Normative data for COGITAB: An Italian tablet-based test battery conceived for the preclinical phase of Alzheimer's disease.

The number of people with dementia is increasing worldwide. Two main approaches have been adopted to identify subjects with Alzheimer's disease (AD): the neuropsychological evaluation and the identification of biomarkers of AD. The first method is less invasive and easier to perform. This study assesses the psychometric properties of COGITAB, a novel web application d esigned to be sensitive to the subtle cognitive changes distinctive of the early Mild Cognitive Impairment (MCI) and the preclinical phase of AD. We enrolled 518 healthy controls, classified according to several risk factors and the presence of a family history of dementia. The participants were given COGITAB after a neuropsychological screening. The COGITAB Total Score (TS) was significantly affected by age and years of education. Acquired risk factors and family history of dementia significantly impacted only the COGITAB total execution time (TET), not the TS. This study provides normative data for a newly developed web application. Control subjects with acquired risk factors performed slower, giving an important role to the TET recording. Further studies should examine the ability of this new technology to discriminate between healthy subjects and subjects with initial cognitive decline, even when not detected by standard neuropsychological assessments.

Dyscalculia in Early Adulthood: Implications for Numerical Activities of Daily Living.

Numerical abilities are fundamental in our society. As a consequence, poor numerical skills might have a great impact on daily living. This study analyzes the extent to which the numerical deficit observed in young adults with Developmental Dyscalculia (DD) impacts their activities of everyday life. For this purpose, 26 adults with DD and 26 healthy controls completed the NADL, a standardized battery that assesses numerical skills in both formal and informal contexts. The results showed that adults with DD had poorer arithmetical skills in both formal and informal settings. In particular, adults with DD presented difficulties in time and measure estimation as well as money usage in real-world numerical tasks. In contrast, everyday tasks regarding distance estimation were preserved. In addition, the assessment revealed that adults with DD were aware of their numerical difficulties, which were often related to emotional problems and negatively impacted their academic and occupational decisions. Our study highlights the need to design innovative interventions and age-appropriate training for adults with DD to support their numerical skills as well as their social and emotional well-being.

Multimodal semantic battery to monitor progressive loss of concepts in the semantic variant of primary progressive aphasia (svPPA): an innovative proposal.

Semantic variant primary progressive aphasia (svPPA) is a rare neurodegenerative disease characterized by a progressive loss of semantic knowledge. Patients with svPPA show anomia, impaired word comprehension, poor object recognition, and difficulties in retrieving semantic information. svPPA is also a unique "natural" model that allows clinicians and cognitive neuroscientists to study the organization of semantic memory because only semantic knowledge is affected in the initial period of the disease, with relative sparing of other cognitive domains. In the clinical practice, semantic memory is commonly tested only with verbal tests. The aim of the present study was to preliminary test a new Multimodal Semantic Battery developed in our laboratory, which comprised 11 subtests designed to assess the semantic knowledge of multiple items via all input modalities. The battery was administered twice, over four years, to a patient diagnosed with svPPA. We found that when extensively tested with multiple tests, in some cases, he was still able to recall semantic features of the items that otherwise would not have emerged with standard semantic tests. These results are discussed for the clinical practice: monitoring semantic memory through all modalities in a practical and reliable way could be useful for both clinicians and experimental researchers to better investigate the breakdown of semantic knowledge.

A 9-year neuropsychological report of a patient with LGI1-associated limbic encephalitis.

