Cognitive dysfunction and dementia in Parkinson’s disease

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia.Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.     

Auditory dysfunction in patients with Huntington’s disease

Objective

Huntington’s disease (HD) is an autosomal, dominantly inherited, neurodegenerative disease. The main clinical features are motor impairment, progressive cognitive deterioration and behavioral changes. The aim of our study was to find out whether patients with HD suffer from disorders of the auditory system.

Determinants of autonomic dysfunction in idiopathic Parkinson’s disease

OBJECTIVES: To determine demographic or disease-related factors that may influence the severity of autonomic dysfunction in idiopathic Parkinson's disease (IPD). METHODS: 532 patients with IPD aged between 55 and 75 years were included. Severity of autonomic dysfunction was assessed using a 9-item autonomic dysfunction score (ADS). In addition, several demographic factors (e. g. age, gender, comorbidities) and disease- related (e. g. motor stage, disease duration, antiparkinsonian therapy) factors were recorded. A group of 67 age-matched healthy volunteers served as a control group. Demographic and clinical data of this cross-sectional survey were analyzed by a logistic stepwise regression model to determine independent predictors of autonomic dysfunction. RESULTS: IPD patients showed significantly higher ADS values than controls, even in the youngest age groups and in mild disease stages. Hoehn & Yahr (H&Y) stage, disease duration, age at onset and various therapy combinations all showed significant correlations with ADS. However, stepwise logistic regression revealed that age (OR 10.71; CI 7.17-16.0) and arterial hypertension (OR 3.05; CI 1.66-5.58) were the only independent risk factors associated with autonomic dysfunction. Linear regression indicated that ADS increases with age in controls as well as in patients, but with a significantly steeper slope in the latter. CONCLUSIONS: Autonomic dysfunction as an inherent feature of IPD is present already in early disease stages. According to a logistic regression model, the severity of autonomic dysfunction in IPD is primarily related to demographic but not to disease-related factors. This and the differences in predictors for motor versus autonomic decline may indicate at least partly independent neurodegenerative processes.     

Cognitive and behavioral dysfunction in Parkinson’s disease: neurochemical and clinicopathological contributions

The cognitive and behavioral sequelae (i.e., nonmotor profile) of Parkinson's disease (PD), with executive dysfunction and depression being most prominent, have typically been overshadowed due to an emphasis on motor symptomatology. The apparent categorization of PD as a disorder isolated to the dopaminergic system may be a generalization of the disease pathology. Dopamine therapy, used for the treatment of motor symptoms, has not consistently been shown to resolve nonmotor impairments. Research evidence indicates that nondopaminergic neurotransmitter systems (i.e., serotonergic, noradrenergic, & cholinergic) are disrupted in PD and may contribute to cognitive and behavioral dysfunction. Furthermore, Lewy bodies within cortical and subcortical structures can add to the nonmotor profile in PD. Pharmacological interventions for the treatment of cognitive and behavioral impairments associated with PD are few, especially for nondemented patients. The current review of the literature highlights evidence that associates nonmotor dysfunctions with neurochemical and clinicopathological correlates of PD.     

Assessment of complex movements reflects dysfunction in Huntington’s disease

Abstract. Results of various complex instrumental tools, rating scales, caudate atrophy and CAG repeat length may reflect the severity of Huntingtons disease (HD). A simple assessment task for dysfunction due to disease is the standardized, computer based performance of peg insertion. The objectives of our study were to compare scored HD symptoms, computed bicaudate diameter ratio (BDR), age related genetic disease load (CAG index = [CAG-35.5 x age]) and peg insertion scores between asymptomatic 34 HD gene carriers, 89 previously untreated HD patients with psychiatric or motor symptoms, or both, and 51 treated HD patients. We measured the period of the total time taken to insert 25 pegs from a rack into a series of appropriate holes, calculated the CAG index, estimated the bicaudate diameter ratio (BDR) of a current brain CT and scored the HD patients under blind conditions. Times for the peg insertion task significantly differed between HD patients and controls, but not between HD gene carriers and controls. BDR and CAG index reflected the increase of symptoms in HD. Peg insertion results and scored severity of HD, BDR and CAG index significantly correlated with each other. Peg insertion scores are not specific diagnostic markers for HD, but they reflect clinical symptoms of neurodegeneration. The performance of peg insertion involves visuospatial cognition, selfelaboration of internal strategies, sorting and planning of movement. Therefore peg insertion particularly reflects executive dysfunction in early HD and additionally motor impairment in advanced HD.     

