[Geriatric particularities of Parkinson's disease: Clinical and therapeutic aspects]. / Particularités gériatriques de la maladie de Parkinson: aspects cliniques et thérapeutiques.

Parkinson's disease (PD) is a frequent and complex progressive neurological disorder that increases in incidence with age. Although historically PD has been characterized by the presence of progressive dopaminergic neuronal loss of the substantia nigra, the disease process also involves neurotransmitters other that dopamine and regions of the nervous system outside the basal ganglia. Its clinical presentation in elderly subjects differs from that in younger subjects, with more rapid progression, less frequent tremor, more pronounced axial signs, more frequent non-motor signs linked to concomitant degeneration of non-dopaminergic systems, and more frequent associated lesions. Despite the high prevalence of PD in elderly subjects, few therapeutic trials have been conducted in geriatric patients. Nevertheless, to improve functional disability while ensuring drug tolerance, the principles of optimized and multidisciplinary clinical management have to be known. The aim of this review is to provide an update on clinical and therapeutic features of PD specifically observed in elderly subjects.

[Normal pressure hydrocephalus: A review and practical aspects]. / Hydrocéphalie à pression normale: mise au point et aspects pratiques.

Idiopathic normal pressure hydrocephalus is a chronic disorder affecting the elderly. It is defined by Adams and Hakim's triad in addition to ventricular dilation visible by brain imaging and normal cerebrospinal fluid pressure during lumbar puncture. The objective of this review was to propose a standard of care for idiopathic normal pressure hydrocephalus based on an extensive literature review conducted on 459 articles published over the last 10 years. Those articles were obtained by searching for the keywords "normal pressure hydrocephalus" in the PubMed database and selecting all the articles published in English or in French. The diagnosis of idiopathic normal pressure hydrocephalus is difficult because of commonly associated diseases, such as Alzheimer's disease and microangiopathy. Brain MRI is one of the key procedures to assist in the diagnosis of idiopathic normal pressure hydrocephalus. Indeed, the presence of certain MRI features is highly predictive of a positive tap test and shunt responsiveness. Nevertheless, tap test remains the standard of care for diagnosis. Continuous cerebrospinal fluid drainage test is an alternative because it improves the sensitivity of diagnosis (but is a more complicated test to perform). Alzheimer's biomarkers dosing in the cerebrospinal fluid seems interesting when diagnosis remains uncertain: the presence of Alzheimer's profile of the biological markers is predictive of a lower response to the tap test.

Neuroinflammation and ß amyloid deposition in Alzheimer's disease: in vivo quantification with molecular imaging.

BACKGROUND/AIMS: Neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Its relationship with underlying ß amyloid deposition remains unclear. In vivo visualization of microglial activation has become possible with the development of molecular imaging ligands when used with positron emission tomography (PET). The translocator protein (TSPO) is upregulated during neuroinflammation. Consequently, targeting TSPO with radiolabeled ligands for PET is an attractive biomarker for neuroinflammation. METHODS: A review of the research literature on PET imaging which studied in vivo neuroinflammation in AD subjects and its relationship with amyloid load was performed, including papers published between 2001 and 2012. RESULTS: Six studies were included using either [(11)C]PK-11195 or another non-TSPO radioligand that binds to the monoaminooxidase B. All the studies evaluated amyloid load with [(11)C]PIB. Microglial activation and astrocytosis are potentially early phenomena in AD. However, the individual levels of amyloid deposition and microglial activation were not correlated. CONCLUSION: Noninvasive in vivo molecular imaging to visualize neuroinflammation in AD may contribute to our understanding of the kinetics of neuroinflammation and its relationship to the hallmarks of the disease. Both are important for the development of future therapeutic modalities and for quantifying the efficacy of future disease-modifying treatments.

Early-onset dementias: Specific etiologies and contribution of MRI.