Introduction: Anti-leucine-rich glioma-inactivated 1 limbic encephalitis (LGI1-LE) is an autoimmune disorder associated with antibodies to voltage-gated potassium channels (VGKC). It is a non-paraneoplastic and partially reversible encephalitis that can be diagnosed via serological testing. Untreated LGI1-LE can be associated with neurocognitive as well as neuropsychiatric sequelae. Here we report the neuropsychological and clinical profile of a patient with LGI1-LE following three different treatment approaches: plasmapheresis (PA), intravenous immunoglobulin (IVIG), and corticosteroids (CO). Method: We investigated our patient with 10 neuropsychological evaluations obtained over a 9-year follow-up period. Multiple MRI scans, EEG recordings, neurological examinations, and serum tests were also obtained. Results: The neurocognitive profile of our patient was characterized by long-term memory impairment (verbal and visual-spatial), and deficits in aspects of executive functioning and language. Neuropsychiatric symptoms of depression and anxiety were noted intermittently. Conclusions: Non-specific treatment prior to diagnosis had marginal effects on neurocognitive profile, neuropsychiatric symptoms, or control of epileptic seizure. In contrast, specific treatments for LGI1-LE following diagnosis resulted in neurocognitive improvement and epileptic control. Among the three treatments, IVIG and CO had the most beneficial impact on neurocognitive status, likely due to the continuity of administration.

Atypical non-progressive semantic impairment following allogeneic bone marrow transplantation in a patient with Waldenström's macroglobulinemia: A case report.

OBJECTIVE: A case report of a 74-year-old male presenting with an atypical multimodal semantic impairment. The patient was diagnosed with Waldenström macroglobulinemia (WM) for which he received allogeneic bone marrow transplantation (BMT) due to disease progression. Following BMT, he developed a sudden onset of semantic difficulties that have remained unchanged for eight years. No other cognitive functions have been affected and his activities of daily living remain fully preserved. METHOD: The patient was assessed at our neuropsychology unit with six neuropsychological evaluations over an 8-years follow-up period following BMT. Additional semantic tests were administered during the last three evaluations. Four MRI scans (at age 62, 66, 69 and 74) and 18F-FDG PET (at age 74) were obtained. RESULTS: The patient presents a multimodal semantic impairment, including naming impairment, visual agnosia, prosopoanomia, associative prosopagnosia, topographical disorientation and impaired retrograde memory for public events. MRI scans and 18F-FDG PET revealed bilateral symmetrical atrophy (temporal > frontal) and inferior bilateral temporal lobe hypometabolism, respectively. Neuroradiological examination was unremarkable prior to BMT. CONCLUSION: Clinical diagnosis remains a challenge given the focal and stable nature of his deficits. We hypothesize that the BMT procedure might have resulted in the temporal lobe damage and subsequent semantic impairment. We recommend obtaining a thorough neuropsychological evaluation of patients who receive allogenic BMT, both prior to and following transplant.

Speech Analysis by Natural Language Processing Techniques: A Possible Tool for Very Early Detection of Cognitive Decline?

Background: The discovery of early, non-invasive biomarkers for the identification of "preclinical" or "pre-symptomatic" Alzheimer's disease and other dementias is a key issue in the field, especially for research purposes, the design of preventive clinical trials, and drafting population-based health care policies. Complex behaviors are natural candidates for this. In particular, recent studies have suggested that speech alterations might be one of the earliest signs of cognitive decline, frequently noticeable years before other cognitive deficits become apparent. Traditional neuropsychological language tests provide ambiguous results in this context. In contrast, the analysis of spoken language productions by Natural Language Processing (NLP) techniques can pinpoint language modifications in potential patients. This interdisciplinary study aimed at using NLP to identify early linguistic signs of cognitive decline in a population of elderly individuals. Methods: We enrolled 96 participants (age range 50-75): 48 healthy controls (CG) and 48 cognitively impaired participants: 16 participants with single domain amnestic Mild Cognitive Impairment (aMCI), 16 with multiple domain MCI (mdMCI) and 16 with early Dementia (eD). Each subject underwent a brief neuropsychological screening composed by MMSE, MoCA, GPCog, CDT, and verbal fluency (phonemic and semantic). The spontaneous speech during three tasks (describing a complex picture, a typical working day and recalling a last remembered dream) was then recorded, transcribed and annotated at various linguistic levels. A multidimensional parameter computation was performed by a quantitative analysis of spoken texts, computing rhythmic, acoustic, lexical, morpho-syntactic, and syntactic features. Results: Neuropsychological tests showed significant differences between controls and mdMCI, and between controls and eD participants; GPCog, MoCA, PF, and SF also discriminated between controls and aMCI. In the linguistic experiments, a number of features regarding lexical, acoustic and syntactic aspects were significant in differentiating between mdMCI, eD, and CG (non-parametric statistical analysis). Some features, mainly in the acoustic domain also discriminated between CG and aMCI. Conclusions: Linguistic features of spontaneous speech transcribed and analyzed by NLP techniques show significant differences between controls and pathological states (not only eD but also MCI) and seems to be a promising approach for the identification of preclinical stages of dementia. Long duration follow-up studies are needed to confirm this assumption.

