Pain and temperature processing in dementia: a clinical and neuroanatomical analysis
TL;DR: Using a semi-structured caregiver questionnaire and MRI voxel-based morphometry in patients with frontotemporal degeneration or Alzheimer’s disease, Fletcher et al. show that symptoms are underpinned by atrophy in a distributed thalamo-temporo-insular network implicated in somatosensory processing.
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.
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TL;DR: A clinical approach to the progressive aphasias is presented, based on the experience of these disorders and directed at non-specialists, and a prospect for future progress is concluded, emphasising generic information processing deficits and novel pathophysiological biomarkers.
Abstract: The primary progressive aphasias are a heterogeneous group of focal 'language-led' dementias that pose substantial challenges for diagnosis and management Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap' After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers
159 citations
TL;DR: This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes.
Abstract: The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome). In about a third of cases FTD is familial, with mutations in the progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72 genes being the major causes. Mutations in a number of other genes including TANK-binding kinase 1 are rare causes of familial FTD. This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes. It will also discuss the current major challenges in FTD research and clinical practice, and potential areas for future research. This review clarifies the terminology of frontotemporal dementia (FTD) and summarizes the various clinical features and most recent diagnostic criteria of sporadic and familial FTD syndromes. It also discusses the current major challenges in FTD research and clinical practice, and highlights potential areas for future research.
113 citations
TL;DR: It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic aggregates, which ultimately overwhelm capacity to function.
Abstract: Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.
113 citations
TL;DR: Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices.
Abstract: Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies.
80 citations
Cites background from "Pain and temperature processing in ..."
...Using MRI voxel-based morphometry analysis pain and temperature symptoms were associated to a right-lateralized network including anterior temporal cortex, posterior thalamus and insula, indicating an altered processing of somatosensory signals.(69) Such failure to interpret pain and temperature variations can put patients at risk of injuries....
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TL;DR: A critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for Behavioral variant frontotemporal dementia is aimed at.
Abstract: Behavioral variant frontotemporal dementia (bvFTD) is the second leading cognitive disorder caused by neurodegeneration in patients under 65 years of age. Characterized by frontal, insular, and/or temporal brain atrophy, patients present with heterogeneous constellations of behavioral and psychological symptoms among which progressive changes in social conduct, lack of empathy, apathy, disinhibited behaviors, and cognitive impairments are frequently observed. Since the histopathology of the disease is heterogeneous and identified genetic mutations only account for ~30% of cases, there are no reliable biomarkers for the diagnosis of bvFTD available in clinical routine as yet. Early detection of bvFTD thus relies on correct application of clinical diagnostic criteria. Their evaluation however, requires expertise and in-depth assessments of cognitive functions, history taking, clinical observations as well as caregiver reports on behavioral and psychological symptoms and their respective changes. With this review, we aim for a critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for bvFTD. We highlight both, practical difficulties as well as current controversies regarding an overlap of symptoms and particularly cognitive impairments with other neurodegenerative and primary psychiatric diseases. We then review more recent developments and evidence on cognitive, behavioral and psychological symptoms of bvFTD beyond the diagnostic criteria which may prospectively enhance the early detection and differential diagnosis in clinical routine. In particular, evidence on specific impairments in social and emotional processing, praxis abilities as well as interoceptive processing in bvFTD is summarized and potential links with behavior and classic cognitive domains are discussed. We finally outline both, future opportunities and major challenges with regard to the role of clinical neuropsychology in detecting bvFTD and related neurocognitive disorders.
66 citations
References
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TL;DR: It is suggested thatright temporal resection contributes to the development of somatoform disorders in patients and that right temporal dysfunctions may contribute to idiopathic somatoforms disorders.
Abstract: OBJECTIVE: Depression, anxiety, and psychosis are the most frequent psychiatric disorders after epilepsy surgery. The only new-onset somatoform disorder reported postoperatively is conversion disorder. We identified 10 patients who developed somatoform disorder other than nonconversion epileptic seizures after anterior temporal lobectomy. METHOD: We retrospectively reviewed the charts of 325 anterior temporal lobectomy and 125 extratemporal surgeries between 1991 and 2000. RESULTS: Seven of the patients developed undifferentiated somatoform disorder after anterior temporal lobectomy, 1 had pain and body dysmorphia, another had pain disorder, and another had body dysmorphia alone, but none were found after extratemporal surgeries (chi-square = 3.93; P < or = 0.05). Somatoform disorder was significantly more common in right anterior temporal lobectomy (n = 9) than left anterior temporal lobectomy (n = 1) (chi-square = 6.5; P < or = 0.025). CONCLUSIONS: Our findings suggest that right temporal resection contributes to the development of somatoform disorders in our patients and that right temporal dysfunctions may contribute to idiopathic somatoform disorders.
22 citations
"Pain and temperature processing in ..." refers background in this paper
...Unpleasant somatic and visceral sensory experiences occur with focal damage involving this region (Naga et al., 2004; Erickson et al., 2006), while anterior temporal lobe dysfunction associated with migraine enhances thalamo-cortical connectivity (Moulton et al....
