Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders

Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.

A case report of late-onset schizophrenia differentiated from a dementing disorder

Background With the increase in life expectancy and the subsequent increase in the older population, the clinical importance of late-onset psychosis also increases. Neuropathological findings play an important role in the differential diagnosis of dementing disorders in older adults. Herein, we report a case of late-onset schizophrenia that required differentiation from a dementing disorder. Case presentation: The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. She was hospitalized for treatment of her psychosis. Initially, various examinations were performed to consider the possibility that she had a dementing disorder such as dementia with Lewy bodies. 123I-meta-iodobenzylguanidine myocardial scintigraphy revealed no decrease in iodine accumulation in the myocardium, and 123I-ioflupane dopamine transporter imaging revealed no decrease in dopamine transporter accumulation in the striatum. The patient had an elevated concentration of total tau (488 pg/mL), a cerebrospinal fluid biomarker. After comprehensive testing, the patient was diagnosed with late-onset schizophrenia. Her psychiatric symptoms such as auditory hallucinations diminished after the administration of the recommended first-line drug risperidone (3 mg/day), and she was discharged on day 90. Conclusions This case was identified as late-onset schizophrenia. However, an elevated total tau concentration was observed, indicating that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.

A Customized NGS-Based Resequencing Gene Panel to Identify Genetic Variants in Dementing Disorders: Preliminary Results

Background: Advancements in the next-generation sequencing (NGS) techniques have allowed for efficient genetic variant detection at reduced costs. Methods: We describe an ad hoc NGS-based custom designed resequencing gene panel to identify genetic variants in 8 patients with dementing disorders. Results: We found variants of TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered as “Disease Causing”. In the remaining subjects, the pathogenicity was evaluated on the in silico analysis, according to the guidelines of the American College of Medical Genetics. In one patient, the p.R205W variant was causative of the disease, thus considered as “Possibly Disease Causing”. The variants found from the other four subjects in the CSF1R, SERPINI1, GRN, and APP genes revealed discordant in silico results and, therefore, it was not possible to assign a definitive pathogenicity. Conclusions: Notwithstanding the limitations of a customized panel, we detected some rare genetic variants with a probable disease association. The future application of NGS techniques and the further replication of these experimental data will replace the so-called “gene by gene” approach with a “panel of genes” strategy, that offers promising perspectives in the diagnosis and management of neurodegenerative disorders.

C-06 Differential and Dual Diagnosis of Alzheimer’s Disease and Personality Disorders: Performance on WAIS-IV Subtests

Objective Certain personality disorder (PD) diagnoses are related to the development of dementing disorders. There is a higher rate of comorbidity of PD in samples of patients with dementing disorders compared to healthy controls, which can lead to difficulties during the diagnostic process. The present study seeks to identify the neurocognitive correlates of those diagnosed with Alzheimer’s dementia (AD) compared to PD, potentially aiding in differential diagnosis. Method Data was collected as part of a large assessment outpatient clinical practice. The data contained 580 participants who came to the clinic with a variety of referral questions (e.g., neurological diagnosis, personality functioning, ADHD assessment). To measure cognitive functioning, participants were administered the WAIS-IV. Participants included 43 people diagnosed with AD and 18 with PD. Results Subtest scores for participants diagnosed with AD were lower than participants with PD. We adjusted the mean level difference using vocabulary. Using regression, we pulled out the variance associated with vocabulary as it is not susceptible to cognitive decline. Block design was significantly different for the two groups even after controlling for vocabulary (r-square = .06; p = .017). Matrix reasoning was significantly different for the two groups even after controlling for vocabulary (r-square = .09; p = .005). Conclusions The differential diagnosis of PD and dementing disorders is important, and thus these findings are important in beginning to understand the cognitive patterns in those with AD and PD. Past research has not controlled for intellectual functioning. However, additional research utilizing larger sample sizes and an extensive test battery is necessary.

Delirium and Dementia (Neurocognitive Disorders)

Delirium and dementia (now subsumed under the label of neurocognitive disorders) are often referred to as organic brain syndromes, and this chapter reviews these disorders at length. Delirium is usually brief and reversible. It is defined as an impairment in consciousness (i.e., reduced awareness of the environment) and memory (i.e., reduced recent memory). It is a topic of particular medical interest currently. Amnestic disorders are rare and characterized as disorders of memory. Dementias are frequently progressive, and chances of recovery are rare except for several uncommon illnesses. Dementias are characterized by impairment in consciousness and inattention, orientation, memory, and other intellectual or cognitive functioning. Because many of these dementing disorders (Alzheimer’s, Pick’s, and Lewy body diseases) have neurological findings previously described at autopsy, historical review is provided.

EEG in Dementing Disorders

This chapter reviews the most relevant literature on qualitative and quantitative abnormalities in resting-state eyes-closed electroencephalographic (rsEEG) rhythms recorded in patients with dementing disorders due to Alzheimer’s disease, frontotemporal lobar degeneration, vascular disease, Parkinson’s disease, Lewy body disease, human immunodeficiency virus infection, and prion disease, mainly Creutzfeldt–Jakob disease. This condition of quiet wakefulness is the most used in clinical practice, as it involves a simple, innocuous, quick, noninvasive, and cost-effective procedure that can be repeated many times without effects of stress, learning, or habituation. While rsEEG has a limited diagnostic value (not reflecting peculiar pathophysiological processes directly), delta, theta, and alpha rhythms might be promising candidates as “topographical markers” for the prognosis and monitoring of disease evolution and therapy response, at least for the most diffuse dementing disorders. More research is needed before those topographical biomarkers can be proposed for routine clinical applications.