Early-onset dementias are defined by onset of first symptoms before the age of 65. They have specific diagnostic features which differ from those of elderly patients in terms of their many causes and atypical clinical presentations. MRI is an essential procedure for identifying the underlying cause of the dementia (degenerative, vascular, infectious, inflammatory, metabolic or toxic). Clinical clues and MRI signs are described, and their defining features are related to the young age of the patients concerned. Diagnostic algorithms are proposed from signs which can be seen on the different MRI sequences (T1-weighted volume acquisition, T2-weighted FLAIR sequences, T2-weighted gradient-echo, diffusion-weighted imaging). Once obvious causes have been excluded, MRI can point towards the rarer causes of dementia which are characteristic in young people (particularly metabolic and autoimmune) and which require specific management and genetic counseling.

[Hashimoto's encephalopathy]. / Encéphalopathie d'Hashimoto.

Hashimoto's encephalopathy was first described by Lord Brain in 1966. Since, other designations have been proposed and the existence of the disease itself has been debated. However, the number of reported cases in the literature is still increasing and physicians are sometimes confronted with patients with neuropsychiatric manifestations and positive thyroid antibodies. This article is an update based upon a search through Medline database that identified 316 references published between 1961 and 2011. Hashimoto's encephalopathy is a rare condition for which there is a need for both diagnostic criteria and therapeutic consensus.

Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment.

PURPOSE: Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with (18)F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC). METHODS: In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. RESULTS: The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55-0.98) and a specificity of 38.1% (95% CI 0.18-0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). CONCLUSION: These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.

Attitudes towards Alzheimer's disease as a risk factor for caregiver burden.

BACKGROUND: There is abundant literature on the determinants of caregiver burden in Alzheimer's disease (AD), but little is known about the possible implication of specific patterns of a caregiver's attitudes towards the disease that could increase their risk of--or protect them from--emotional distress and burden. The aim of this study was to test the hypothesis that negative attitudes towards AD are associated with an increased level of burden experienced by caregivers of AD patients. METHODS: Family caregivers of 51 patients with AD were asked to complete a questionnaire regarding their attitudes towards AD. In addition, we assessed the level of their quality of life, anxiety and depression as well as their perceived level of burden. In parallel, we documented the patients' characteristics: global cognitive efficiency (Mini-Mental State Examination), behavioral and affective symptoms (Neuropsychiatric Inventory) and functional level (Instrumental Activities of Daily Living). RESULTS: The score of caregiver burden was positively correlated with negative attitudes such as authoritarianism (r = 0.41, p < 0.01) and social restrictiveness (r = 0.49, p < 0.001) as well as emotional reactions of anxiety (r = 0.44, p < 0.01) and aggressiveness (r = 0.47, p < 0.001). In addition, scores of social restrictiveness, rejection and anxiety were significantly higher in women than in men. CONCLUSION: These results may have implications in terms of the prevention of caregiver burden. In particular, educational and support programs for caregivers should not be limited to developing their knowledge and skills but should also target attitudes towards the disease.

Novel micelle formulations to increase cutaneous bioavailability of azole antifungals.

