell degeneration, are a heterogeneous group of diseases ranging from asymptomatic forms to legal blindness. STATE OF KNOWLEDGE: Two most frequent phenotypes are Kjer's disease, an autosomal dominant optic atrophy caused by OPA1 gene mutations, and Leber's disease due to maternally inherited mitochondrial DNA mutations. PROSPECTS AND CONCLUSION: Both optic neuropathies usually isolated are sometimes associated with extraocular symptoms, especially neurological symptoms, thus justifying a systematic neurological evaluation and brain imaging.

A call to incorporate the prevention and treatment of geriatric disorders in the management of diabetes in the elderly.

The prevalence of type 2 diabetes increases with age. However, the management of diabetes in the elderly has received surprisingly little attention. Diabetes in the elderly is associated with a high risk of geriatric syndromes including malnutrition and sarcopenia, functional impairments, falls and fractures, incontinence, depression and dementia. Tight glycaemic control for the prevention of vascular complications is often of limited value in the elderly. However, glycaemic control and non-pharmacological therapy may prevent diabetes symptoms and delay geriatric syndromes. The prevention, screening and treatment of both conventional diabetic complications and geriatric syndromes should be integrated in a management plan to optimize the patients' overall health status and quality of life.

GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination.

Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.

Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Mitochondrial DNA A3243G mutation involved in familial diabetes, chronic intestinal pseudo-obstruction and recurrent pancreatitis.

AIMS: To report on a family with five members who carry the A3243G mutation in mitochondrial tRNA for leucine 1 (MTTL1) and present with diabetes, chronic intestinal pseudo-obstruction (CIPO) and recurrent pancreatitis, and to screen for this mutation in a cohort of 36 unrelated patients with recurrent pancreatitis. METHODS: The mutation was quantified in several tissue samples from patients. Respiratory chain activity was studied in muscle biopsies and fibroblast cultures. In addition, the thymidine phosphorylase gene (TP) involved in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and three genes involved in chronic pancreatitis - PRSS1, SPINK1 and CFTR - were sequenced in affected patients. Finally, the MTTL1 gene was examined in 36 unrelated patients who had recurrent pancreatitis, but no mutations in the PRSS1 and SPINK1 genes. RESULTS: Heteroplasmy for the mtDNA A3243G mutation was found in all tissue samples from these patients, but no mutations were found in the genes coding for thymidine phosphorylase, PRSS1, SPINK1 and CFTR. Also, none of the 36 unrelated patients with recurrent pancreatitis were carrying any MTTL1 mutations. CONCLUSION: The mtDNA A3243G mutation associated with the gastrointestinal manifestations observed in the affected family should be regarded as a possible cause of CIPO and unexplained recurrent pancreatitis. However, the mutation is probably only weakly involved in cases of isolated recurrent pancreatitis.

Haemoglobin A1c and 5-year all-cause mortality in French type 2 diabetic patients aged 70 years and older: The GERODIAB observational cohort.

AIM: The role of glycaemic control in the mortality of elderly diabetic patients remains uncertain. GERODIAB is the first multi-centre, prospective, observational study that aims to describe the link between HbA1c and 5-year mortality in French, type 2 diabetic patients aged ≥70 years. METHODS: Consecutive patients (n=987; mean age 77 years) were included from 56 diabetes centres and followed for five years. Individual histories, risk factors, standard diabetes parameters and geriatric evaluations were regularly recorded. Survival was studied using the Kaplan-Meier method. Multivariable analyses used Cox regression. RESULTS: Twenty-one percent of the patients died, 13% were lost during follow-up. Patients with a 5-year mean HbA1c in the range [40-50) mmol/mol ([5.8-6.7) %) had the highest survival (84%); those in the range [50-70) mmol/mol ([6.7-8.6) %) or <40mmol/mol (<5.8%) an intermediary survival rate (79%); patients with HbA1c ≥70mmol/mol (≥8.6%) the worst survival (71%). Patients with mean HbA1c ≥70mmol/mol (≥8.6%) had a significantly higher mortality than those with lower HbA1c (P=0.011), and HbA1c remained a significant predictor of mortality after adjusting for individual, diabetic and geriatric factors (hazards ratio [95%CI]: 1.76 [1.21 to 2.57], P=0.0033). Survival was also significantly associated with both HbA1c variability and with the frequency of HbA1c determinations. CONCLUSION: In this large sample of elderly French type 2 diabetic patients, an HbA1c level <70mmol/mol (<8.6%) was associated with lower mortality. The range [40-50) mmol/mol ([5.8-6.7) %) could be an acceptable target provided patients are not exposed to hypoglycaemia.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

Cognitive changes in asymptomatic carriers of the Huntington disease mutation gene.

