Presymptomatic Huntington's Disease Gene Carriers Research Articles

The pathobiology of depression in Huntington's disease: an unresolved puzzle.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

Diffusion imaging studies of Huntington's disease: A meta-analysis

BackgroundDiffusion tensor imaging (DTI) could detect abnormal brain microstructural alterations. DTI studies of Huntington's Disease(HD) have yielded inconsistent results. ObjectiveTo integrate the existing DTI studies of HD and explore the validity of DTI to detect microstructural damages in HD brain via meta-analysis. MethodsSystematic and comprehensive searches of the databases were performed for DTI studies of HD. The data from the studies that met our inclusion criteria were extracted and analyzed using the CMA2 software. Random effect models were utilized to minimize the potential between-study heterogeneity. One-way sensitivity analysis was conducted to test the robustness of the results. ResultsThe meta-analysis included 140 pre-symptomatic HD (PreHD), 235 symptomatic HD (SymHD) patients and 302 controls, revealing significantly increased fractional anisotropy (FA) in the caudate, putamen, and globus pallidus, while decreased FA in the corpus callosum of both PreHD and SymHD patients compared with controls. In addition, significantly increased mean diffusivity (MD) was identified in the putamen and thalamus of both PreHD and SymHD patients, and in the caudate of SymHD patients, while no significant difference in MD in the caudate of PreHD patients. In the corpus callosum, there was a significant increase of radial diffusivity and axial diffusivity in SymHD patients compared with controls. Meta-regression showed gender-based difference in MD values of the caudate. ConclusionsOur meta-analysis provides further evidence that DTI detects microstructural damage of both white matter and gray matter even in PreHD gene carriers. MD is less sensitive than FA in detecting structural changes in PreHD.

Decreased Diffusivity in the Caudate Nucleus of Presymptomatic Huntington Disease Gene Carriers: Which Explanation?

The neostriatum is known to be affected in HD. In this work, our aim was to determine whether microstructural and volumetric alterations occur in the neostriatum of presymptomatic HD gene carriers and in patients with early-stage HD. We studied a group of 15 presymptomatic gene carriers who were far from the estimated symptom onset (16% probability of developing the disease within 5 years), a group of 9 patients with early symptomatic HD, and 2 groups of age-matched controls. Volumetric MR imaging and DWIs were acquired, and statistical analyses were performed on the volumes of the caudate nucleus and putamen and on the corresponding MD measurements. Neostriatal volumes were significantly smaller in both presymptomatic HD gene carriers and symptomatic patients with respect to controls. However, whereas the diffusivity in the caudate nucleus was increased in the symptomatic patients, it was decreased in the presymptomatic gene carriers. Altered diffusivity and reduced volume of the caudate nucleus in presymptomatic HD gene carriers indicate that the neostriatum is affected well before the onset of symptoms. The observed initial decrease and subsequent increase of MD might be related to the combined effect of increased oligodendroglial population, putatively a developmental abnormality, and incipient neurodegeneration.

Poster 11: Motor Symptom–Related Metabolic Network in Huntington's Disease

Objective To describe a brain metabolic network selectively expressed in symptomatic Huntington's disease (HD) gene carriers. Background A metabolic network specifically associated with HD motor symptoms may be useful in assessing new therapies. We used PET imaging and network analysis to identify a spatial covariance pattern expressed in newly symptomatic HD patients. Design/Methods We utilized serial FDG PET to study 12 presymptomatic HD gene carriers at baseline, 18, and 44 months. Four subjects became symptomatic by 44 months. Additionally, two phenoconverters and two non-phenoconverters were scanned at 68 months. To identify a symptom-related pattern, we conducted network analysis to compare the phenoconverted and non-phenoconverted scans at 44 months. Scans from 12 age-matched healthy controls were included for comparison. Results We identified an HD symptom-related metabolic covariance pattern (HDSP), which separated symptomatic and preclinical gene carriers ( p p p Conclusion The HDSP network emerged as preclinical HD subjects neared clinical onset; its expression also increased as symptoms progressed. A unique feature of the HDSP is its high sensitivity for the motor symptoms of HD. The correlation of pattern activity with clinical ratings indicates that this network may be particularly useful in assessing the emergence of HD symptoms and their response to therapy.

Implicit and explicit aspects of sequence learning in pre-symptomatic Huntington's disease

Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in 11 pre-symptomatic HD gene carriers (pHD) and 11 normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQ test). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQ test these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve.

Longitudinal Evaluation of "Presymptomatic" Carriers of Huntington's Disease

Longitudinal Evaluation of "Presymptomatic" Carriers of Huntington's Disease

Proximity to Clinical Onset Influences Motor and Cognitive Performance in Presymptomatic Huntington Disease Gene Carriers

Neuroimaging studies of Huntington disease (HD) gene carriers have shown that characteristic striatal atrophy begins long before symptom onset, but findings regarding the presence of preclinical functional deficits are inconsistent. To further investigate potential motor and cognitive deficits in presymptomatic gene carriers (PSGCs), and relationships between performance and estimated proximity to HD symptom onset. PSGCs and age-matched controls performed motor tasks involving cued sequential button presses, and cognitive tasks involving simple and complex choice responses to visuospatial stimuli. PSGCs demonstrated similar motor performance speed, and nonsignificantly slower cognitive reaction times, to controls. PSGCs made more errors than controls to stimuli requiring a spatially incongruent response, possibly suggesting some difficulty in inhibiting automatic responses. Movement times for motor conditions where little advance information was provided, and reaction times for low demand cognitive tasks, were positively correlated with PSGCs' estimated probability of symptom onset within 5 years. Response speed was slower for those PSGCs estimated to have higher probabilities of close onset. These findings suggest that to provide improved knowledge of how HD begins, knowledge that may be used in clinical trials, future research should further explore relationships between function and proximity to onset.

