Commentary on 'Somewhere out there in a place no one knows: Yoko Ogawa's The Memory Police and the literature of forgetting' by John Henning

The Memory Police is a disconcerting novel set on a mysterious island. Inhabitants of this island suffer objects being 'disappeared', and we follow our narrator's journey as they try to navigate these disappearances. Henning in their compelling recent essay suggests that the novel can be more fully appreciated by engaging with a literature of forgetting and draws parallels between the events in the book and the course of the neurodegenerative process of Alzheimer's disease. In this commentary, I suggest that the progressive deterioration of conceptual knowledge described in the novel most closely resembles that seen in the rare neurodegenerative disease, semantic dementia

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

Teaching NeuroImages: Nonfluent variant primary progressive aphasia: A distinctive clinico-anatomical syndrome

A 66-year-old woman presented with 4 years of progressive speech difficulty. She had nonfluent speech with phonemic errors but intact single-word comprehension and object knowledge. Her grammar was impaired in both speech and writing, and she exhibited orofacial apraxia. A clinico-radiologic (see figure) diagnosis of nonfluent variant primary progressive aphasia was made

Teaching Neuro Images: Nonfluent variant primary progressive aphasia: A distinctive clinico-Anatomical syndrome

A 66-year-old woman presented with 4 years of progressive speech difficulty. She had nonfluent speech with phonemic errors but intact single-word comprehension and object knowledge. Her grammar was impaired in both speech and writing, and she exhibited orofacial apraxia. A clinico-radiologic (see figure) diagnosis of nonfluent variant primary progressive aphasia was made

Two cases of food aversion with semantic dementia

Accounts of altered eating behavior in semantic dementia generally emphasize gluttony and abnormal food preferences. Here we describe two female patients with no past history of eating disorders who developed early prominent aversion to food in the context of an otherwise typical semantic dementia syndrome. One patient (aged 57) presented features in line with anorexia nervosa while the second patient (aged 58) presented with a syndrome more suggestive of bulimia nervosa. These cases add to the growing spectrum of apparently dichotomous behavior patterns in the frontotemporal dementias and illustrate a potentially under-recognized cause of eating disorders presenting in later life

Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration

Tau protein inclusions are a frequent hallmark of a variety of neurodegenerative disorders. The 10+16 intronic mutation in MAPT gene, encoding tau, causes frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), by altering the splicing of the gene and inducing an increase in the production of 4R tau isoforms, which are more prone to aggregation. However, the molecular mechanisms linking increased 4R tau to neurodegeneration are not well understood. Here, we have used iPSC-derived neurons from patients of FTDP-17 carrying the 10+16 mutation to study the molecular mechanisms underlying neurodegeneration. We show that mitochondrial function is altered in the neurons of the patients. We found that FTDP-17 neurons present an increased mitochondrial membrane potential, which is partially maintained by the F1Fo ATPase working in reverse mode. The 10+16 MAPT mutation is also associated with lower mitochondrial NADH levels, partially supressed complex I-driven respiration, and lower ATP production by oxidative phosphorylation, with cells relying on glycolysis to maintain ATP levels. Increased mitochondrial membrane potential in FTDP-17 neurons leads to overproduction of the ROS in mitochondria, which in turn causes oxidative stress and cell death. Mitochondrial ROS overproduction in these cells is a major trigger for neuronal cell death and can be prevented by mitochondrial antioxidants

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification

The Language Profile of Behavioral Variant Frontotemporal Dementia

BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group. METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images. RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker

No temporal contrast enhancement of simple decreases in noxious heat

Offset analgesia (OA) studies have found that small decreases in the intensity of a tonic noxious heat stimulus yield a disproportionately large amount of pain relief. In the classic OA paradigm, the decrease in stimulus intensity is preceded by an increase of equal size from an initial noxious level. While the majority of researchers believe this temporal sequence of two changes is important for eliciting OA, it has also been suggested that the temporal contrast mechanism underlying OA may enhance detection of simple, isolated decreases in noxious heat. To test whether decreases in noxious heat intensity, by themselves, are perceived better than increases of comparable sizes, we used an adaptive two-interval alternative forced choice task to find perceptual thresholds for increases and decreases in radiant and contact heat. Decreases in noxious heat were more difficult to perceive than increases of comparable sizes from the same initial temperature of 45°C. In contrast, decreases and increases were perceived equally well within a common range of noxious temperatures (i.e., when increases started from 45°C and decreases started from 47°C). In another task, participants rated the pain intensity of heat stimuli that randomly and unpredictably increased, decreased or remained constant. Ratings of unpredictable stimulus decreases also showed no evidence of perceptual enhancement. Our results demonstrate that there is no temporal contrast enhancement of simple, isolated decreases in noxious heat intensity. Combined with previous OA findings, they suggest that long-lasting noxious stimuli that follow an increase-decrease pattern may be important for eliciting the OA effect