Advance preparation of set-switches in Parkinson's disease

Eighteen patients with Parkinson's disease (PD) and 18 healthy control subjects were presented with a switching task where stimuli elicited either one (no-conflict condition) or two (conflict condition) task-relevant stimulus-response mappings. The response stimulus interval (RSI) between trials was varied to allow investigation of the extent to which participants engaged in advanced preparation of task set. In line with previous findings, set-switching deficits of PD patients were only observed in the conflict condition. Prolonging the RSI led to a reduction of switch costs for control subjects in both the conflict and the no-conflict task, whereas this effect was attenuated for PD patients in the conflict condition. This deficit was explained in terms of a reduced ability to maintain cue-action representations active in working memory in high interference conditions, and was related to the possible role of the frontostriatal circuit in maintaining focussed attention.     

Reality monitoring and visual hallucinations in Parkinson's disease

Between 8 and 40% of Parkinson disease (PD) patients will have visual hallucinations (VHs) during the course of their illness. Although cognitive impairment has been identified as a risk factor for hallucinations, more specific neuropsychological deficits underlying such phenomena have not been established. Research in psychopathology has converged to suggest that hallucinations are associated with confusion between internal representations of events and real events (i.e. impaired-source monitoring). We evaluated three groups: 17 Parkinson's patients with visual hallucinations, 20 Parkinson's patients without hallucinations and 20 age-matched controls, using tests of visual imagery, visual perception and memory, including tests of source monitoring and recollective experience. The study revealed that Parkinson's patients with hallucinations appear to have intact visual imagery processes and spatial perception. However, there were impairments in object perception and recognition memory, and poor recollection of the encoding episode in comparison to both non-hallucinating Parkinson's patients and healthy controls. Errors were especially likely to occur when encoding and retrieval cues were in different modalities. The findings raise the possibility that visual hallucinations in Parkinson's patients could stem from a combination of faulty perceptual processing of environmental stimuli, and less detailed recollection of experience combined with intact image generation.     

Intact artificial grammar learning in patients with cerebellar degeneration and advanced Parkinson's disease

In an artificial grammar learning task, subjects were asked to memorise short lists of letter strings formed according to complex rules for letter order. After an interval they were unexpectedly asked to discriminate new grammatical strings from strings which used the same letters but violated the sequential constraints of the grammar. Artificial grammar learning can be mastered successfully by amnesic patients and is considered to be an implicit learning task independent of declarative learning and memory mechanisms. In this study, 10 patients with cerebellar degeneration (CD), 21 Parkinson's disease (PD) and 15 control subjects were tested on artificial grammar learning. Additionally PD patients with advanced disease were examined under adequate medication and dopaminergic withdrawal. All patient groups showed intact artificial grammar learning. Neither cerebellar damage nor basal ganglia dysfunction nor dopaminergic medication impairs or affects artificial grammar learning. Although the patients showed significant executive dysfunction, implicit learning remains intact. The conclusion is that cerebellar and basal ganglia circuits play no essential part in this kind of implicit learning. The results suggest that artificial grammar learning is a cortically mediated function comparable to the mechanism of visual priming.     

Dissociable processing of temporal structure in repetitive eye-hand movements in Parkinson's disease

Movement takes place in multiple dimensions, including the temporal dimension, which itself may be made up of dissociable aspects. From this perspective, the present research tests three hypotheses: first, that the generation of regular, repetitive movement frequency is neurophysiologically dissociable from the generation of appropriate phase relations, or latencies, of such movements with respect to external stimuli; second, that the frontostriatal system is critically involved in the control of latency and not frequency and third that while the control of latency is closely linked to the effector motor system (e.g. eye, hand, etc.) the control of movement frequency is a more centralized function.These three hypotheses were investigated in nine Parkinson's disease (PD) patients with asymmetric akinetic-rigid syndrome and in nine age-matched control subjects in the context of repetitive eye-hand movements generated in response to regularly displaced visual stimuli and then the continuation of these movements in the immediate absence of the stimuli. PD patients demonstrated increased latencies for pointing movements, particularly with the affected hand, while their ability to follow and then reproduce the movement frequency remained largely intact. Interestingly, saccade latency was improved for controls and PD patients when pointing with the Less-affected hand and impaired with the More-affected hand. In contrast, saccade frequency was unaffected in these pointing conditions. These results support the hypothesis that movement frequency and latency controls are dissociable, with the frontostriatal system playing an important role in latency but not frequency control. The fact that pointing and saccade latency displayed a hand-effect, while movement frequency did not, also tends to support the hypothesis that latency control is linked to specific motor systems, including their interaction, whereas frequency control is more centralized.     

