Camilla Ferrari

How can elderly apolipoprotein E ε4 carriers remain free from dementia

Apolipoprotein E (APOE) ε4 is a major risk factor for Alzheimers disease (AD) and dementia, but not all ε4 carriers develop dementia. We sought to identify factors that may play a role in modifying the risk of dementia due to ε4. A cognitively intact cohort (n = 932, age ≥ 75) was followed for 9 years to detect incident dementia cases. At baseline, information on education, leisure activities, and vascular risk factors was collected, and APOE was genotyped. During the follow-up, 324 subjects developed dementia, including 247 AD cases. The hazard ratio (HR, 95% confidence interval [95% CI]) of dementia related to the ε4 was 1.39 (1.11-1.76), while the risk was reduced when ε4 carriers had high education, no vascular risk factors, or high score of leisure activities. Among ε4 carriers, the multiadjusted HRs of dementia that were associated with high education, high level of leisure activities, and absence of vascular risk factors were 0.59 (0.40-0.87), 0.49 (0.29-0.85), and 0.61 (0.41-0.90), respectively. The ε4 carriers with these factors had about 1.2 years delayed time to dementia onset compared with those without these factors. High education, active leisure activities, or maintaining vascular health seems to reduce the risk of dementia related to APOE ε4. The ε4 carriers with these characteristics appear to have similar dementia-free survival time to non-ε4 carriers.

Imaging and cognitive reserve studies predict dementia in presymptomatic Alzheimer's disease subjects.

There is strong evidence that Alzheimers disease (AD) pathology starts decades before clinical onset. Cognitive reserve (CR) and brain reserve can be a good predictive model for AD development. Neuroimaging can help in describing cerebral reserves, as well as in detecting AD brain pathology before the onset of clinical dementia. Education and occupation act as proxies for CR and are associated with a lower risk of AD and delayed onset of symptoms. The apolipoprotein E (ApoE)-ε4 allele is a strong risk factor for AD and is associated with lower hippocampal volume even in normal aging. A fluorodeoxyglucose positron emission tomography study of brain metabolism shows different metabolic phenotypes among subjects with different educational levels and ApoE genotypes. More highly educated subjects reach a clinical level when the cerebral areas involved in coping with network disruption are seriously impaired, and the AD-ε4 carriers show more global metabolic brain impairment compared with non-ε4 carriers. Thus, CR can counteract a genetically unfavorable background, suggesting a possible preventive strategy. AD research findings have already produced results, since recent epidemiological studies report a decreasing incidence of AD in the last years.

Rethinking on the concept of biomarkers in preclinical Alzheimer’s disease

The neuropathological processes eventually leading to Alzheimer’s disease (AD) are thought to start decades before the appearance of clinical symptoms and the clinical diagnosis of AD dementia. The term “preclinical AD” has been recently introduced to identify this “silent stage” of AD, when the disease is already present, but symptoms are not yet clinically evident. Advances in AD biomarkers have dramatically improved the ability to detect AD pathological processes in vivo in cognitively intact subjects, thus demonstrating the presence of AD pathology in the preclinical phase. This review focuses on the recent advances in the field of neuroimaging and CSF AD biomarkers specifically in the preclinical phase of AD, and aims to discuss the significance that such biomarkers could have in cognitively intact subjects. Even though the use of such biomarkers in AD preclinical phase has contributed to improve our understanding of AD early pathological processes, it raised also a number of new challenges that still remain to be overcome, such as a better definition of the clinical and individual significance of currently known biomarkers in preclinical stages and the development of novel biomarkers of different early AD-related events.

Cognitive functioning among patients with diabetic foot.