Huntington disease (HD) is a neurodegenerative disorder due to an excessive number of CAG repeats in the IT15 gene on chromosome 4. Studies of cognitive function in asymptomatic gene carriers have yielded contradictory results. This study compared cognitive performance in 44 subjects with the HD mutation (group of carriers) who had no clinical signs of HD and 39 at-risk individuals without HD mutation (group of non-carriers). Neuropsychological evaluation focused on global cognitive efficiency, psychomotor speed, attentional, executive and memory functions. Significant differences, with lower performances in the group of gene carriers, were detected for some measures of psychomotor speed, attention and executive functioning (all P < 0.01). More differences between groups were observed for memory measures, in particular on the California Verbal Memory Test. Complementing these observations, cognitive scores were correlated with age in the group of gene carriers, but not in the group of non-carriers. This suggests that the cognitive changes precede the appearance of the motor and psychiatric symptoms in HD and that tests proved to be sensitive to early HD deficiencies are better suited than global cognitive efficiency scales to observe them.

Congestive heart failure in the elderly diabetic.

The elderly diabetic is a potential congestive heart failure patient. Cardiac involvement is multifactorial, particularly ischemic conditions because of the accumulation at that age of vascular risk factors and therefore the frequency of coronary damages. The elderly diabetic very often has high blood pressure, with the risk of developing a hypertensive heart disease. Beyond these issues, the effects of chronic hyperglycaemia and insulin resistance on the heart specifically alter left ventricle compliance and therefore diastolic function, thus accelerating the effects proper to aging. No specific recommendation has been published on the management of the elderly diabetic with congestive heart failure. Even at an advanced age, with a clinical diagnosis of congestive heart failure that is sometimes difficult to make, the cardiological evaluation should be conducted rigorously within a global evaluation, and treatment should follow the same rules as in younger patients, with great caution given to the iatrogenic risks inherent to this population.

Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease.

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.

[Idiopathic acute transverse myelitis: application of new diagnosis criteria to 17 patients]. / Myélite aiguë transverse idiopathique: application des nouveaux critères diagnostiques à une cohorte de 17 patients.

INTRODUCTION: Idiopathic Acute Transverse Myelitis (ATM) is an inflammatory and immune-mediated disorder, distinct from infectious ATM, ATM of systemic lupus erythematosus or Sjögren's syndrome, and medullary manifestation of multiple sclerosis. Prognosis is not well-known. OBJECTIVE: To evaluate clinical, paraclinical and pronognosis data in patients selected with new diagnosis criteria, classically described in idiopathic ATM. METHODS: Seventeen patients with diagnosis criteria were retrospectively (1996-2005) studied. A telephone investigation was conducted in 2005 to obtained data on the clinical course. RESULTS: Seven men and 10 women, ranging in age from 15 to 75 years (mean: 39.8 years) met these new criteria. Our study showed that epidemiological and clinical findings as well as laboratory results were in agreement with those presented in the literature. Conversely, prognosis was better since 76p.cent of the patients could walk without assistance. The clinical presentation of some of our patients and/or their progression towards other multifocal inflammatory disorders, suggests there might be links between ATM, neuromyelitis optica (NMO) and Acute Dissemined Encephalomyelitis (ADEM). CONCLUSION: Patients with idiopathic ATM, selected with new criteria, have a rather good prognosis. ATM seems to be part of a continuum of neuroimmunologic disorders including NMO or ADEM although reasons explaining distinct focal disorders remain unclear.

Management of dyslipidemia in elderly diabetic patients.

The prevalence of diabetes increases with age, potentially affecting 20% of the 75 years and older elderly population. Overmortality and increased cardiovascular morbidity-mortality are common in diabetic populations, including elderly diabetes. This increased cardiovascular risk must therefore be taken into consideration when discussing management of dyslipidemia in elderly diabetics. Should dyslipidemia be treated in elderly diabetics? What are the objectives and with what means? Whether the significance of dyslipidemia is different in this growing population compared with younger subjects remains unknown due to the lack of specific studies. The only results available come from a few primary or secondary cardiovascular prevention trials using statins or fibrates with subgroups of elderly diabetic patients, or subgroups of diabetic patients and also subgroups of patients aged over 65. Three recent studies detailed the potential benefit of such treatment: PROSPER in elderly subjects aged 70-82 years, HPS in diabetics before and after the age of 70 years and CARDS in diabetics aged up to 75 years. The results of these studies provide a few indirect elements of interest, keeping in mind the generally higher iatrogenic risk of treatment in elderly populations.