Cognitive changes in patients with Huntington?s disease (HD) and asymptomatic carriers of the HD mutation

Lemiere, Jurgen; Decruyenaere, Marleen; Evers‐Kiebooms, Gerry; Vandenbussche, Erik; Dom, René

doi:10.1007/s00415-004-0461-9

Cited by 236 publications

(189 citation statements)

References 60 publications

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“…These findings replicate similar previous results (Berrios et al, 2002;Campodonico et al, 1998;Hahn-Barma et al, 1998;Lemiere et al, 2004), but are in contrast to others (de Boo et al, 1999;Giordani et al, 1995;Rothlind et al, 1993;Strauss & Brandt, 1990). Given that effect sizes were small in the CL0 group and medium in the CL1 group, previous null findings may well reflect inadequate power to detect these subtle effects, especially in samples that include only individuals with a near or total absence of motor signs or who are very far from estimated age of onset.…”

Section: Discussionsupporting

confidence: 89%

“…Similarly, a pre-HD group demonstrated selective impairments in verbal memory on a word list learning task (Lundervold & Reinvang, 1995). In addition, longitudinal data from a sample of pre-HD participants indicates that declines in verbal learning and memory are detectable prior to clinical symptom onset (Lemiere, Decruyenaere, Evers-Kiebooms, Vandenbussche, & Dom, 2004). Specifically, studies of memory in pre-HD have documented significantly poorer performance, relative to non-CAG expanded individuals, on measures of learning (Rosenberg, Sorensen, & Christensen, 1995), semantic clustering (Rosenberg et al, 1995), recall (Hahn-Barma et al, 1998;Rosenberg et al, 1995), and recognition discriminability (Berrios et al, 2002;Lanto, Riege, Mazziotta, Pahl, & Phelps, 1990).…”

Section: Introductionmentioning

confidence: 96%

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Verbal episodic memory declines prior to diagnosis in Huntington's disease

et al. 2007

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 96%

Verbal episodic memory declines prior to diagnosis in Huntington's disease

et al. 2007

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“…In line with the notion that WM processes are subserved by frontoparietal and striatal areas, WM deficits and frontostriatal dysfunction have also been demonstrated in other disorders of the basal ganglia, e.g., Parkinson's disease [PD] [Altgassen et al, 2007;Lewis et al, 2003;Monchi et al, 2000]. In HD, WM dysfunction is present during early stages of the illness [Lemiere et al, 2004] and has been demonstrated in both patients with manifest HD and individuals with the HD gene mutation who are presymptomatic for the motor symptoms of the disorder [pre-HD individuals] [Lawrence et al, 1996;Montoya et al, 2006;Nehl et al, 2001]. In a sample of pre-HD individuals, we have recently shown aberrant activation of the dorsolateral prefrontal cortex (DLPFC) during WM performance [Wolf et al, 2007b], demonstrating that DLPFC dysfunction may occur several years before the onset of manifest HD symptoms.…”

Section: Introductionmentioning

confidence: 66%

“…We also sought to provide additional information about the studied HD population by using a complementary behavioral assessment of other cognitive domains in addition to verbal WM, including attention, inhibition of prepotent responses, and executive function. As demonstrated by previous studies [Lemiere et al, 2004;Snowden et al, 2001;Ward et al, 2006], we predicted behavioral deficits in HD patients during WM and executive performance. On the functional level, we were particularly interested in the circuitry involving the lateral prefrontal cortex, since impaired prefrontal circuitry has been recognized to play a crucial role in the pathophysiology of the cognitive symptoms found in manifest HD [Montoya et al, 2006;Snowden et al, 2001;Zakzanis, 1998].…”

Section: Introductionmentioning

confidence: 87%

Cortical dysfunction in patients with Huntington's disease during working memory performance

Wolf

Vasić

Schönfeldt‐Lecuona

et al. 2008

Human Brain Mapping

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Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy-related activation confounds. Voxel-based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso-and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM-related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy.

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“…Although severe motor impairments characterize the disease, cognitive and memory deficits are also present and often appear in advance of other symptoms (3)(4)(5)(6). Impaired learning that occurs before or concurrent with motor dysfunction or neuron loss has been described for HD mouse models (7)(8)(9) as have deficits in hippocampal long-term potentiation (LTP) (10)(11)(12)(13), a form of synaptic plasticity widely regarded as a neurobiological substrate for memory.…”

mentioning

confidence: 99%

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

Simmons¹,

Rex

Palmer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brainderived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD.actin polymerization ͉ CAG140 ͉ long-term potentiation ͉ theta burst stimulation ͉ unsupervised learning H untington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation involving the trinucleotide CAG in the huntingtin gene (1, 2). Although severe motor impairments characterize the disease, cognitive and memory deficits are also present and often appear in advance of other symptoms (3-6). Impaired learning that occurs before or concurrent with motor dysfunction or neuron loss has been described for HD mouse models (7-9) as have deficits in hippocampal long-term potentiation (LTP) (10-13), a form of synaptic plasticity widely regarded as a neurobiological substrate for memory. Understanding why LTP is severely impaired in HD mice could explain the cognitive dysfunction seen in patients with the disease.Our recent investigations into HD-associated plasticity deficits established that actin polymerization in dendritic spines, which normally stabilizes LTP (14, 15), is defective in HD knockin mice and most likely explains the rapid decay of potentiation (11). Pertinent to this finding, both HD mice and patients have reduced forebrain levels of brain-derived neurotrophic factor (BDNF) and its TrkB receptor (16,17). BDNF is a releasable neurotrophin that promotes activity-driven actin polymerization in dendritic spines (15, 18) and potently facilitates LTP induction by theta burst stimulation (TBS; refs. 19 and 20). Thus, an HD-related failure in BDNF signaling could remove an essential element of the system that modifies the spine cytoskeleton, thereby disrupting the stable synaptic changes needed to encode memory. Accordingly, applying low concentrations of BDNF fully restored TBS-induced actin polymerization and LTP in hippocampal slices prepared from HD ...

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Cognitive changes in patients with Huntington?s disease (HD) and asymptomatic carriers of the HD mutation

Cited by 236 publications

References 60 publications

Verbal episodic memory declines prior to diagnosis in Huntington's disease

Verbal episodic memory declines prior to diagnosis in Huntington's disease

Cortical dysfunction in patients with Huntington's disease during working memory performance

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

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