Reasons that prevent the inclusion of Alzheimer's disease patients in clinical trials.

AIM: To assess reasons that prevent Alzheimer's disease (AD) patients from being included in clinical trials. METHODS: In 2009, we reviewed the Lille Memory Clinic's case database to identify patients suitable for inclusion in four AD clinical trials. An initial selection was made on the basis of four criteria: (i) a diagnosis of AD (with or without white matter lesions [WML]), (ii) age, (iii) mini mental state examination (MMSE) score and (iv) symptomatic treatment of AD (cholinesterase inhibitors/memantine). Next, data on patients fulfilling these criteria were reviewed against all the inclusion/exclusion criteria for four clinical trials performed in 2009 at the Memory Clinic. Reasons for non-inclusion were analyzed. RESULTS: Two hundred and five patients were selected according to the four initial criteria. Reasons for subsequently not including some of patients in clinical trials were abnormalities on MRI (56.9%, 88.9% of which were WML), unauthorized medication (37.3%), the lack of a study partner/informant (37.1%), the presence of a non-authorized disease (24.4%), contraindication to MRI (9%), a change in diagnosis over time (3.9%), visual/auditory impairments (2.9%), alcohol abuse (2%) and an insufficient educational level (1%). CONCLUSION: A high proportion of AD patients presented with vascular abnormalities on MRI. This was not unexpected, since the patients were selected from the database and, as shown in epidemiologic studies, cerebrovascular diseases are frequently associated with AD. The presence of a study partner is essential for enabling a patient to participate in clinical trials because of the need to record reliably primary and secondary outcomes.

Cognitive Outcome After Islet Transplantation.

Severe or repeated hypoglycemia events may favor memory complaints in type 1 diabetes (T1D). Pancreatic islet transplantation (IT) is an alternative option to exogenous insulin therapy in case of labile T1D, implying a maintenance immunosuppression regimen based on sirolimus or mycophenolate, associated with tacrolimus, that may also have neurological toxicity. The objective of this study was to compare a cognitive rating scale Mini-Mental State Examination (MMSE) between T1D patients with or without IT and to identify parameters influencing MMSE. Methods: This retrospective cross-sectional study compared MMSE and cognitive function tests between islet-transplanted T1D patients and nontransplanted T1D controls who were transplant candidates. Patients were excluded if they refused. Results: Forty-three T1D patients were included: 9 T1D patients before IT and 34 islet-transplanted patients (14 treated with mycophenolate and 20 treated with sirolimus). Neither MMSE score (P = 0.70) nor higher cognitive function differed between islet versus non-islet-transplanted patients, whatever the type of immunosuppression. In the whole population (N = 43), MMSE score was negatively correlated to glycated hemoglobin (r = -0.30; P = 0.048) and the time spent in hypoglycemia on the continuous glucose monitoring (r = -0.32; P = 0.041). MMSE score was not correlated to fasting C-peptide level, time spent in hyperglycemia, average blood glucose, time under immunosuppression, duration of diabetes, or beta-score (success score of IT). Conclusions: This first study evaluating cognitive disorders in islet-transplanted T1D patients argues for the importance of glucose balance on cognitive function rather than of immunosuppressive treatment, with a favorable effect of glucose balance improvement on MMSE score after IT.

Phenotype and imaging features associated with APP duplications.

BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network.

BACKGROUND: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator. METHODS: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE). RESULTS: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients. CONCLUSIONS: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.

Poststroke dementia: influence of hippocampal atrophy.