Efficient topical drug administration for the treatment of superficial fungal infections would deliver the therapeutic agent to the target compartment and reduce the risk of systemic side effects. However, the physicochemical properties of the commonly used azole antifungals make their formulation a considerable challenge. The objective of the present investigation was to develop aqueous micelle solutions of clotrimazole (CLZ), econazole nitrate (ECZ) and fluconazole (FLZ) using novel amphiphilic methoxy-poly(ethylene glycol)-hexyl substituted polylactide (MPEG-hexPLA) block copolymers. The CLZ, ECZ and FLZ formulations were characterized with respect to drug loading and micelle size. The optimal drug formulation was selected for skin transport studies that were performed using full thickness porcine and human skin. Penetration pathways and micellar distribution in the skin were visualized using fluorescein loaded micelles and confocal laser scanning microscopy. The hydrodynamic diameters of the azole loaded micelles were between 70 and 165nm and the corresponding number weighted diameters (d(n)) were 30 to 40nm. Somewhat surprisingly, the lowest loading efficiency (<20%) was observed for CLZ (the most hydrophobic of the three azoles tested); in contrast, under the same conditions, ECZ was incorporated with an efficiency of 98.3% in MPEG-dihexPLA micelles. Based on the characterization data and preliminary transport experiments, ECZ loaded MPEG-dihexPLA micelles (concentration 1.3mg/mL; d(n)<40nm) were selected for further study. ECZ delivery was compared to that from Pevaryl® cream (1% w/w ECZ), a marketed liposomal formulation for topical application. ECZ deposition in porcine skin following 6h application using the MPEG-dihexPLA micelles was >13-fold higher than that from Pevaryl® cream (22.8±3.8 and 1.7±0.6µg/cm(2), respectively). A significant enhancement was also observed with human skin; the amounts of ECZ deposited were 11.3±1.6 and 1.5±0.4µg/cm(2), respectively (i.e., a 7.5-fold improvement in delivery). Confocal laser scanning microscopy images supported the hypothesis that the higher delivery observed in porcine skin was due to a larger contribution of the follicular penetration pathway. In conclusion, the significant increase in ECZ skin deposition achieved using the MPEG-dihexPLA micelles demonstrates their ability to improve cutaneous drug bioavailability; this may translate into improved clinical efficacy in vivo. Moreover, these micelle systems may also enable targeting of the hair follicle and this will be investigated in future studies.

[Building and validation of a test evaluating verbal recognition memory: The Forty test (f40)]. / Mise au point et validation d'une épreuve d'évaluation de la mémoire de reconnaissance verbale: le Forty test (f40).

INTRODUCTION: Neuropsychologic evaluation is a primordial diagnostic tool. Numerous tests explore episodic memory but few tests exist to assess incidental verbal episodic memory or verbal recognition memory. This memory is however impaired early in certain neurodegenerative diseases such as Alzheimer's disease. Our objective was to create a test sensitive and specific to this cognitive dysfunction. METHOD: Our test was performed by 33 healthy volunteers and 51 patients (19 with idiopathic Parkinson's disease, 16 with Alzheimer's disease at the prodromal stage and 16 with Alzheimer's disease). RESULTS AND DISCUSSION: Independently of age, education level and global cognitive impairment, the young and old healthy volunteers and the patients with idiopathic Parkinson's disease displayed results significantly better than the group of Alzheimer's disease at the prodromal stage and Alzheimer's disease patients. Our test appears to be sensitive to dysfunction of verbal recognition memory. A score of 30/40 or less on the Forty test discriminates 91% of subjects with a cortical pattern of memory. This test could be recommended for clinical neuropsychological practice.

Novel cyclosporin A formulations using MPEG-hexyl-substituted polylactide micelles: a suitability study.

The immunosuppressive agent Cyclosporin A (CsA) has very poor solubility in water and, in consequence, non-aqueous formulations have been developed for its intravenous administration to treat patients with transplant rejection. In this article, aqueous micelle solutions of novel amphiphilic copolymers based on methoxy-poly(ethylene glycol) (MPEG) and hexyl-substituted poly(lactides) (hexPLA) were studied for possible incorporation and formulation of CsA, and for their biocompatibility towards novel pharmaceutical applications. Above the critical micellar concentration (CMC), MPEG-hexPLA block-copolymers self-assemble into unimodal micelles with diameters of around 30 nm, either unloaded or drug-loaded. The best shelf-life stability of these formulations was observed when stored at 4°C with a drug loss inferior to 7% after 1 year. The polymer and micelle toxicities were evaluated in vitro for three different cell lines and in vivo using the chick embryo chorioallantoic membrane (CAM) model. The hemolytic property was assessed using human blood samples. As the studies revealed, MPEG-hexPLAs are non-toxic and do not show hemolysis; the same was found for the comparable MPEG-PLAs, both as unimers below their CMC and as polymeric micelles up to copolymer concentrations of 20 mg/mL. At this concentration, CsA was efficiently incorporated into MPEG-hexPLA micelles up to 6 mg/mL, which corresponds to a 500-fold increase of its water solubility. The current recommended clinical concentration administered per infusion (0.5-2.5 mg/mL) can be easily achieved and requires four times less copolymer than with the often-used Cremophor®EL surfactant. In this regard, MPEG-hexPLA micelle formulations can be an applicable formulation in transplant rejection treatments as an injectable CsA carrier system.