Mitochondrial dysfunction and Huntington disease

Huntington disease (HD) is a chronic autosomal-dominant neurodegenerative disease. The gene coding Huntingtin has been identified, but the pathogenic mechanisms of the disease are still not fully understood. This paper reviews the involvement of mitochondrial dysfunction in pathogenesis of HD.     

Neuroinflammation in Huntington’s disease

Huntington’s disease (HD) is a monogenic neurodegenerative disease characterized by abnormal motor movements, personality changes and early death. In contrast to other neurodegenerative diseases, very little is known about the role of neuroinflammation in HD. While the current data clearly demonstrate the existence of inflammatory processes in HD pathophysiology, the question of whether neuroinflammation is purely reactive or might actively participate in disease pathogenesis is currently a matter of ongoing research and debate. This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.     

The Addenbrooke’s Cognitive Examination-Revised accurately detects cognitive decline in Huntington’s disease

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington’s disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke’s Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington’s disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington’s disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington’s disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington’s disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington’s disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.     

Structural brain correlates of irritability and aggression in early manifest Huntington’s disease

Brain Imaging and Behavior - In Huntington’s disease (HD), irritability and aggressive behavior represent highly prevalent and disabling neuropsychiatric symptoms. However, their structural...     

Self-reported impulsivity in Huntington’s disease patients and relationship to executive dysfunction and reward responsiveness

Introduction: Few studies have directly investigated impulsivity in Huntington’s disease (HD) despite known changes in dopaminergic and frontal functioning, changes that have been associated with impulsivity in other disorders and in the normal population. This study sought to further categorize impulsivity in HD through examining differences in self-reported impulsivity between community controls and HD patients, the relationship between executive dysfunction and impulsivity, and the relationship of a reward/punishment behavioral inhibition task in relation to these self-report measures. It was expected that HD patients would report higher impulsivity and executive dysfunction and that these measures would relate to a reward/punishment behavioral inhibition task. Method: The Barratt Impulsivity Scale (BIS–11) and Behavioral Inhibition/Behavioral Activation Scale (BIS/BAS) were completed, and the Mini-Mental State Examination (MMSE) and a reward-based flanker task with punishing and rewarding conditions were administered to 22 HD patients and 14 control participants. Results: HD patients reported higher trait impulsivity (BIS–11) and executive dysfunction (Frontal Systems Behavior Scale, FrSBE) but not increased impulsivity on the BIS/BAS relative to controls. Higher BIS–11 scores were related to increased self-reported executive dysfunction and the attention/working memory factor of the MMSE. On a reward/punishment behavioral inhibition task, BAS was uniquely related to increased accuracy on rewarding trials of the flanker task, but was not related to punishing trials in HD patients. Conclusions: The relationships found suggest that trait impulsivity is reported higher in HD and may not be driven by altered reward evaluation and the appetitive nature of stimuli but rather by increased executive dysfunction and lack of sensitivity to punishment. Impulsivity in HD may represent a combination of trait impulsivity, altered dopaminergic circuitry, and executive dysfunction. Understanding impulsivity in HD is important as it is related to increased risk to the patient and difficult behaviors for the caregiver, and sheds light on the disease process.     

Total recognition discriminability in Huntington’s and Alzheimer’s disease

Both the original and second editions of the California Verbal Learning Test (CVLT) provide an index of total recognition discriminability (TRD) but respectively utilize nonparametric and parametric formulas to compute the index. However, the degree to which population differences in TRD may vary across applications of these nonparametric and parametric formulas has not been explored. We evaluated individuals with Huntington’s disease (HD), individuals with Alzheimer’s disease (AD), healthy middle-aged adults, and healthy older adults who were administered the CVLT–II. Yes/no recognition memory indices were generated, including raw nonparametric TRD scores (as used in CVLT–I) and raw and standardized parametric TRD scores (as used in CVLT–II), as well as false positive (FP) rates. Overall, the patient groups had significantly lower TRD scores than their comparison groups. The application of nonparametric and parametric formulas resulted in comparable effect sizes for all group comparisons on raw TRD scores. Relative to the HD group, the AD group showed comparable standardized parametric TRD scores (despite lower raw nonparametric and parametric TRD scores), whereas the previous CVLT literature has shown that standardized TRD scores are lower in AD than in HD. Possible explanations for the similarity in standardized parametric TRD scores in the HD and AD groups in the present study are discussed, with an emphasis on the importance of evaluating TRD scores in the context of other indices such as FP rates in an effort to fully capture recognition memory function using the CVLT–II.     