Space-based but not object-based inhibition of return is impaired in Parkinson's disease

Impairments in certain aspects of attention have frequently been reported in Parkinson's disease (PD), including reduced inhibition of return (IOR). Recent evidence suggests that IOR can occur when attention is directed at objects or locations, but previous investigations of IOR in PD have not systematically compared these two frames of reference. The present study compared the performance of 18 nondemented patients with PD and 18 normal controls on an IOR task with two conditions. In the “object-present” condition, objects surrounded the cues and targets so that attention was cued to both a spatial location and to a specific object. In the “object-absent” condition, surrounding objects were not presented so that attention was cued only to a spatial location. When participants had to rely on space-based cues, PD patients demonstrated reduced IOR compared to controls. In contrast, when objects were present in the display and participants could use object-based cues, PD patients exhibited normal IOR. These results suggest that PD patients are impaired in inhibitory aspects of space-based attention, but are able to overcome this impairment when their attention can be directed at object-based frames of reference. This dissociation supports the view that space-based and object-based components of attention involve distinct neurocognitive processes.     

Spatial learning in a virtual reality-based task is altered in very preterm children

Very preterm births prevent a complete development of the nervous system. The hippocampus is especially vulnerable in this population since the perinatal period is critical for its growth and development. Learning and memory abilities, like spatial memory, depend on the hippocampal integrity. In this study we applied virtual-reality-based tasks to assess spatial memory in a sample of 20 very preterm children of 7 and 8 years of age. Two different conditions of difficulty were used. Very preterm children performed poorly in the task in comparison with the control group. They committed more errors than controls searching for the rewarded positions. However, no significant differences were observed in the mean speed, an index of the motor abilities and joystick handling. These results suggest that the hippocampal function is affected in this sample. Nevertheless, other variables to consider are discussed.     

Learning of ambiguous versus hybrid sequences by patients with Parkinson's disease

Implicit motor learning as indexed by the serial reaction time (SRT) task has been shown to be impaired in patients with Parkinson's disease (PD). This has only been conclusively demonstrated for sequences that require learning of second-order sequential information (ambiguous sequences). This study examines implicit learning of ambiguous sequences as well as sequences which contain first-order information (hybrid sequences) in a sample of 12 early to middle stage Parkinson's disease patients and matched controls. The study used dual-task methodology in order to prevent strategic/attentional learning of second-order information. The results showed that while ambiguous sequences were not learned by either group, both patient and control groups demonstrated learning of the hybrid sequence under dual-task conditions. This suggests that first-order associations may be learned by people with Parkinson's disease, even under attentionally demanding conditions. This may be interpreted as providing evidence for a non-attentional learning mechanism which is relatively intact in Parkinson's disease.     

Protective effect of melatonin in a chronic experimental model of Parkinson's disease

Parkinson's disease is a chronic condition characterized by cell death of dopaminergic neurons mainly in the substantia nigra. Among the several experimental models used in mice for the study of Parkinson's disease 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced parkinsonism is perhaps the most commonly used. This neurotoxin has classically been applied acutely or sub-acutely to animals. In this paper we use a chronic experimental model for the study of Parkinson's disease where a low dose (15 mg/kg bw) of MPTP was administered during 35 days to mice to induce nigral cell death in a non-acute way thus emulating the chronic condition of the disease in humans. Free radical damage has been implicated in the origin of this degeneration. We found that the antioxidant melatonin (500 microg/kg bw) prevents cell death as well as the damage induced by chronic administration of MPTP measured as number of nigral cells, tyrosine hydroxylase levels, and several ultra-structural features. Melatonin, which easily passes the blood-brain barrier and lacks of any relevant side-effect, is proposed as a potential therapy agent to prevent the disease and/or its progression.     