Review of cerebral microangiopathy and Alzheimer's disease: relation between white matter hyperintensities and microbleeds.

Although Alzheimer's disease (AD) is basically considered to be a neurodegenerative disorder, cerebrovascular disease is also involved. The role of vascular risk factors and vascular disease in the progression of AD remains incompletely understood. With the development of brain MRI, it is now possible to detect small-vessel disease, whose prevalence and severity increase with age. The first types of small-vessel disease to be described were white matter hyperintensities (WMHs). More recently, small areas of signal loss on T(2)*-weighted images, also called microbleeds (MBs), have been reported. Cerebral MBs are focal deposits of hemosiderin that indicate prior microhemorrhages around small vessels, related to either ruptured atherosclerotic microvessels or amyloid angiopathy. Consequently, using brain MRI for the detection of microangiopathy may prove useful to improve our understanding of the impact of the vascular burden in AD pathology. The relationship between microangiopathy and the clinical course of AD or the conversion of mild cognitive impairment to AD remains questionable in terms of cognitive or affective symptoms, particularly if we consider MBs.

Central auditory processing in aging: the dichotic listening paradigm.

OBJECTIVE: Aging is associated with cognitive changing. Central auditory processing dysfunction may explain some understanding difficulties in elderly. It may be evaluated with the dichotic listening (DL) test, a widely-used experimental paradigm for studying inter-hemispheric interactions and attentional processes. This study examines central auditory language processing with a dichotic listening task in right-handed old subjects according to their age. DESIGN: Cross sectional-study. SETTING: memory clinic and geriatric unit. PARTICIPANTS: Adult group (Ad) consisted in 26 subjects (21 women and 5 men) aged 50-69 years and an old adults group (Old-Ad) consisted in 20 subjects (19 women and 1 man) aged 70 to 89 years. MEASUREMENTS: DL consisted in a free-recall word task and a digit forced-attention task (forced-right: FR and forced-left: FL) in order to study central auditory language processing. In addition, we used neuropsychological tests to study executive functions and cognitive control, sustained by the prefrontal cortex. RESULTS: In the free recall condition, we confirmed the classic right ear advantage (REA) in both groups, particularly in older subjects. In the forced condition, we observed an ear advantage with a change in ear asymmetry as a consequence of instruction: REA in FR and a left-ear advantage (LEA) in FL. We compared contaminations by the contra-lateral inattentive ear: reports of the left ear (LE) in the FR condition and reports of the right ear (RE) in the FL condition. Contaminations by the RE in the FL condition were more pronounced in Old-Ad suggesting difficulties in competition between the natural tendency for the RE and the instruction. In the Old-Ad group, the correlation between the RE score in FL and TMT B-A/A suggests an impairment in mental flexibility. CONCLUSION: DL may be helpful to study central auditory dysfunction in aging. Our results suggest difficulties in attentional control and executive functions. Central auditory dysfunction should be evaluated in elderly because it potentially contributes to difficulty of hearing in noisy environment with consequences in the rehabilitation of presbyacousic subjects. More studies are needed to investigate the predictive value of DL as a marker of cognitive decline, particularly executive functions.

[Vitamin B12 deficiency and neurological disorders: a case report and literature review]. / Carence en vitamine B12, ataxie cérébelleuse et troubles cognitifs.

INTRODUCTION: Vitamin B12 deficiency is often associated with neurological disorders of which combined sclerosis of the spinal cord is a common manifestation. CASE REPORT: We report the case of a woman who presented cerebellar ataxia and cognitive deficits associated with leukoencephalopathy on the brain MRI. These symptoms were associated with vitamin B12 deficiency due to Biermer's disease. Vitamin B12 supplementation led to symptom improvement. Later her treatment was discontinued and the patient's clinical status worsened to a bedridden status. CONCLUSION: Ataxia cerebellar dementia and leukoencephalopathy can result from vitamin B12 deficiency. To limit the risks of sequelae, vitamin B12 supplementation should be started at an early stage.