Alzheimer’s disease,Huntington’s disease and cancer

Neurodegenerative disorders and cancer are two of the most common groups of conditions in our world. Some studies have proposed that neurodegenerative disorders may be protective of the development of cancer.We tested this hypothesis using two neurodegenerative disorders with different molecular pathophysiology – Alzheimer’s disease (AD) and Huntington’s disease (HD) – to see if the inverse relationship between cancer and neurodegeneration was generalizable. Five-year cancer incidence was determined in two large datasets: AD using the C-Path Online Date Repository (CODR) database (n = 6383) and HD using the ENROLL-HD database (n = 2608). Cancer incidence was determined in the populations and compared to normal population data for Australia, United Kingdom and the United States of America. Age-sex standardized rates of cancer were determined and expressed as 95% confidence intervals. We describe an age-sex standardized cancer rate of 1179.6/per 100,000 population to 1253.7/per 100,000 population in normal populations.The rate in AD was 815.2/per 100,000 population (95% CI 813.32–817.5/per 100,000 population) and for HD 1296.6/per 100,000 population (95% CI 1288–1308.2/per 100,000 population).We conclude that patients with AD have a reduced age-sex standardized rate of developing cancer not shared with HD, a finding that hints at different molecular mechanisms.     

Sensory processing in Huntington’s disease

Objective

An intriguing electrophysiological feature of patients with Huntington’s disease (HD) is the delayed latency and decreased amplitude of somatosensory long-latency evoked potentials (LLeps). We investigated whether such dysfunction was associated with delayed conscious perception of the sensory stimulus.

Cell therapy in Huntington’s disease

Huntington’s disease is an autosomal dominant genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation is identified, involving an abnormal CAG expansion within thehtt gene on chromosome 4, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Thus, in addition to the search for molecular and genetic strategies to inhibit development of the disease, we still need to identify effective strategies for cellular repair in affected individuals. Aspects of the human neuropathology can be well modeled by excitotoxic or metabolic lesions in experimental animals, and in transgenic mice carrying thehtt mutation, providing the basis for testing alternative therapeutic strategies. The rationale and efficacy of alternative cell therapies are reviewed, including transplantation repair with embryonic striatal tissues, expansion and differentiation of striatal-like cells from stem cells, andin vivo andex vivo gene therapy for delivery of neuroprotective growth factor molecules. Pilot and experimental clinical trials of several approaches are now also underway, and the alternative strategies are compared.     

Drug-induced hyperthermia in Huntington’s disease

Abstract. Until now, only three patients with Huntingtons disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntingtons disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic malignant syndrome, or the serotonin syndrome. Possible contributing factors that may have been specific for HD patients could be identified and included advanced neurological disease with severe illness, occurrence in summer, with possible infectious disease, dehydration, and pre-existing extra-pyramidal signs that may mask incipient NMS/serotonin syndrome. Measures to avoid these potentially lifethreatening conditions are discussed.     

Relationship between CAG repeat length and brain volume in premanifest and early Huntington’s disease

Huntington’s disease (HD) is caused by an expanded CAG repeat on the gene encoding for the protein huntingtin. There are conflicting findings about the extent to which repeat length predicts signs of the disease or severity of disease progression in adults. This study examined the relationship between CAG repeat length and brain volume in a large cohort of pre- and post-motor onset HD gene carriers, using voxel-based morphometry (VBM), an approach which allowed us to investigate the whole brain without defining a priori regions of interest. We also used VBM to examine group differences between 20 controls, 21 premanifest, and 40 early HD subjects. In the 61 mutation-positive subjects higher CAG repeat length was significantly associated with reduced volume of the body of the caudate nucleus bilaterally, left putamen, right insula, right parahippocampal gyrus, right anterior cingulate, and right occipital lobe, after correcting for age. The group contrasts showed significant reduction in grey matter volume in the early HD group relative to controls in widespread cortical as well as subcortical areas but there was no evidence of difference between controls and premanifest subjects. Overall we have demonstrated that increased CAG repeat length is associated with atrophy in extra-striatal as well as striatal regions, which has implications for the monitoring of disease-modifying therapies in the condition. denotes equal senior author     

Bladder and bowel dysfunction in Parkinson’s disease

Summary. Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson’s disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients’ quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency. Correspondence: Ryuji Sakakibara, Sakura Medical Center, Neurology Division, Department of Internal Medicine, Toho University, 564-1 Shimoshizu, Sakura 285-8741, Japan     

Heart rate variability and falls in Huntington’s disease

Clinical Autonomic Research - Persons with Huntington's disease (HD) have a high incidence of falls. Autonomic nervous system dysfunction has been reported even in early stages of this disease....