Ainara Estanga

Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease

Objective: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). Methods: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging–Alzheimers Association classification: stage 0, 1, 2, 3, and SNAP. Results: The median age in the whole cohort was 58.8 years (range 39.8–81.6). Participants in stages 2–3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. Conclusions: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.

A Novel PRNP Y218N Mutation in Gerstmann-Straussler-Scheinker Disease With Neurofibrillary Degeneration

Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrPres), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrPres deposits, and expression of mutant ubiquitin (UBB+1) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.

Gray matter network disruptions and amyloid beta in cognitively normal adults.

Gray matter networks are disrupted in Alzheimers disease (AD). It is unclear when these disruptions start during the development of AD. Amyloid beta 1-42 (Aβ42) is among the earliest changes in AD. We studied, in cognitively healthy adults, the relationship between Aβ42 levels in cerebrospinal fluid (CSF) and single-subject cortical gray matter network measures. Single-subject gray matter networks were extracted from structural magnetic resonance imaging scans in a sample of cognitively healthy adults (N = 185; age range 39-79, mini-mental state examination >25, N = 12 showed abnormal Aβ42 < 550 pg/mL). Degree, clustering coefficient, and path length were computed at whole brain level and for 90 anatomical areas. Associations between continuous Aβ42 CSF levels and single-subject cortical gray matter network measures were tested. Smoothing splines were used to determine whether a linear or nonlinear relationship gave a better fit to the data. Lower Aβ42 CSF levels were linearly associated at whole brain level with lower connectivity density, and nonlinearly with lower clustering values and higher path length values, which is indicative of a less-efficient network organization. These relationships were specific to medial temporal areas, precuneus, and the middle frontal gyrus (all p < 0.05). These results suggest that mostly within the normal spectrum of amyloid, lower Aβ42 levels can be related to gray matter networks disruptions.

“Frontotemporoparietal” dementia Clinical phenotype associated with the c.709-1G>A PGRN mutation

Background: Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration with tau-negative and ubiquitin-positive neuronal inclusions. Most previous studies aimed at characterizing the clinical and neuropsychological phenotype of PGRN mutation carriers included patients with different PGRN mutations, assuming that the common proposed pathogenetic mechanism of haploinsufficiency will lead to a comparable phenotype. Methods: We studied 21 patients with a single pathogenic splicing mutation in the PGRN gene (c.709-1G>A) in the same tertiary referral center using homogenous diagnostic criteria and protocols. All patients were of Basque descent. Results: Patients exhibited a variable phenotype both in age at onset and initial symptoms. Behavioral variant frontotemporal dementia (52.4%) and progressive nonfluent aphasia (23.8%) were the most common presenting syndromes. Apathy was the most common behavioral symptom. Patients developed a relatively rapidly progressive dementia with features that led to a secondary diagnosis in 61.9% of cases 2 years after primary diagnosis. Notably, this secondary or tertiary diagnosis was corticobasal syndrome in 47.6% of cases, which confirmed the neuropsychological features of parietal lobe dysfunction seen at the initial assessment in 81.8% of patients. Conclusions: Patients carrying the c.709-1G>A mutation in the PGRN gene showed heterogeneous clinical and neuropsychological features and commonly developed corticobasal syndrome as the disease progressed.

Longitudinal Assessment of the Pattern of Cognitive Decline in Non-Demented Patients with Advanced Parkinson's Disease

BACKGROUND Dementia and mild cognitive impairment (MCI) are frequent in Parkinsons disease (PD). Deficits in some cognitive tests are considered risk factors for dementia in PD. However, how cognitive deficits progress in aged and long-lasting non-demented PD is not known. OBJECTIVE To study the rate and pattern of progression of cognitive deficits in aged and long-lasting non-demented PD. METHODS Forty-nine non-demented patients (23 cognitively normal (PD-CN) and 26 with MCI (PD-MCI)) were studied over 31 months using individual tests and z-scores covering five cognitive domains. All patients were at least 60 year old and have had PD ≥ 10 years. RESULTS Attention, executive function and memory worsened in 5 PD-CN patients who progressed to MCI (21.7% of the sample) and in 1 patient who became demented (4.3% of the sample). Eleven PD-MCI patients who developed dementia (42.3% of the sample) showed aggravation of visuospatial, executive and attention domains. Multidomain-MCI and poor execution of Stroop-Words, copy of intersecting pentagons and Raven Progressive Matrices tests were associated with conversion to dementia. CONCLUSIONS This pilot study shows that in long-lasting PD 21.7% of PD-CN patients progress to MCI and 42.3% of PD-MCI progress to dementia over a 31 months observation period. The transition from cognitively normal to MCI is featured by attention, executive and memory dysfunction and the evolution from MCI to dementia is marked by the appearance of visuospatial deficits and worsening of attention and executive function. These data are compatible with the concept that cognitive decline in PD follows a distinct dysfunction pattern with progressive anterior to posterior cortical involvement.