Cognitive changes in prodromal Parkinson's disease: A review

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at‐risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society     

Subjective memory decline in Parkinson's disease patients with and without fatigue

IntroductionPrevious studies on Parkinson's disease (PD) have shown that memory complaints and fatigue co-occur since premotor stages of disease, but whether Subjective Memory Decline (SMD, defined as memory complaints with normal objective cognitive performance) and fatigue were associated in PD has not been explored yet.MethodsOne-hundred PD patients underwent measures of memory complaints (Multifactorial Memory Questionnaire, MMQ), neuropsychological test (Parkinson's Disease-Cognitive Rating Scale), and assessment of behavioural symptoms. Fatigue was diagnosed according to current diagnostic criteria. Mann-Whitney test or Pearson chi-square test were used to compare fatigued and nonfatigued patients for prevalence of SMD and for demographic, clinical, and behavioural features, memory complaint, and objective cognitive measures. The confounding effect of sample's features on results was controlled by logistic regression and Quade's rank analysis.ResultsTwenty-three patients were diagnosed as fatigued whereas 15 patients met SMD criteria. Fatigued patients showed higher levodopa equivalent daily dose and more marked behavioural symptoms than nonfatigued patients (p_s < 0.01). The prevalence of SMD was higher in fatigued patients than in those nonfatigued (35% vs 9%, p < 0.01). After controlling for confounds, the patients with fatigue had an odds ratio for SMD 5.97 [CI 95%, 1.18–30.03] times higher and presented significantly lower scores on Contentment subscales of MMQ (p < 0.01) than those without fatigue.ConclusionFatigue in PD is associated with SMD mainly characterized by less contentment with one's own memory ability. These findings suggest possible shared pathogenic mechanisms underlying these two nonmotor manifestations and foster to identify potential phenotypes of patients requiring multistrategic therapeutic approaches.     

Facial expression recognition in people with medicated and unmedicated Parkinson's disease

Recognition of facial expressions of emotion was investigated in people with medicated and unmedicated Parkinson's disease (PD) and matched controls (unmedicated PD, n=16; medicated PD, n=20; controls, n=40). Participants in the medicated group showed some visual impairment (impaired contrast sensitivity) and performed less well on perception of unfamiliar face identity, but did not show significant deficits in the perception of sex, gaze direction, or familiar identity from the face. For both Parkinson's disease groups, there was evidence of impaired recognition of facial expressions in comparison to controls. These deficits were more consistently noted in the unmedicated group, who were also found to perform worse than the medicated group at recognising disgust from prototypical facial expressions, and at recognising anger and disgust in computer-manipulated images. Although both Parkinson's disease groups showed impairments of facial expression recognition, the consistently worse recognition of disgust in the unmedicated group is consistent with the hypothesis from previous studies that brain regions modulated by dopaminergic neurons are involved in the recognition of disgust.     

Spatial learning deficits in Parkinson's disease with and without mild cognitive impairment

BackgroundSeveral MRI studies have demonstrated hippocampal atrophy in Parkinson's disease (PD), a structure considered a key element in spatial learning. Despite this, no study has been undertaken to investigate spatial navigation in PD using a virtual version of the Morris water maze, which is the gold standard for testing hippocampal function in rodents.MethodsWe studied 17 cognitively unimpaired PD patients, 12 PD patients with mild cognitive impairment (MCI) and 15 controls in a virtual water maze procedure.ResultsMeasured by the main outcome parameters latency to locate the target and heading error (average difference between direction of movement toward anticipated target and real direction toward the target), controls performed significantly better on the virtual water maze task than cognitively unimpaired PD patients or PD patients with MCI, while there was no significant difference between latter two groups.ConclusionsThe virtual water maze test differentiates PD patients from controls, but does not distinguish between cognitively normal and cognitively impaired PD patients, indicating a possible dopamine dependent component in spatial learning. Spatial performance deficits might thus constitute very early signs of dopamine depletion independent of the presence of MCI in Parkinson's disease.     

