title: Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.
abstract: Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Fletcher
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Downey
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Golden
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Camilla N
authors.initials: CN
authors.lastname: Clark
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Slattery
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Paterson
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK jason.warren@ucl.ac.uk.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000473:pathology / Q000503:physiopathology*; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D059225:Nociception; D058748:Pain Perception; D010465:Perception; D010468:Perceptual Disorders / Q000473:pathology / Q000503:physiopathology; D057178:Primary Progressive Nonfluent Aphasia / Q000473:pathology / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics; D020886:Somatosensory Disorders / Q000473:pathology / Q000503:physiopathology*; D013788:Thalamus / Q000473:pathology*; D013697:Thermosensing; D016875:tau Proteins / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C054369:MAPT protein, human; D011506:Proteins; D016875:tau Proteins
keywords: Alzheimer’s disease; frontotemporal dementia; pain; sensory; temperature