Chapter 6 - Cerebrospinal fluid in the dementias

Alzheimer disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia are the most common central nervous system disorders that cause progressive neurocognitive dysfunction and ultimately dementia. A number of biomarkers for pathologies reflecting each condition have been developed. Here, we review these and give an overview of the current state of practice and research regarding cerebrospinal fluid biomarkers for these disorders. The chapter discusses both established (most of which are tau- and amyloid β-related) and upcoming biomarkers and details, wherever appropriate, clinical use and differential diagnostics aspects

In your eyes only? Discrepancies and agreement between self- and other-reports of personality from age 14 to 29

Do others perceive the personality changes that take place between the ages of 14 and 29 in a similar fashion as the aging person him- or herself? This cross-sectional study analyzed age trajectories in self- versus other-reported Big Five personality traits and in self-other agreement in a sample of more than 10,000 individuals from the myPersonality Project. Results for self-reported personality showed maturation effects (increases in extraversion, conscientiousness, openness to experience, and emotional stability), and this pattern was generally also reflected in other-reports, albeit with discrepancies regarding timing and magnitude. Age differences found for extraversion were similar between the self- and other-reports, but the increase found in self-reported conscientiousness was delayed in other-reports, and the curvilinear increase found in self-reported openness was slightly steeper in other-reports. Only emotional stability showed a distinct mismatch with an increase in self-reports, but no significant age effect in other-reports. Both the self- and other-reports of agreeableness showed no significant age trends. The trait correlations between the self- and other-reports increased with age for emotional stability, openness, agreeableness, and conscientiousness; by contrast, agreement regarding extraversion remained stable. The profile correlations confirmed increases in self-other agreement with age. We suggest that these gains in agreement are a further manifestation of maturation. Taken together, our analyses generally show commonalities but also some divergences in age-associated mean level changes between self- and other-reports of the Big Five, as well as an age trend towards increasing self-other agreement

Molecular nexopathies: a new paradigm of neurodegenerative disease.

Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with 'molecular nexopathies': specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types (e.g., clustered versus distributed connections) to particular pathogenic proteins; and differential impact of molecular effects (e.g., toxic-gain-of-function versus loss-of-function) on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology

A physiological signature of sound meaning in dementia.

The meaning of sensory objects is often behaviourally and biologically salient and decoding of semantic salience is potentially vulnerable in dementia. However, it remains unclear how sensory semantic processing is linked to physiological mechanisms for coding object salience and how that linkage is affected by neurodegenerative diseases. Here we addressed this issue using the paradigm of complex sounds. We used pupillometry to compare physiological responses to real versus synthetic nonverbal sounds in patients with canonical dementia syndromes (behavioural variant frontotemporal dementia - bvFTD, semantic dementia - SD; progressive nonfluent aphasia - PNFA; typical Alzheimer's disease - AD) relative to healthy older individuals. Nonverbal auditory semantic competence was assessed using a novel within-modality sound classification task and neuroanatomical associations of pupillary responses were assessed using voxel-based morphometry (VBM) of patients' brain MR images. After taking affective stimulus factors into account, patients with SD and AD showed significantly increased pupil responses to real versus synthetic sounds relative to healthy controls. The bvFTD, SD and AD groups had a nonverbal auditory semantic deficit relative to healthy controls and nonverbal auditory semantic performance was inversely correlated with the magnitude of the enhanced pupil response to real versus synthetic sounds across the patient cohort. A region of interest analysis demonstrated neuroanatomical associations of overall pupil reactivity and differential pupil reactivity to sound semantic content in superior colliculus and left anterior temporal cortex respectively. Our findings suggest that autonomic coding of auditory semantic ambiguity in the setting of a damaged semantic system may constitute a novel physiological signature of neurodegenerative diseases

Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia

Background: Interoception (the perception of internal bodily sensations) is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD) syndromes, but remains poorly defined. Methods: Patients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients’ daily-life sensitivity to the emotions of others. Results: Interoceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain. Conclusion: Interoception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms

Genetic testing in dementia — utility and clinical strategies

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information

Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy

OBJECTIVE: To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features. METHODS: ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database. RESULTS: A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly frontoparietal, periventricular pattern of white matter disease with subcortical U-fiber sparing; pyramidal tract and corpus callosum involvement; and diffusion changes in the white matter which we have termed "deep white matter diffusion dots." Central atrophy and corpus callosal thinning were prominent in ALSP and disproportionately mild in AARS2-L when present. ALSP also occasionally showed ventricular abnormalities and calcifications in the frontal periventricular white matter, features not seen in AARS2-L. AARS2-L demonstrates white matter rarefaction which suppresses on fluid-attenuated inversion recovery MRI sequences, a feature not seen in ALSP. CONCLUSIONS: ALSP and AARS2-L share similar clinical, imaging, and pathologic characteristics with key differentiating features that we have highlighted

Interphase chromosome positioning in in vitro porcine cells and ex vivo porcine tissues

Copyright @ 2012 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and 85 reproduction in any medium, provided the original author and source are credited. The article was made available through the Brunel University Open Access Publishing Fund.BACKGROUND: In interphase nuclei of a wide range of species chromosomes are organised into their own specific locations termed territories. These chromosome territories are non-randomly positioned in nuclei which is believed to be related to a spatial aspect of regulatory control over gene expression. In this study we have adopted the pig as a model in which to study interphase chromosome positioning and follows on from other studies from our group of using pig cells and tissues to study interphase genome re-positioning during differentiation. The pig is an important model organism both economically and as a closely related species to study human disease models. This is why great efforts have been made to accomplish the full genome sequence in the last decade. RESULTS: This study has positioned most of the porcine chromosomes in in vitro cultured adult and embryonic fibroblasts, early passage stromal derived mesenchymal stem cells and lymphocytes. The study is further expanded to position four chromosomes in ex vivo tissue derived from pig kidney, lung and brain. CONCLUSIONS: It was concluded that porcine chromosomes are also non-randomly positioned within interphase nuclei with few major differences in chromosome position in interphase nuclei between different cell and tissue types. There were also no differences between preferred nuclear location of chromosomes in in vitro cultured cells as compared to cells in tissue sections. Using a number of analyses to ascertain by what criteria porcine chromosomes were positioned in interphase nuclei; we found a correlation with DNA content.This study is partly supported by Sygen International PLC

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Traumatic life experiences and religiosity in eight countries

We present two datasets from a project about the relationship between traumatic life experiences and religiosity. These include data from 1,754 individuals in the United States (n = 322), Brazil (n = 205), China (n = 202), India (n = 205), Indonesia (n = 205), Russia (n = 205), Thailand (n = 205), and Turkey (n = 205). Surveys were consistent across samples: they include measures of traumatic life experiences, negative affective traits, existential security, life satisfaction, death anxiety, and various religious beliefs, attitudes, and behaviours. Psychometric evaluations of measures of supernatural belief and death anxiety were conducted