Visual inspection time in Parkinson's disease: deficits in early stages of cognitive processing

Inspection time (IT) is a simple information processing paradigm dependent on a participant's ability to identify physical properties of a stimulus presented for a specified time interval. In contrast with reaction time (RT) studies, the dependent variable of interest in IT is not related to the motoric speed with which the individual is able to respond, but rather the minimum presentation time necessary for participants to reliably identify physical properties of the stimulus. It is well documented that individuals with Parkinson's disease (PD) experience significant impairment on tests of simple RT, but it is unclear whether such deficits can be interpreted as 'pure' slowness of information processing, or a delay in the selection and output of a motor response. In the first experiment described here, a sample of 'optimally medicated' PD patients was compared with an age-matched control group, on an IT task. Results of this experiment suggested that individuals with PD required significantly longer stimulus presentation times than healthy participants. The second experiment compared a sample of PD patients (tested both "ON" and "OFF" their typical dopaminergic medications), with an age-matched control group, on the same test of IT. Results again indicated a significant IT deficit in participants with PD, and suggested that these deficits do not significantly resolve with levodopa treatment. Overall, the results of these two experiments suggest that information processing deficits associated with PD are distinct from motor impairment. These findings are further discussed in terms of existing neurochemical models of information processing ability.     

Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease

Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.     

Impaired intentional content learning but spared incidental retention of contextual information in non-demented patients with Parkinson's disease

We investigated the incidental and intentional learning performance of 29 patients with idiopathic Parkinson's disease (PD) and 20 healthy volunteers. Measures of incidental and intentional memory were assessed with a spoken verbal recall task followed by a temporal word order task, a picture recall task followed by a spatial picture location task, and a written word recall task followed by a judgement of word frequency task. A multivariate analysis of variance and appropriate post hoc tests revealed significant differences for all intentional learning variables. In all cases, PD patients performed worse than normal controls. No group differences were found for the incidental retention of contextual information. The results indicate that PD patients have a selective problem of intentional learning, whereas incidental learning of contextual information remains intact. Elaborate processing, attentional and organizing strategies in the systematic encoding, and recollection of information have been attributed to dorsolateral prefrontal activation. Preferential dysfunction of dorsolateral prefrontal cortex-associated memory processes is consistent with the previously reported uneven patterns of dopamine loss in the striatum of patients with idiopathic PD showing most severe dopamine depletion in the portion of the caudate nucleus that is anatomically connected to the dorsolateral frontal cortex.     

Disruptive influences of a cued voluntary shift on coordinated movement in Parkinson's disease

A temporary and/or involuntary stoppage of movement is identifiable in the execution phase of writing, walking, and turning movements in individuals with Parkinson's disease (PD) and may be referred to as freezing. However, the unpredictability of such akinetic impairments has made it difficult to study experimentally. The present study compared PD and age-matched control groups in their ability to coordinate continuous and simultaneous upper limb movements in trials involving two parts. In the first part of each trial, participants performed either in-phase movements (symmetric, simultaneous movement toward and away from the midline of the body), or anti-phase movements (isodirectional). At the midpoint of the trial, they were signaled by an auditory metronome to execute an intentional and voluntarily switch from the coordination currently being performed to the opposite coordination pattern. In the second half of the trial participants were required to maintain performance in the other coordination mode. All trials were paced by an auditory metronome at one of three different speeds (0.75, 1.25, 1.75 Hz). Measures of temporal coordination (relative phase) indicated that overall, participants with PD required significantly longer periods of time to achieve a switch between coordination patterns compared to healthy controls, and experienced greater difficulty changing from the in-phase to anti-phase mode of coordination. As well, movement stoppage was observed in 53.9% of the in-phase to anti-phase switch trials, but in only 15.5% of the anti-phase to in-phase trials. We conclude that interruptions to movement execution are most common when switching to coordinated movements that impose greater motor demands in individuals with PD.     

Comparison of dementia with Lewy bodies to Alzheimer's disease and Parkinson's disease with dementia.

