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Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology., Competing Interests: Declaration of Competing Interest The authors have no Conflict of Interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: People with dementia become increasingly dependent on others for care as cognition declines. Decision making about placement of people with dementia into long-term institutional care can be emotionally complex. The objective of this review is to describe experiences and perspectives of people with dementia and their family caregivers in making decisions about institutional care placement., Research Design and Methods: MEDLINE, Embase, PsycINFO, and CINAHL were searched from inception to August 2018. Thematic synthesis was used to analyze results., Results: We included 42 studies involving 123 people with dementia and 705 family caregivers from 12 countries. We identified five themes: ensuring safety (avoiding injury due to frailty, protecting against dangerous behaviors, preventing aggressive encounters), reaching breaking point (insufferable burden of caregiving, needs exceeding capabilities, intensifying family conflict, loneliness and isolation, straining under additional responsibilities, making extreme personal sacrifices), vulnerability in lacking support (ill-prepared for crisis, unable to access professional expertise, unpredictable prognostic trajectory, uncertainty navigating health care services, pressured by limited placement opportunities, high cost of placement, resenting loss of autonomy), avoiding guilt of abandonment (sharing accountability, mitigating against disagreement and stigma, reluctance to relinquish caregiving, seeking approval), and seeking reassurance and validation (preserving personhood and former identity, empowerment through engagement, assurance of care quality, acceptance from other care residents)., Discussion and Implications: People with dementia and family caregivers feel vulnerable, disempowered, and guilty in decision making about institutionalization. Person-centered communication and support strategies that foster confidence and reassurance are needed to assist people with dementia and caregivers to make decisions about placement into long-term institutional care settings., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We assessed the significance and nature of delusions in frontotemporal lobar degeneration (FTLD), an important cause of young-onset dementia with prominent neuropsychiatric features that remain incompletely characterised. The case notes of all patients meeting diagnostic criteria for FTLD attending a tertiary level cognitive disorders clinic over a three year period were retrospectively reviewed and eight patients with a history of delusions were identified. All patients underwent detailed clinical and neuropsychological evaluation and brain MRI. The diagnosis was confirmed pathologically in two cases. The estimated prevalence of delusions was 14%. Delusions were an early, prominent and persistent feature. They were phenomenologically diverse; however paranoid and somatic delusions were prominent. Behavioural variant FTLD was the most frequently associated clinical subtype and cerebral atrophy was bilateral or predominantly right-sided in most cases. We conclude that delusions may be a clinical issue in FTLD, and this should be explored further in future work.

Background: Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND., Methods: Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing., Results: Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree., Conclusion: Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.

Little information is available concerning olfactory processing in frontotemporal lobar degeneration (FTLD). We undertook a case-control study of olfactory processing in three male patients fulfilling clinical criteria for FTLD. Odour identification (semantic analysis) and odour discrimination (perceptual analysis) were investigated using tests adapted from the University of Pennsylvania Smell Identification Test. General neuropsychometry and structural volumetric brain magnetic resonance imaging (MRI) were also performed. The three patients with FTLD exhibited a disorder of olfactory processing with the characteristics of a predominantly semantic (odour identification) deficit. This olfactory deficit was more prominent in patients with greater involvement of the temporal lobes on MRI. Central deficits of odour identification may be more common in FTLD than previously recognised, and these deficits may assist in clinical characterisation.

The brain bases of specific human behaviours in health and disease are not well established. In this voxel-based morphometric (VBM) study we demonstrate neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption, or hyperphagia) in individuals with frontotemporal lobar degeneration (FTLD). Sixteen male patients with FTLD were assessed using the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia and classified according to the presence or absence of abnormal eating behaviours. Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol. Compared with healthy controls, the FTLD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTLD group, grey matter changes associated with different abnormal behaviours were assessed independently using a covariate-only model. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral OFC bilaterally (Brodmann area 11). In accord with emerging evidence in humans and other species, our findings implicate distinct components of a multi-component brain network in the control of specific aspects of eating behaviour.