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.

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.

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.

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.

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.

Predicting factors of hypoglycaemia in elderly type 2 diabetes patients: Contributions of the GERODIAB study.

The burden of hypoglycaemia is important, particularly in elderly type 2 diabetes (T2D) patients. Unfortunately, however, few studies are available concerning this population. GERODIAB is a prospective, multicentre, observational study that aims to describe the 5-year morbidity and mortality of 987 T2D patients aged 70 years and older. After analyzing the frequency of and factors associated with hypoglycaemia in the 6 months prior to study inclusion, it was found that hypoglycaemia was associated with retinopathy, lower levels of LDL cholesterol and altered mini-Geriatric Depression Scale (GDS) scores.

Orthostatic hypotension is associated with more severe hypertension in elderly autonomous diabetic patients from the French Gerodiab study at inclusion.

UNLABELLED: Orthostatic hypotension (OH) has deleterious effects on patients' cardiovascular prognoses. The combination of increased age and diabetes adds to the risk of OH. The aim of the study was to describe the elderly diabetic population relative to the degree of hypertension, the occurrence of complications, medications and cognitive function. METHODS: In the Gerodiab study (a 5-year French multicentre, prospective, observational study), a total of 987 type 2 diabetic autonomous patients, aged 77±5 years, were recruited between June 2009 and July 2010. Clinical blood pressure measurements were taken supine and then after 1, 3 and 5minutes in a standing position. OH was defined as a decrease in systolic blood pressure (SBP) of at least 20mmHg and/or a decrease in diastolic blood pressure (DBP) of at least 10mmHg at any of the measurements while standing. RESULTS: At inclusion 301 (30.5%) patients had OH; SBP and DBP at rest were higher in patients with OH than in those without (146±21/78±11mmHg vs. 138±17/72±10mmHg; P<0.001). Individuals with OH exhibited higher pulse pressure (PP) than individuals without (68±18 vs. 65±15mmHg; P<0.05). A significant increase in waist-to-hip ratio was recorded in those with OH versus patients without (P<0.01). Despite more severe hypertension (SBP>160mmHg at inclusion; P<0.01), no significant difference was recorded in the mean number of antihypertensive drugs (1.7±1.1), or in the class of antihypertensive drugs, including beta-blockers (P=0.19) and diuretics (P=0.84). Patients with OH were more likely to have a history of peripheral arterial disease and amputations (31% vs. 24%, P<0.05, and 3.3% vs. 1.5%, P=0.056). There was no significant association between OH and history of peripheral neuropathy (P=0.37), stroke, heart failure or ischemic heart disease. In multivariate analysis, OH remained associated with severe hypertension (P<0.01), increased waist-to-hip ratio (P<0.05) and amputations (P<0.05). CONCLUSION: About one-third of elderly, autonomous diabetic patients had OH. They had more severe hypertension, with higher SBP, DBP and PP at rest. However, the number of anti-hypertensive drugs did not differ compared to patients without OH. This could reflect the medical teams' fears about intensifying treatment.

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.

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.

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.

GERODIAB: Glycaemic control and 5-year morbidity/mortality of type 2 diabetic patients aged 70 years and older: 1. Description of the population at inclusion.

AIMS: The GERODIAB study is the first French multicentre, prospective, observational study that aims, through a 5-year cohort follow-up, to evaluate the link between glycaemic control and morbidity/mortality of type 2 diabetic (T2D) patients aged 70 years and older. This first report describes the study population at inclusion. PATIENTS AND METHODS: A total of 987 T2D autonomous patients, aged ≥70 years, were recruited between June 2009 and July 2010 at 56 investigator centres. Their general parameters, diabetes characteristics and standard geriatric parameters were recorded. RESULTS: The patients' mean age was 77±5 years, with 65.2% aged 75 years or more. The mean BMI was close to 30 kg/m(2). Hypertension was found in 89.7% of patients, and 85.0% had at least one cholesterol abnormality. The mean duration of the diabetes was around 18 years, and the mean HbA(1c) level was about 7.5%. During the previous six months, 33.6% of patients had experienced one or several hypoglycaemias. Also, 26% of patients presented with diabetic retinopathy, 37.3% had a GFR<60 mL/min, 31.2% had coronary insufficiency, 10.1% had heart failure, 15.8% had cerebrovascular involvement and 25.6% had peripheral vascular disease of the lower extremities. In addition, 30.5% of patients had orthostatic hypotension, 12.4% had malnutrition and 28.8% had cognitive impairment, all of which were often diagnosed at inclusion. Three-quarters of patients were taking an oral antidiabetic drug and nearly six in every 10 patients were using insulin. CONCLUSION: This population can be considered representative of elderly, autonomous T2D patients, and its follow-up should clarify the link between glycaemic control and mortality/morbidity.

[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.

[Alzheimer's disease and visual impairment]. / Les troubles visuels au cours de la maladie d'Alzheimer.

Alzheimer disease is the most prevalent cause of cognitive decline in older adults. The typical presentation of Alzheimer disease is memory dysfunction, however, presentations with impairment in other domains may occur. Visual symptoms may be the first manifestation of Alzheimer disease. The purpose of this article is to review the spectrum of visual system disturbances found in Alzheimer disease.

[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.

High insulinlike growth factor I is associated with cognitive decline in Huntington disease.

OBJECTIVE: The somatotropic axis (growth hormone [GH] and insulinlike growth factor I [IGFI]) play a role in the cognitive deficits seen with aging, GH deficiency, and neurodegenerative disorders such as Alzheimer disease. We recently reported elevations in basal plasma GH and IGFI levels in patients with Huntington disease (HD). Here, our objective was to determine whether somatotropic axis abnormalities predicted cognitive dysfunction in HD. METHODS: In this prospective cohort study of 109 patients with genetically documented HD, aged 21 to 85 years, we determined fasting blood levels of total IGFI, GH, and insulinlike factor binding protein 3 at baseline, and we used the cognitive Unified Huntington's Disease Rating Scale to assess cognitive impairment at baseline and for up to 5 years subsequently. Associations were evaluated using mixed linear model analysis. RESULTS: Higher plasma IGFI concentrations were associated with greater cognitive decline (beta Stroop Words, -6.01, p = 0.003; beta Stroop Color, -4.41, p = 0.01; beta Stroop Color/Words, -3.86, p = 0.02; beta Symbol Digit Modalities, -3.69, p = 0.03; and beta verbal fluency, -5.01, p = 0.03). Higher free IGFI concentrations and higher GH concentrations in men also predicted greater cognitive decline. CONCLUSIONS: Our findings in patients with HD suggest that a high IGFI level at baseline may be associated with greater subsequent declines in executive function and attention.