Is the clinical phenotype impact the prognosis in dementia with Lewy bodies?

INTRODUCTION: The first predominant clinical symptoms of dementia with Lewy bodies (DLB) are highly variable; however, the prognosis based on initial predominant symptoms remains poorly understood. METHODS: Multicenter retrospective study in 4 French expert neurological centers. Patients were categorized in 3 groups according to their first more predominant symptoms: cognitive, psychiatric, or motor. RESULTS: Analysis of 310 DLB patients. The mean age was 73.5 years old (SD 7.5) including 32.3% of women. The mean follow-up was 7.25 years (SD 3.6). We observed that the full clinical picture was more frequent in the motor group than in the cognitive group (p = 0.01); male gender and age at onset were associated with a significant excess risk of instantaneous mortality (p = 0.01). CONCLUSION: Initial symptoms may affect the clinical course of patients, but no significant difference in mortality was observed.

Testing the therapeutic effects of transcranial direct current stimulation (tDCS) in semantic dementia: a double blind, sham controlled, randomized clinical trial.

BACKGROUND: Semantic dementia is a neurodegenerative disease that primarily affects the left anterior temporal lobe, resulting in a gradual loss of conceptual knowledge. There is currently no validated treatment. Transcranial stimulation has provided evidence for long-lasting language effects presumably linked to stimulation-induced neuroplasticity in post-stroke aphasia. However, studies evaluating its effects in neurodegenerative diseases such as semantic dementia are still rare and evidence from double-blind, prospective, therapeutic trials is required. OBJECTIVE: The primary objective of the present clinical trial (STIM-SD) is to evaluate the therapeutic efficacy of a multiday transcranial direct current stimulation (tDCS) regime on language impairment in patients with semantic dementia. The study also explores the time course of potential tDCS-driven improvements and uses imaging biomarkers that could reflect stimulation-induced neuroplasticity. METHODS: This is a double-blind, sham-controlled, randomized study using transcranial Direct Current Stimulation (tDCS) applied daily for 10 days, and language/semantic and imaging assessments at four time points: baseline, 3 days, 2 weeks and 4 months after 10 stimulation sessions. Language/semantic assessments will be carried out at these same 4 time points. Fluorodeoxyglucose positron emission tomography (FDG-PET), resting-state functional magnetic resonance imaging (rs-fMRI), T1-weighted images and white matter diffusion tensor imaging (DTI) will be applied at baseline and at the 2-week time point. According to the principle of inter-hemispheric inhibition between left (language-related) and right homotopic regions we will use two stimulation modalities - left-anodal and right-cathodal tDCS over the anterior temporal lobes. Accordingly, the patient population (n = 60) will be subdivided into three subgroups: left-anodal tDCS (n = 20), right-cathodal tDCS (n = 20) and sham tDCS (n = 20). The stimulation will be sustained for 20 min at an intensity of 1.59 mA. It will be delivered through 25cm2-round stimulation electrodes (current density of 0.06 mA/cm2) placed over the left and right anterior temporal lobes for anodal and cathodal stimulation, respectively. A group of healthy participants (n = 20) matched by age, gender and education will also be recruited and tested to provide normative values for the language/semantic tasks and imaging measures. DISCUSSION: The aim of this study is to assess the efficacy of tDCS for language/semantic disorders in semantic dementia. A potential treatment would be easily applicable, inexpensive, and renewable when therapeutic effects disappear due to disease progression. TRIAL REGISTRATION: ClinicalTrials.gov NCT03481933. Registered on March 2018.

[Current concepts in vascular dementia]. / Démences vasculaires : concepts actuels.

Vascular dementias, VD, are dementias due to cerebrovascular lesions. Subgroups of VD include multi-infarct dementia, single infarct (or strategic infarct) dementia, subcortical ischemic vascular dementia, hemorrhagic dementia, hypoperfusion dementia. VD are also related to post-stroke dementia, mixed Alzheimer's disease and vascular dementia and vascular cognitive impairment. These various entities allow to characterize more homogenous subgroups within the heterogeneous group of vascular dementias. However, ambiguities in their definitions, associated with frequent overlaps as well as lack of consensual definition for mixed dementia limit both their theoretical value and use in clinical practice. The diagnosis of cerebrovascular diseases should be dissociated from that of dementia, which could be associated with other pathologies.

Awareness of memory deficits in early stage Huntington's disease.

Patients with Huntington's disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson's disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients' functional decline rather than by patients' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.

White-matter lesions without lacunar infarcts in CADASIL.