Imaging microglial activation in Huntington's disease

Activated microglia have been proposed to play a major role in the pathogenesis of Huntington's Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using 11C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with 11C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.

Evaluation of psychological symptoms among presymptomatic HD gene carriers as measured by selected MMPI scales

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) ( n=363), presymptomatic gene carriers (PSGC) ( n=149), and those with manifest HD (MHD) ( n=26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P=0.005; MHD vs. NGC, P=0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P=0.0005; MHD vs. NGC, P=0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms.

Quantitative neuropathological changes in presymptomatic Huntington's disease

Morphometric studies of the tail of the caudate nucleus, the site where the pathology is first seen, were performed on 16 brain specimens collected from individuals at risk for inheriting Huntington's disease (HD). Medical records and information obtained from immediate family members indicated that all had died without symptoms of HD. Six individuals had 37 or more CAG repeats and were designated HD gene carriers, whereas 10 were determined to be non-carriers. Cell counts of the tail of the caudate nucleus revealed an increased density of oligodendrocytes among the presymptomatic HD gene carriers (mean cells/field: carriers = 40.0, noncarrier = 21.3; age, sex, repeated measure adjusted F[126] = 11.7, p = 0.0008). No statistically significant differences were found between HD carriers and noncarriers in the density of neurons (carriers = 16.9, noncarriers = 15.5), astrocytes (carriers = 27.8, noncarriers = 21.3) or microglial cells (carriers = 7.9, noncarriers = 5.6). Ubiquitin immunostaining performed in 3 gene carriers revealed intranuclear inclusions in all 3 cases, including 1, with 37 repeats, who died 3 decades before the expected age for onset of the clinical syndrome. Normal densities of other cell types and careful macroscopic examination suggest that the increase in oligodendroglial density is not a consequence of atrophy and may instead reflect a developmental effect of the HD gene. Ann Neurol 2001;49:29–34

Quantitative neuropathological changes in presymptomatic Huntington's disease

Morphometric studies of the tail of the caudate nucleus, the site where the pathology is first seen, were performed on 16 brain specimens collected from individuals at risk for inheriting Huntington's disease (HD). Medical records and information obtained from immediate family members indicated that all had died without symptoms of HD. Six individuals had 37 or more CAG repeats and were designated HD gene carriers, whereas 10 were determined to be non-carriers. Cell counts of the tail of the caudate nucleus revealed an increased density of oligodendrocytes among the presymptomatic HD gene carriers (mean cells/field: carriers = 40.0, noncarrier = 21.3; age, sex, repeated measure adjusted F[126] = 11.7, p = 0.0008). No statistically significant differences were found between HD carriers and noncarriers in the density of neurons (carriers = 16.9, noncarriers = 15.5), astrocytes (carriers = 27.8, noncarriers = 21.3) or microglial cells (carriers = 7.9, noncarriers = 5.6). Ubiquitin immunostaining performed in 3 gene carriers revealed intranuclear inclusions in all 3 cases, including 1, with 37 repeats, who died 3 decades before the expected age for onset of the clinical syndrome. Normal densities of other cell types and careful macroscopic examination suggest that the increase in oligodendroglial density is not a consequence of atrophy and may instead reflect a developmental effect of the HD gene.

Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers.

To determine whether longitudinal changes in cognitive and motor function can be detected among clinically presymptomatic individuals carrying the Huntington disease (HD) allele. A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and non-gene carriers at risk for HD examined an average of 3.7 years apart. The Department of Medical and Molecular Genetics at a general clinic research center in Indianapolis, Ind. A sample of 43 at-risk individuals consisting of presymptomatic gene carriers (n = 12) and non-gene carriers (n = 31). Huntington disease gene status was determined by molecular testing of the HD gene. Subscales from the Wechsler Adult Intelligence Scale-Revised and a quantified neurologic rating scale were administered. Scores on the digit symbol subscale of the Wechsler Adult Intelligence Scale-Revised (P<.05) and 2 neurologic variables-optokinetic nystagmus (P<.01) and rapid alternating movements (P<.005)-declined more rapidly among presymptomatic gene carriers than among non-gene carriers. At follow-up examination, compared with nongene carriers, presymptomatic gene carriers had significantly lower scores on the digit symbol subscale (P = .02) and for 4 neurologic variables-rapid alternating movements (P<.005), optokinetic nystagmus (P<.001), overall ocular movements (P<.02), and chorea of the trunk (P<.02). Psychomotor speed, optokinetic nystagmus, and rapid alternating movements demonstrated significant decline early in the pathological process of HD. These results suggest that subtle worsening of psychomotor, oculomotor, and motor functions occurs before the onset of signs sufficient to make a clinical diagnosis in individuals who have inherited the HD allele.