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...Unpleasant somatic and visceral sensory experiences occur with focal damage involving this region (Naga et al., 2004; Erickson et al., 2006), while anterior temporal lobe dysfunction associated with migraine enhances thalamo-cortical connectivity (Moulton et al., 2011)....
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06 Sep 2014
TL;DR: The results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration.
Abstract: Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating.
20 citations
"Pain and temperature processing in ..." refers background or result in this paper
...Pathological data have demonstrated heavy thalamic involvement in a series of C9orf72 mutation cases reporting a high frequency of unexplained somatic and visceral pains during life (Landqvist Waldo et al., 2013)....
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...In line with our prior hypotheses and previous work (Bathgate et al., 2001; Snowden et al., 2001, 2013; Pijnenburg et al., 2004; Mahoney et al., 2012; Ahmed et al., 2015; Downey et al., 2014; Landqvist Waldo et al., 2014), certain syndromic signatures were identified....
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...Altered processing of sensory signals is an important feature of these diseases (Bathgate et al., 2001; Snowden et al., 2001; Pijnenburg et al., 2004; Jesso et al., 2011; Omar et al., 2011a, 2013; Rohrer et al., 2012; Fletcher et al., 2013; Downey et al., 2014; Landqvist Waldo et al., 2014; Perry et al., 2014; Woolley et al., 2014; Zhou and Seeley, 2014)....
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...…of these diseases (Bathgate et al., 2001; Snowden et al., 2001; Pijnenburg et al., 2004; Jesso et al., 2011; Omar et al., 2011a, 2013; Rohrer et al., 2012; Fletcher et al., 2013; Downey et al., 2014; Landqvist Waldo et al., 2014; Perry et al., 2014; Woolley et al., 2014; Zhou and Seeley, 2014)....
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...Unpleasant somatic symptoms, often with a nociceptive component (including non-specific unexplained headaches, musculoskeletal, abdominal or urogenital discomfort, vague migrating pains, chest pain and pruritus), have been described in a substantial proportion of patients with FTLD and may be early and prominent (Snowden et al., 2001); such symptoms may be particularly salient in the syndromes of semantic dementia and behavioural variant frontotemporal dementia (FTD), especially with C9orf72 mutations (Landqvist Waldo et al., 2013)....
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29 Nov 2013
TL;DR: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD, and the clinical symptom profile was strikingly homogenous.
Abstract: Background: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings. Methods: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion. Results: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive. Conclusions: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.
19 citations
"Pain and temperature processing in ..." refers background in this paper
...Pathological data have demonstrated heavy thalamic involvement in a series of C9orf72 mutation cases reporting a high frequency of unexplained somatic and visceral pains during life (Landqvist Waldo et al., 2013)....
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...…proportion of patients with FTLD and may be early and prominent (Snowden et al., 2001); such symptoms may be particularly salient in the syndromes of semantic dementia and behavioural variant frontotemporal dementia (FTD), especially with C9orf72 mutations (Landqvist Waldo et al., 2013)....
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TL;DR: It is proposed that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion.
Abstract: An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric features may be early and prominent, although a putative cortico-thalamo-cerebellar network has been implicated in the pathogenesis of the clinical phenotype. Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia. We undertook a detailed behavioral analysis of self-other attribution in a 67-year-old male patient with behavioral variant frontotemporal dementia (bvFTD) due to the C9ORF72 expansion by using a novel paradigm requiring differentiation of the effects of self- and non-self-generated actions. The patient's performance was assessed in relation to two older male patients with bvFTD not attributable to the C9ORF72 expansion and four healthy older male subjects. Compared with the healthy control group, the patient with the C9OFR72 mutation showed a deficit of self-other differentiation that was disproportionate to his otherwise relatively indolent clinical phenotype. The performance of the other patients with bvFTD was similar to that of healthy subjects. We propose that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion. We offer this preliminary observation as a stimulus to further work.
13 citations
"Pain and temperature processing in ..." refers background in this paper
...Besides pain and temperature, this spectrum includes signals related to eating and satiety (Whitwell et al., 2007; Woolley et al., 2014), music and other complex sounds (Fletcher et al., 2013, 2015) and somatosensory boundaries (Downey et al., 2012, 2014)....
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...…targeted by the pathological process in FTLD. Impaired body schema integrity has recently been demonstrated in patients with C9orf72 mutations (Downey et al., 2012, 2014) and may be a generic pathophysiological mechanism of somatic delusions, somatization and other neuropsychiatric symptoms…...
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...…according to the colour bar. and prominent and may be underpinned by disintegration of a large-scale cortico-thalamo-cerebellar brain network (Downey et al., 2012; Mahoney et al., 2012; Snowden et al., 2012, 2013; Takada and Sha, 2012; Whitwell et al., 2012; Lee et al., 2014; Rohrer et al.,…...
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...and prominent and may be underpinned by disintegration of a large-scale cortico-thalamo-cerebellar brain network (Downey et al., 2012; Mahoney et al., 2012; Snowden et al., 2012, 2013; Takada and Sha, 2012; Whitwell et al., 2012; Lee et al., 2014; Rohrer et al., 2015)....
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