To better characterize the clinical spectrum related to white-matter hyperintensities (WMH) in small vessel disease, 66 patients with WMH but without any lacunar infarct were selected out of a cohort of 248 CADASIL individuals. Characteristics of these patients were compared to those of patients with lacunar infarcts. Relationships between the normalized volume of WMH (nWMH), presence of microhemorrhages, brain parenchymal fraction (BPF). and cognitive performances were assessed. The Trail Making Test (TMT) A and B times, Mattis Dementia Rating Scale (MDRS) total score, attention subscore, verbal fluency score and delayed memory recall were significantly correlated with nWMH but not with BPF. Presence of microhemorrhages was associated with worse TMT B time and attention MDRS subscore after adjustment for WMH. All subjects had Mini-Mental Status Examination scores ≥24 and presented with no or only mild disability. These results suggest that CADASIL patients with isolated WMH can present with executive and attention deficit but not with severe disability and that additional lesions are needed to cause significant disability and/or dementia.

CSF Aß1₋42 levels and glucose metabolism in Alzheimer's disease.

Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-ß peptide 1-42 (Aß1₋42), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aß1₋42 level was inversely associated with CSF to plasma glucose ratio (Spearman's coefficient = -0.27, p = 0.008). This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (ß [SE] of linear regression = -0.93 [0.37], p = 0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD.

Inverse association between CSF Aß 42 levels and years of education in mild form of Alzheimer's disease: the cognitive reserve theory.

In Alzheimer's disease (AD), the cognitive reserve theory predicts that at any level of assessed clinical severity, the underlying brain pathology is more advanced in patients with more cognitive reserve. Recent evidences suggest that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We investigated the relationship between education level and CSF concentrations of ß-amyloid, total tau and phosphorylated tau (ptau-181) in a cohort of 70 subjects newly diagnosed with AD. We report that CSF concentration of ß-amyloid was inversely associated with years of education, after adjustment for age, sex, and severity of the disease. We further demonstrate in stratified analysis that this relation was mainly present in mild form of the disease (CDR1), and was attenuated in more advanced forms of the disease. These results are consistent with the cognitive reserve theory, and suggest that cognitive reserve may be protective against amyloid related cognitive impairment at the onset of the clinical dementia.

Diagnostic criteria of vascular dementia in CADASIL.

BACKGROUND AND PURPOSE: Subcortical ischemic vascular dementia (SIVD) is a major subtype of vascular dementia (VaD). Recently, the diagnostic criteria of VaD have been modified to encompass this entity. Application of these criteria in CADASIL, a genetic model of SIVD, may help to better assess their significance. The aim of this study was to compare different sets of diagnostic criteria of VaD in a population of CADASIL patients. METHODS: Different sets of diagnostic criteria of VaD (DSMIV, ICD10, standard NINDS-AIREN, modified NINDS-AIREN for SIVD) were applied to 115 CADASIL patients. Diagnosis of VaD was made through 2 steps: (1) diagnosis of dementia and (2) association of dementia to lesions of vascular origin. The percentage of patients satisfying the different sets and the concordance between these criteria was analyzed. RESULTS: At least 1 set of criteria was satisfied for diagnosis in 29 subjects with dementia. In this group of patients, the sensitivity of the DSM IV, ICD 10, and standard NINDS-AIREN criteria for VaD was, respectively, 79%, 72%, and 45%. In contrast, the sensitivity of the NINDS-AIREN criteria for SIVD was 90%. The incomplete sensitivity of these last criteria was related to the absence of focal signs in some patients. The neuroimaging criteria were satisfied in all patients with dementia. CONCLUSIONS: The modified NINDS-AIREN criteria of SIVD are the most sensitive VaD criteria in CADASIL. Among these criteria, the neuroimaging criteria, although poorly specific to dementia, have a complete sensitivity. In contrast, focal signs were inconstant in CADASIL patients with dementia.

[Impairment of executive function in elderly patients with major unipolar depression: influence of psychomotor retardation]. / L'atteinte des fonctions exécutives chez la personne âgée présentant un épisode dépressif majeur unipolaire sévère: influence du ralentissement dépressif.

The results from several studies assessing the executive function in depressed patients compared to control subjects varied from significant impairment to normal performance. To assess the executive impairment in elderly patients with major unipolar depression and to evaluate the influence of psychomotor retardation and severity of depression in the executive deficits, the performance of 15 elderly patients with unipolar depression was compared to that of 15 elderly control subjects on executive tasks. The severity of depression was evaluated by the Montgomery and Asberg depressive scale and that of psychomotor retardation by the Widlöcher's scale. In depressed patients, deficits were found on tasks assessing cognitive flexibility (Modified card sorting test (MCST) and Trail making test B), planification and elaboration of strategies (cognitive estimates), motor initiation (graphic sequences), categorisation and hypothesis making (MCST) and interference resistance (Stroop test). However, depressed patients performed normally on the Hayling test assessing the inhibition processes. Intensity of psychomotor retardation was not correlated to the performance of executive tasks. Conversely, severity of depression was related to the scores of MCST (number of errors and perseverations), Stroop and Hayling tests (time taken to complete the end of the sentence). Unipolar depressed patients showed deficits in most tasks assessing executive function. However, inhibition processes appeared to be intact in depressed patients although their implementation was difficult. The severity of depression but not that of psychomotor retardation was associated with executive deficits.