AIMS Using diabetic foot (DF) as an indicator of severe diabetes, we aimed to investigate the cognitive profile of DF patients and the relations between cognitive functioning and both diabetes complications and comorbidities. METHODS Dementia-free patients with DF aged 30-90 (n=153) were assessed through medical records and a cognitive battery. Information on diabetes complications and comorbidities was collected via interview; glycated hemoglobin (HbA1c) was tested. Data were analyzed using robust logistic or quantile regression adjusted for potential confounders. RESULTS The mean Mini-Mental Examination (MMSE) score of patients was 24.6 (SD=3.6), and 40% had global cognitive dysfunction (MMSE ≤24). Among elderly patients (aged ≥65), MMSE impairment was related to amputation (OR 3.59, 95% CI 1.07-12.11). Episodic memory impairment was associated with foot amputation (OR 4.13, 95% CI 1.11-15.28) and microvascular complications (OR 9.68, 95% CI 1.67-56.06). Further, elderly patients with HbA1c <7% had increased odds of psychomotor slowness (OR 7.75, 95% CI 1.55-38.73) and abstract reasoning impairment (OR 4.49, 95% CI: 1.15-17.46). However, such significant associations were not shown in adult patients aged <65. CONCLUSION Amputation, microvascular diseases and glycemic control were associated with impaired global cognitive function and its domains among patients aged ≥65.

The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimers disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.

Alzheimer's Disease Progression: Factors Influencing Cognitive Decline

BACKGROUND Alzheimers disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors. OBJECTIVE The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients. METHODS We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period. RESULTS Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ4-carriers. CONCLUSION At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier

According to the literature, the APP Ala713Thr mutation is associated with Alzheimers disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

The diagnosis of dementias: a practical tool not to miss rare causes

Dementia represents one of the most diffuse disorders of our Era. Alzheimer’s disease is the principle cause of dementia worldwide. Metabolic, infectious, autoimmune, inflammatory, and genetic dementias represent a not negligible number of disorders, with increasing numbers in younger subjects. Due to the heterogeneity of patients and disorders, the diagnosis of dementia is challenging. In the present article, we propose a practical diagnostic approach following the two-step investigation procedure. The first step includes basic blood tests and brain neuroimaging, performed on all patients. After this first-line investigation, it is then possible to rule out metabolic causes of dementia and to identify three main subgroups in dementia: predominant gray matter atrophy, white matter disease, basal ganglia pathologies. The predominant gray matter atrophy subgroup includes neurodegenerative causes of dementia and some lysosomal storage disorders. The white matter subgroup indicates a comprehensive list of vascular dementia causes, mitochondrial diseases, and leukodystrophies. Whereas, the basal ganglia alterations are due to metal accumulation pathologies, such as iron, copper, or calcium. Each category has specific clinical hallmarks, accurately reported in the article, and requires specific second-line investigation. Thus, we indicate the distinct second diagnostic step of each disease. The proposed diagnostic flow-chart follows the clinical reasoning and helps clinicians through the differential diagnosis of dementia.

Biomarkers study in atypical dementia: proof of a diagnostic work-up

BackgroundAn early differentiation between Alzheimer’s Disease (AD) and other dementias is crucial for an adequate patients’ management, albeit it may result difficult for the occurrence of “atypical presentations.” Current diagnostic criteria recognize the importance of biomarkers for AD diagnosis, but still an optimal diagnostic work-up isn’t available.ObjectiveEvaluate the utility and reproducibility of biomarkers and propose an “optimal” diagnostic work-up in atypical dementia.Methods(1) a retrospective selection of “atypical dementia cases”; (2) a repetition of diagnostic assessment by two neurologists following two different diagnostic work-ups, each consisting of multiple steps; (3) a comparison between diagnostic accuracy and confidence reached at each step by both neurologists and evaluation of the inter-rater agreement.ResultsIn AD, regardless of the undertaken diagnostic work-up, a significant gain in accuracy was reached by both neurologists after the second step, whereas in frontotemporal dementia (FTD), adding subsequent steps was not always sufficient to increase significantly the baseline accuracy. A relevant increment in diagnostic confidence was detectable after studying pathophysiological markers in AD, and after assessing brain metabolism in FTD. The inter-rater agreement was higher at the second step for the AD group when the pathophysiological markers were available and for the FTD group when the results of FDG-PET were accessible.ConclusionsIn atypical cases of dementia, biomarkers significantly raise diagnostic accuracy, confidence, and agreement. This study introduces a proof of diagnostic work-up that combines imaging and CSF biomarkers and suggests distinct ways to proceed on the basis of a greater diagnostic likelihood.

Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration

BACKGROUND During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimers disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimers disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). METHODS The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. RESULTS Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. CONCLUSION Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.