Transient global amnesia caused by painless aortic dissection.

Neurological syndromes secondary to acute aortic dissection (AAD) are uncommon and usually consist of focal deficits after an embolic cerebral infarction. This article reports the observation of an AAD with the chief complaint of transient acute memory impairment-that is, a non-usual stroke-like symptom.

[Progressive anarthria: an individual entity]. / Anarthrie progressive: une entité propre.

INTRODUCTION: First described 15 years ago, primary progressive anarthria is a focal cortical atrophy defined as a rare progressive impairment of speech associated with orofacial apraxia and leading to mutism with a frontal lobe syndrome. The aim of this study was to analyze clinical and neuropsychological data and results of complementary tests in a series of patients presented with primary progressive anarthria. MATERIAL AND METHODS: We, retrospectively, studied five patients with primary progressive anarthria. We particularly analyzed the following parameters: age at onset, age at the diagnostic, disease time from onset to first consultation, the initial orientation, the neuropsychological and clinical data at the first visit, electromyography, brain MRI, and single photon emission computed tomography (SPECT) findings. Clinical and neuropsychological data were used to monitor disease course. RESULTS: The mean age at onset of symptoms was 75.2+/-5.8 years. Patients were primarily referred to a specialist in memory disease (n=3) or a specialist in motor neuron disease (n=2). The time from onset to first consultation was 11.2+/-3 months. Anarthria was associated with dysexecutive syndrome and sometimes, with impaired comprehension. Electromyography was always normal. Cranial MRI showed temporal or left frontal atrophy (n=3). Spect revealed decreased cerebral blood flow predominating in the left frontal or temporal region (n=4). CONCLUSION: Long delay for specialist consultation and inadequate initial orientation retard disease diagnosis, leading to severe incapacity. Complementary studies are required to confirm diagnostic and to rule out lateral amyotrophic sclerosis. During the early stages, involvement of the premotor cortex may be considered due to the speech apraxia. Secondary motor orofacial disturbances suggest an extension to the motor cortex. Primary progressive anarthria is a distinct individual entity within the spectrum of focal cortical atrophies.

Epilepsy and dementia in the elderly.

Epilepsy is a frequent condition in the elderly; however, it remains a relatively understudied condition in older adults with dementia. The diagnosis of a seizure is particularly difficult and is most often based on questions to the caregiver. Epilepsy in dementia has significant consequences on the prognosis of the underlying dementia: it can result in a worsening of cognitive performance, particularly in language, as well as a reduction in autonomy, a greater risk of injury and a higher mortality rate. In this review, management strategies are recommended for the clinician. The presence of pre-existing Alzheimer's disease does not exempt the clinician from ruling out other symptomatic causes of seizures. Anti-epileptic drugs (AED) should be started only after the diagnosis has been clearly established, when the risk of recurrence is high, and with monotherapy whenever possible. Although few data are available, the more recent AED offer significant advantages over the older medications in this context.

[Primary progressive aphasia: a specific consideration among the neurodegenerative pathology]. / L'aphasie progressive primaire: un cadre à part dans les pathologies neurodégénératives.

INTRODUCTION: Isolated progressive speech and language difficulties are often the first symptom of primary progressive aphasia. EXEGESIS: We report a 63-year-old woman with progressive language impairment that remained isolated for at least two years, related to a greater atrophy within the left hemisphere. There was no impairment in daily living during two years and six months. Progressively, she developed a frontal dementia. CONCLUSION: Isolated language impairment may be the inaugural symptom of a focal form of a neurodegenerative disease. Progressive language deterioration without impairment in daily life activity or behavioral changes must be differentiated from Alzheimer disease. Brain imaging is important for the diagnosis.