We compared the clinical and neuropsychological pattern of dementia with Lewy bodies (DLB) to Alzheimer's disease (AD) and Parkinson's disease with dementia (PD-d). Sixteen patients clinically diagnosed with DLB were compared with two groups of patients with PD-d (n = 15) and AD (n = 16) matched for level of dementia. Isolated cognitive impairment was the most common form of presentation in AD (93.8%) and DLB (31.3%) groups, while parkinsonism was in 100% of PD-d subjects. Psychoses associated with cognitive impairment at the beginning of the disease were more frequent in DLB patients (31.3%) than in AD (6.3%) and PD-d (0%) groups. There were no significant differences in Unified Parkinson Disease Rating Scale motor-subscale scores between DLB and PD-d patients. DLB and PD-d patients performed significantly worse on attentional functions and better on memory tests than AD. DLB patients also showed lower scores than AD subjects on visual memory, visuoperceptive, and visuoconstructive tests. No significant differences were found between PD-d group and DLB subjects on any neuropsychological test. We were unable to find any differences in cognitive tasks between PD-d and DLB subjects. Clinical features and neuropsychological deficiencies of DLB (attentional, visuoperceptive, and visuoconstructive deficits) and PD (attentional deficits) compared to AD (amnesic syndrome) can contribute to accurate identification of these entities and to the understanding of the neuropathological and neurochemical substrate underlying these diseases.     

Transiently impaired neurogenesis in MPTP mouse model of Parkinson's disease

It is still being debated whether neurogenesis in the subventricular zone (SVZ) is enhanced in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injury in the adult mouse brain. Our previous studies provided evidence that MPTP induces apoptosis of migrating neuroblasts (neural progenitor cells, A cells) in the SVZ and rostral migratory stream (RMS). We investigated cellular kinetics in the adult SVZ and olfactory bulb (OB) after MPTP damage. Cells were labeled with bromodeoxyuridine (BrdU), and the effects of MPTP on the survival and fate of migrating and residing neuroblasts were evaluated. Two days after BrdU labeling and MPTP treatment, the number of BrdU-positive cells in the SVZ and OB of MPTP-treated mice was significantly lower than in the SVZ and OB of saline controls. Additionally, fewer BrdU-positive cells migrated to the OB of treated mice than to that of saline controls, and the cells that did migrate diffused radially into the granule cell layer (GCL) when observed at 7, 14, and 28 days. In the OB GCL, the differentiation of BrdU-positive cells into mature neurons significantly attenuated 14 and 28 days after MPTP injury. Moreover, the impaired neurogenesis was followed by a recovery of A cells in the SVZ and OB, suggesting activation of the self-repair process as a result of MPTP-induced depletion of BrdU-positive cells. Our findings clarify the kinetics underlying neurogenesis in MPTP-treated mice and may contribute to the development of an animal model of Parkinson's disease, and the demonstration of cellular kinetics in SVZ may also provide a new insight into assessing neurogenesis in MPTP-treated mouse.     

Risk factors for Parkinson's disease and impaired olfaction in relatives of patients with Parkinson's disease.

Our objective was to assess the association between risk factors for Parkinson's disease (PD) and abnormal olfaction in first-degree relatives of patients with PD. Factors including lower cigarette smoking and lower caffeine consumption have been associated with increased risk of PD. Idiopathic hyposmia has also been associated with an increased risk of PD. The relationship between risk factors for PD and impaired olfactory function has not been evaluated in relatives of PD patients. We conducted a mail survey of odor identification ability in 173 first-degree relatives of PD patients using the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Respondents also completed a questionnaire inquiring about risk factors for PD including caffeine consumption, tobacco use, exercise, and exposures to heavy metals, well-water, and pesticides. There was a direct relationship between olfactory performance and lifetime caffeine intake. After adjustment for age, gender, and smoking status, subjects who reported drinking 2 to 3 cups of caffeinated beverages per day (2.6 points higher 95% CI: 0.5, 4.5) and 4 or more cups per day (3.7 points higher, 95% CI: 0.6, 6.7) had significantly better UPSIT scores than those who consumed less than 1 cup per day. There was no significant relationship between olfactory performance and other risk factors. In conclusion, abnormal olfaction is associated with significantly lower lifetime caffeine consumption in first-degree relatives of PD patients. Further research is warranted to determine whether a history of lower caffeine consumption confers additional risk for the development of PD in hyposmic relatives of PD patients.