Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.

A combination of total tau and neurofilaments discriminates between neurodegenerative and primary psychiatric disorders.

BACKGROUND AND PURPOSE: Neuropsychiatric symptoms are commonly observed in neurodegenerative diseases. No biomarker is currently available to diagnose psychiatric conditions. As a consequence, the distinction between psychiatric and neurodegenerative disorders can be challenging in daily practice. METHODS: This retrospective study included a cohort of 64 primary psychiatric patients (PSY) and 162 patients suffering from various neurodegenerative disorders (NDG). Total tau (t-Tau), phosphorylated tau (p-Tau), Aß1-42 peptide (Aß1-42) and neurofilament light chain protein (NfL) were analysed in cerebrospinal fluid. The discrimination between PSY and NDG patients was assessed using both individual and combined analysis of cerebrospinal fluid markers. RESULTS: Cerebrospinal fluid t-Tau and NfL exhibited the best diagnostic performances: they were able to discriminate between PSY and each subgroup of NDG patients. t-Tau had the highest sensitivity (93.8%) but a poor specificity (67.3%). Indeed, some NDG subgroups exhibited low t-Tau levels comparable to PSY patients. A sequential combination t-Tau + NfL improved the characterization of patients, especially in these particular subgroups, increasing specificity up to 89.6% without modification of sensitivity. Finally, this combination of markers led to a high classification rate of 90.7% for the whole cohort of patients. CONCLUSION: The sequential combination t-Tau + NfL enables the biological detection of neurodegeneration in patients with psychiatric features. This association of markers seems to be a promising strategy for a differential diagnosis in clinical practice between primary psychiatric conditions and neurodegenerative disorders, thus improving medical care of patients.

Amyloid imaging in Alzheimer's disease: a literature review.

Therapies targeting amyloid-ß peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aß immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-ß peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation.

CSF biomarkers in posterior cortical atrophy.

OBJECTIVE: To describe CSF biomarker profiles in posterior cortical atrophy (PCA), which induces high-order visual deficits often associated with Alzheimer disease (AD) pathology, and relate these findings to clinical and neuropsychological assessment. METHODS: This prospective observational study included 22 patients with PCA who underwent CSF biomarker analysis of total tau (t-tau), phosphorylated tau on amino acid 181 (p-tau181), and amyloid ß (Aß(42)). At group level, the CSF profiles of patients with PCA were compared to those of patients with typical AD and patients with other dementia (OD). Individually, the clinical presentation of patients with PCA was correlated to their CSF profile to assess the predictability of clinical features for diagnosis of underlying AD pathology. RESULTS: At group level, the PCA biomarker profile was not different from that of the AD group, but very different from that of the OD group (p < 0.001). More than 90% of patients with PCA had CSF profiles consistent with AD. All patients with PCA with either isolated higher-order visual deficit (n = 8) or visual deficit associated with memory impairment (n = 11) had CSF profiles consistent with AD. Only one of the 3 patients with PCA with asymmetric motor signs fulfilled biological CSF criteria for AD. CONCLUSIONS: PCA syndrome is usually associated with CSF biomarkers suggestive of AD, as shown by previous neuropathologic studies. This does not apply in case of motor signs suggesting associated corticobasal syndrome. CSF biomarkers help to discriminate AD from non-AD processes associated with this condition.

Stenting of a cerebral venous thrombosis.

Cerebral venous and sinus thrombosis (CVT) is a rare but potentially alarming condition, which remains a diagnostic and therapeutic challenge. Endovascular procedure may be a therapeutic option when evolution is unfavourable despite medical treatment, but the use of stenting is rarely reported in CVT treatment. We report the case of a man who presented a jugular vein thrombosis responsible for severe intracranial hypertension. Because of clinical worsening despite intravenous heparin and symptomatic treatment, endovascular procedure including the placement of five venous stents, thrombolysis and balloon angioplasty, was performed and led to venous recanalization with successful clinical outcome. The patient is still asymptomatic 3 years later. Our report shows that venous stenting could represent an efficient alternative in the management of decoagulation refractory CVT.

[Homonymous hemianopia and posterior cortical atrophy]. / Hémianopsie latérale homonyme et atrophie corticale postérieure.

INTRODUCTION: Posterior cortical atrophy (PCA) is a clinically and radiologically defined syndrome, in which predominant symptoms focus on higher visual dysfunction with progressive course and association with cortical atrophy or hypometabolism that predominates in the posterior part of the hemispheres. Homonymous hemianopia (HH) has rarely been described in this syndrome. METHODS: We report on six patients (four females, two males, aged 63 to 80) referred for visual disorder which led to demonstration of HH using perimetry testing. These patients were followed for 1 to 5 years after discovery of HH. Brain imaging with MRI or CT scan was obtained in the six cases and a SPECT scan was performed in four cases. RESULTS: HH was left-sided in four cases and right-sided in two cases. Associated symptoms related to higher visual dysfunction were simultagnosia, alone or as part of a full Balint's syndrome, alexia, constructional apraxia, dressing apraxia, visual form agnosia, prosopagnosia and hemispatial neglect. These symptoms were mild at onset but invariably worsened with disease progression. Dementia eventually developed in all cases. The clinical diagnosis was probable Alzheimer's disease in five cases and corticobasal degeneration in one case. Radiology showed posterior cortex atrophy in all cases as well as reduced cerebral blood flow in the same region, with an asymmetrical pattern compatible with the side of HH. CONCLUSION: Elementary cortical lesions in PCA can develop mainly in the associative visual areas and even in the primary visual area, resulting in HH. HH has rarely been documented in PCA, but its prevalence would probably be higher if systematic search was conducted. Apparently isolated HH of insidious onset should suggest PCA and lead to neuropsychological testing and search for discrete atrophic changes of the posterior cortex on MRI as well as for metabolic alterations with SPECT or PET.

[Statin induced neuropathy: myth or reality?]. / Neuropathies aux statines, mythe ou réalité?

BACKGROUND: Statins are lipid-lowering drugs widely used in the world. They are effective and safe in the treatment and in the primary and secondary prevention of cerebrovascular and cardiovascular diseases. Besides they are known for their muscular side-effects. It has been suggested that they also have a toxic effect on the peripheral nervous system. STATE OF ART: Case reports and retrospective studies emphasize the possibility that statins can induce peripheral nerves side-effects. A single prospective study contradicts this hypothesis. Statins are hydroxymethyl glutaryl coenzyme A reductase (HMGCoA reductase) inhibitors, this action is responsible for the lipid-lowering effect but can also explain the nervous toxicity. Statins interfere with cholesterol synthesis that may alter myelin and nerve membrane function and they prevent mitochondrial respiratory chain enzyme synthesis which may disturb neuron energy use. CONCLUSIONS: It can be considered that statins have an insignificant toxicity on peripheral nerves. The relevance of their prescription must be however well evaluated and treated patients must be closely followed.