Behavioural abnormalities contribute to functional decline in Huntington's disease

Hamilton, Joanne M.; Salmon, David P.; Corey–Bloom, Jody; Gamst, Anthony; Paulsen, Jane S.; Jerkins, S; Jacobson, Mark W.; Peavy, Guerry M.

doi:10.1136/jnnp.74.1.120

Cited by 157 publications

(123 citation statements)

References 14 publications

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“…Behavioral apathy is a common feature of HD and other neurodegenerative diseases (Cummings, 1995) that increases in severity with illness duration, in parallel with motor and cognitive dysfunction (Paulsen et al, 2001b;Thompson et al, 2002;Baudic et al, 2006). It has been suggested that apathy correlates with the cognitive changes in HD, especially with the executive dysfunction Hamilton et al, 2003;Baudic et al, 2006). If the lack of rousability that we measured in R6/2 mice is a correlate of apathy, then the data obtained with Alprazolam indicate that apathy may be treatable.…”

Section: Discussionmentioning

confidence: 86%

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Pharmacological Imposition of Sleep Slows Cognitive Decline and Reverses Dysregulation of Circadian Gene Expression in a Transgenic Mouse Model of Huntington's Disease

Pallier¹,

Maywood²,

Zheng³

et al. 2007

J. Neurosci.

186

135

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Transgenic R6/2 mice carrying the Huntington's disease (HD) mutation show disrupted circadian rhythms that worsen as the disease progresses. By 15 weeks of age, their abnormal circadian behavior mirrors that seen in HD patients and is accompanied by dysregulated clock gene expression in the circadian pacemaker, the suprachiasmatic nucleus (SCN). We found, however, that the electrophysiological output of the SCN assayed in vitro was normal. Furthermore, the endogenous rhythm of circadian gene expression, monitored in vitro by luciferase imaging of organotypical SCN slices removed from mice with disintegrated behavioral rhythms, was also normal. We concluded that abnormal behavioral and molecular circadian rhythms observed in R6/2 mice in vivo arise from dysfunction of brain circuitry afferent to the SCN, rather than from a primary deficiency within the pacemaker itself. Because circadian sleep disruption is deleterious to cognitive function, and cognitive decline is pronounced in R6/2 mice, we tested whether circadian and cognitive disturbances could be reversed by using a sedative drug to impose a daily cycle of sleep in R6/2 mice. Daily treatment with Alprazolam reversed the dysregulated expression of Per2 and also Prok2, an output factor of the SCN that controls behavioral rhythms. It also markedly improved cognitive performance of R6/2 mice in a two-choice visual discrimination task. Together, our data show for the first time that treatments aimed at restoring circadian rhythms may not only slow the cognitive decline that is such a devastating feature of HD but may also improve other circadian gene-regulated functions that are impaired in this disease.

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Section: Discussionmentioning

confidence: 86%

“…If the lack of rousability that we measured in R6/2 mice is a correlate of apathy, then the data obtained with Alprazolam indicate that apathy may be treatable. This would be valuable to HD patients, because apathy and executive dysfunction are strongly related to decline in activities of daily living in HD (Hamilton et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Imposition of Sleep Slows Cognitive Decline and Reverses Dysregulation of Circadian Gene Expression in a Transgenic Mouse Model of Huntington's Disease

Pallier¹,

Maywood²,

Zheng³

et al. 2007

J. Neurosci.

186

135

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“…In recent years, apathy has been often associated with deficits of the prefrontal-Basal Ganglia circuits, as it can occur after focal lesions of specific structures of the basal ganglia, such as the caudate nuclei and the internal pallidum [60][61][62], and in degenerative diseases affecting basal ganglia [7][8][9][10][11]. However, only one neuroimaging study in depressed PD patients [63] has directly supported this hypothesis by showing a significant association between apathy and reduced activity in the ventral striatum (see for a review, Benoit and Filippi [64]).…”

Section: Discussionmentioning

confidence: 99%

Apathy and Related Executive Syndromes in Dementia Associated with Parkinson’s Disease and in Alzheimer’s Disease

Grossi

Santangelo

Barbarulo

et al. 2013

Behavioural Neurology

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Abstract. Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer's disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A-and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy. The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-Aon frontal tasks. The AD-A+ had poorer performance than AD-A-on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales. The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an 'apathetic syndrome', characterized by specific cognitive and psychological symptoms.