BACKGROUND: The prevalence of dementia is increased after stroke. Medial temporal lobe atrophy (MTLA) is associated with Alzheimer disease, and with prestroke dementia in patients who have had a stroke. OBJECTIVE: To determine the influence of MTLA on the long-term risk of dementia after stroke, after excluding the patients who had prestroke dementia. METHODS: The study was conducted in 144 consecutive patients who had a stroke, who were aged 40 years or older (66 women and 78 men; median age, 72 years), and who had an Informant Questionnaire on Cognitive Decline in the Elderly score lower than 104. On admission to the hospital all patients underwent a noncontrast computed tomographic scan including temporal lobe-positioned slices. A cut-off of 11.5 mm was used to differentiate patients with MTLA from those without MTLA. Patients were followed up with clinical and cognitive assessments over a 3-year period. RESULTS: Three years after stroke, 34 patients (23.6%) had developed new-onset dementia. The cumulative proportion of survivors without dementia was 57.6% in patients with MTLA and 80.8% in patients without MTLA (P =.02). The unadjusted relative risk of poststroke dementia associated with MTLA was 2.3 (95% confidence interval, 1.1-4.7). However, using the Cox proportional hazards model, MTLA did not seem to be an independent predictor of poststroke dementia. Independent predictors of poststroke dementia were increasing age, diabetes mellitus, severity of the clinical deficit at admission, and severity of leukoaraiosis on computed tomography. CONCLUSIONS: Patients who had a stroke and MTLA more frequently develop dementia than patients without MTLA, but our study does not suggest that MTLA independently contributes to dementia. A longer follow-up may be necessary to reevaluate the influence of MTLA.

Memory loss during lenalidomide treatment: a report on two cases.

BACKGROUND: There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as "chemo brain" or "chemo fog". CASE PRESENTATION: Two male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment. On withdrawal of the drug, one patient recovered normal cognitive function and independence in activities of daily living, whereas mild cognitive impairment persisted in the other patient. The Naranjo Adverse Drug Reaction Probability Scale score was 6 out of 13 for the first patient and 5 out of 13 for the second, suggesting a probable causal relationship between the adverse event and lenalidomide administration. CONCLUSION: Lenalidomide may induce particular cognitive disorders (notably episodic memory impairments) in some patients. The drug's putative neurotoxicity is probably promoted by specific risk factors (such as previous chemotherapy, prior mild cognitive impairment, age and the presence of cerebrovascular lesions).

A new decision tree combining Abeta 1-42 and p-Tau levels in Alzheimer's diagnosis.

The objective of this work was to improve the clinical diagnosis of Alzheimer's disease (AD) by proposing a simple decision tree based on three major biomarkers of AD found in the cerebrospinal fluid (CSF): amyloid peptide Aß1- 42, total Tau (t-Tau) and Tau phosphorylated at Thr181 (p-Tau). Two consecutive cohorts comprising 548 patients in total were recruited by the Memory and Neurology Clinics at Lille University Hospital (France). These included 293 patients with AD, 171 patients with other dementias and 84 healthy controls. All patients underwent lumbar puncture for the assessment of CSF concentrations of Aß1-42, t-Tau and p-Tau. International criteria for dementias were used for diagnosis by investigators blind to CSF test results. To identify the combination of biomarkers that best predicted the 3 diagnoses, we used the CHAID decision tree method with the first cohort. Our analysis yielded a two-step decision tree, with a first stratification step based on the Aß1-42/p-Tau ratio of the CSF, and a second step based on CSF p-Tau concentrations. The second cohort was then used to determine the power (0.618), sensitivity (82%) and specificity (81%) of this tree in AD diagnosis. These were found to be at least as high as those of other known algorithms based on the three CSF biomarkers, Aß1-42, t-Tau and p-Tau.For the first time, diagnostic rules for AD based on CSF variables were compared in a single study. Our findings indicate that the measurement of Aß1-42 and p-Tau levels in the CSF is sufficient to diagnose AD.

[Vascular dementia]. / Démences vasculaires.

Vascular dementias are the second leading cause of dementia after Alzheimer disease (AD). In recent years, the concept of "cognitive disorders of a vascular origin" has replaced that of vascular dementias. The new term combines vascular dementia in the strict sense of the term with milder cognitive disorders not including dementia but of vascular origins. Their diagnosis nonetheless remains difficult because of the diversity of vascular lesions that cause cognitive disorders and their frequent association with AD. The neuropsychological profile is frontal subcortical, with more marked damage to executive functions, and the possibility of damage to more cortical functions depending on the site of the vascular lesions. Beyond preventive treatments, there is no validated treatment and it remains essential to screen for risk factors to diminish the risk of onset of these cognitive disorders of vascular origin.