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

BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's 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 Alzheimer's 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.

Silent reading fluency: Implications for the assessment of adults with developmental dyslexia.

INTRODUCTION: Understanding silent reading fluency (SRF) is of a paramount importance, given that silent reading is the principal manner of reading for capable readers. But the assessment of SRF is not commonly useful for identifying students with reading difficulties and monitoring their progress. The paper presents the SRF scores of adults with dyslexia compared to SRF scores of skilled readers and discusses the power of the SRF measure in identifying adults with specific learning disorders with impairment in reading. METHOD: Participants recruited were 68 dyslexic and age-matched skilled adult readers (18-48 years old). Among them, 24 were skilled readers with a university degree (GRS), 22 were skilled readers with a high school diploma (DSR), and 22 participants had been diagnosed with dyslexia (DR). We used a standardized oral reading fluency (ORF) test and an original SRF task to measure the reading fluency. RESULTS: All participants increased their reading fluency in silent mode (p < .001). Nonetheless, the average speed of the oral reading was 7.19 syllables per second (syl/s) for the GSR group, 7.11 syl/s for the DSR group, and 4.95 syl/s for the DR group. The average speed of the silent reading was 11.62 syl/s and 10.75 syl/s for GSR and DSR, respectively, and 6.15 syl/s for DR. The reading fluency differential (Δf) between ORF and SRF was significantly different among the dyslexic participants and the other two groups. CONCLUSIONS: Our results strongly suggest that dyslexic readers are less capable of significantly improve their reading speed when they read silently. Thus SRF could be considered a suitable parameter for identifying older students and adults with impairment in reading. A broader investigation of the issues surrounding silent reading is needed.

Should we screen for cognitive decline and dementia?

Due to increased life expectancy, the prevalence of cognitive decline related to neurodegenerative diseases and to non-neurological conditions is increasing in western countries. As with other diseases, the burden might be reduced through personalized interventions delivered at early stages of the disease. Thus, there is an increasing demand, from both social and healthcare systems, for instruments and strategies to recognize cognitive decline, and possibly distinguish the precursor of serious neurodegeneration from "benign senile forgetfulness" or the temporary consequences of illness or trauma. However, this goal faces both technical and ethical issues. In this article we deal with the following: (i) re-definition of cognitive decline and its relationship with frailty definitions, starting from the recent work of international consensus groups for presymptomatic Alzheimer disease recognition; (ii) ethical problems concerning anonymous and personalized cognitive screening and the need for appropriate counselling; (iii) the need for more sensitive and specific tools to detect and distinguish pathological levels of cognitive decline and delineate the contribution of non-pathological decline to accumulated frailty impacts and (iv) the potential of the language domain and spontaneous speech analyses.

A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features.

We report a novel presenilin1 (PSEN1) gene mutation (I143 V) in a four-generation family with Alzheimer's disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-ß (Aß) deposits were abundant, diffuse to grey structures and contained Aß42, but very few Aß40. Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, and the frontal involvement, together with the rather complete absence of Aß40 and of amyloid angiopathy, widen the spectrum of PSEN1-linked phenotypes.

Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.

BACKGROUND: Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in beta-amyloid precursor protein (betaAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). OBJECTIVE: To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the betaAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. DESIGN AND METHODS: Polymerase chain reaction-single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD. RESULTS: We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the betaAPP Val717Ile mutation. CONCLUSIONS: One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and betaAPP genes was beneficial in characterizing gene function in FAD.