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“…A growing number of functional neuroimaging studies have characterized the neural correlates of motor and cognitive decline in HD both before and after clinical diagnosis (Wolf et al, 2007, Klöppel et al, 2009, Paulsen, 2009, Wolf et al, 2009, Wolf et al, 2011, Georgiou-Karistianis et al, 2013, Georgiou-Karistianis et al, 2013, Poudel et al, 2014; however, studies investigating changes in brain function linked with progression of neuropsychiatric symptoms remain sparse (Wolf and Kloppel, 2013). Psychiatric disturbance is often cited as the most debilitating feature of HD symptomatology with direct implications for functional capacity and quality of life (Hamilton et al, 2003, Duijn et al, 2007. Establishing the underlying functional brain changes associated with the development of psychiatric symptoms is of great importance in the context of identifying target brain regions with functional relevance that could be used for drug development (Katz, 2004, Kozauer andKatz, 2013), new alternative treaments such as stem cell therapy (Maucksch, Vazey, Gordon, & Connor, 2013), multidisciplinary rehabilitation (Cruickshank, et al, 2015), and transcranial magnetic stimulation (Berardelli & Suppa, 2013;Medina & Tunez, 2010).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal changes in the fronto-striatal network are associated with executive dysfunction and behavioral dysregulation in Huntington's disease: 30 months IMAGE-HD data

Poudel

Stout

et al. 2017

Cortex

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Neuropsychiatric disturbance−particularly executive dysfunction and behavioral dysregulation−is a common feature of Huntington's disease (HD), with implications for functional capacity and quality of life. No study to date has ascertained whether longitudinal change in brain activity is associated with neuropsychiatric deficits in HD. We used a set-response-shifting task together with functional magnetic resonance imaging to investigate 30-month longitudinal blood-oxygen level dependent (BOLD) signal changes in the fronto-striatal attentional control network in premanifest and symptomatic HD (pre-HD and symp-HD, respectively), relative to healthy control participants. We also assessed the extent to which changes in the BOLD signal over time were related to neuropsychiatric measures in the domains of executive dysfunction and behavioral dysregulation.Associations were also evaluated with clinical and disease severity. We found no longitudinal BOLD differences between pre-HD and controls over 30 months. In contrast, reduction in BOLD response over time was greater in symp-HD, relative to controls, in task-related areas (e.g., anterior cingulate cortex and striatum) and in regions from the default mode network (e.g., medial prefrontal cortex and posterior cingulate/precuneus). Moreover, when considered across both premanifest and symptomatic stages, longitudinal BOLD signal decline in the right dorsolateral prefrontal cortex and putamen was associated with executive dysfunction and behavioral dysregulation measures. In addition, longitudinal reduction in BOLD signal, in fronto-striatal and default mode networks, correlated with disease severity. These results suggest that longitudinal change in fronto-striatal and default mode networks may be useful in understanding the biological underpinnings of functional decline in HD.Such findings offer new avenues for targeted treatments in terms of minimizing psychiatric impairment and potentially maximizing cognitive function.

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Behavioural abnormalities contribute to functional decline in Huntington's disease

Cited by 157 publications

References 14 publications

Pharmacological Imposition of Sleep Slows Cognitive Decline and Reverses Dysregulation of Circadian Gene Expression in a Transgenic Mouse Model of Huntington's Disease

Pharmacological Imposition of Sleep Slows Cognitive Decline and Reverses Dysregulation of Circadian Gene Expression in a Transgenic Mouse Model of Huntington's Disease

Apathy and Related Executive Syndromes in Dementia Associated with Parkinson’s Disease and in Alzheimer’s Disease

Longitudinal changes in the fronto-striatal network are associated with executive dysfunction and behavioral dysregulation in Huntington's disease: 30 months IMAGE-HD data

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