Prevalence of cancer in Parkinson's disease related to R1441G and G2019S mutations in LRRK2

An inverse relationship between Parkinsons disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population‐based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD‐G2019S carriers (20%) than in PD‐R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non‐skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population.

Neuropsychological Features of Asymptomatic c.709-1G>A Progranulin Mutation Carriers

Mutations in the progranulin (PGRN) gene have been identified as a cause of frontotemporal dementia (FTD). However, little is known about the neuropsychological abilities of asymptomatic carriers of these mutations. The aim of the study was to assess cognitive functioning in asymptomatic c.709-1G>A PGRN mutation carriers. We hypothesized that poorer neuropsychological performance could be present before the development of clinically significant FTD symptoms. Thirty-two asymptomatic first-degree relatives of FTD patients carrying the c.709-1G>A mutation served as study participants, including 13 PGRN mutation carriers (A-PGRN+) and 19 non-carriers (PGRN-). A neuropsychological battery was administered. We found that the A-PGRN+ participants obtained significantly poorer scores than PGRN- individuals on tests of attention (Trail-Making Test Part A), mental flexibility (Trail-Making Test Part B), and language (Boston Naming Test). Poorer performance on these tests in asymptomatic PGRN mutation carriers may reflect a prodromal phase preceding the onset of clinically significant symptoms of FTD.

Distinctive age-related temporal cortical thinning in asymptomatic granulin gene mutation carriers

Studies in asymptomatic granulin gene (GRN) mutation carriers are essential to improve our understanding of the pattern and timing of early morphologic brain changes in frontotemporal lobar degeneration. The main objectives of this study were to assess the effect of age in cortical thickness changes (CTh) in preclinical GRN mutation carriers and to study the relationship of CTh with cognitive performance in GRN mutation carriers. We calculated CTh maps in 13 asymptomatic carriers of the c.709-1G>A GRN mutation and 13 age- and sex-matched healthy subjects. Asymptomatic GRN mutation carriers presented different patterns of age-related cortical thinning in the right superior temporal and middle temporal gyri and the banks of the superior temporal sulcus bilaterally when compared with controls. Cortical thickness was correlated with neuropsychological test scores: Trail Making Tests A and B, and the Boston Naming Test. Distinctive age-related cortical thinning in asymptomatic GRN mutation carriers in lateral temporal cortices suggests an early and disease-specific effect in these areas.

Advances on Automatic Speech Analysis for Early Detection of Alzheimer Disease: A Non-linear Multi-task Approach

OBJECTIVE Nowadays proper detection of cognitive impairment has become a challenge for the scientific community. Alzheimers Disease (AD), the most common cause of dementia, has a high prevalence that is increasing at a fast pace towards epidemic level. In the not-so-distant future this fact could have a dramatic social and economic impact. In this scenario, an early and accurate diagnosis of AD could help to decrease its effects on patients, relatives and society. Over the last decades there have been useful advances not only in classic assessment techniques, but also in novel non-invasive screening methodologies. METHODS Among these methods, automatic analysis of speech -one of the first damaged skills in AD patients- is a natural and useful low cost tool for diagnosis. RESULTS In this paper a non-linear multi-task approach based on automatic speech analysis is presented. Three tasks with different language complexity levels are analyzed, and promising results that encourage a deeper assessment are obtained. Automatic classification was carried out by using classic Multilayer Perceptron (MLP) and Deep Learning by means of Convolutional Neural Networks (CNN) (biologically- inspired variants of MLPs) over the tasks with classic linear features, perceptual features, Castiglioni fractal dimension and Multiscale Permutation Entropy. CONCLUSION Finally, the most relevant features are selected by means of the non-parametric Mann- Whitney U-test.

Cortical microstructural changes along the Alzheimer's disease continuum

Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimers disease (AD).