Paradoxical effect of dopamine medication on cognition in Parkinson's disease: relationship to side of motor onset.

Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n = 36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n = 42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing.

Improved function after combined physical and mental practice after stroke: a case of hemiparesis and apraxia.

This study describes change in functional performance and self-perception after participation in combined training with physical practice followed by mental practice. The patient was a 44-yr-old white man who experienced a single left ischemic stroke 7 mo before enrollment in the study. He engaged in physical and mental practice of two functional tasks: (1) reaching for and grasping a cup and (2) turning pages in a book with the more-affected arm. Practice took place 3 times per week during 60-min sessions for 6 consecutive wk. Primary outcome measures were the Arm Motor Ability Test (AMAT) and the Canadian Occupational Performance Measure (COPM). An abbreviated version of the Florida Apraxia Battery gesture-to-verbal command test approximated severity of ideomotor apraxia. After intervention, the patient demonstrated increased functional performance (AMAT) and self-perception of performance (COPM) despite persistent ideomotor apraxia. The results of this single-case report indicate functional benefit from traditional rehabilitation techniques despite comorbid, persisting ideomotor apraxia.

Dopaminergic modulation of the planning phase of skill acquisition in Parkinson's disease.

Patients with Parkinson's disease (PD) are often impaired when performing motor acts and in the acquisition of new motor skills. However, the role of dopamine in developing plans for skill acquisition is unclear. To assess the role of dopamine on the planning of actions, we tested 12 PD and 12 matched normal participants on two skill acquisition tasks matched for motor demands, but varying in requirements for planning. The participants with PD were tested on these tasks when they were on and off dopaminergic medications. To minimize influence of movement related deficits, the subjects used a computer track-pointer that generated the required straight lines when the subjects applied a slight force and clicked the track-pointer to initiate and terminate each line segment. The amount of time the track-pointer was deflected determined the line lengths, while clicking of the mouse determined the location of the line. The simple figure replication task only required the subjects to repeatedly generate lines of two sizes, while the complex figure replication task required subjects to generate lines of different sizes. Thus, this complex task demanded more anticipatory planning. Compared to controls, the subjects with PD were slower to learn the programs needed to produce these figures and produced figures with reduced amplitudes on both the simple and complex tasks. Dopamine treatment, however, only improved the speed of figure completion on the complex task, suggesting that dopamine is important in action planning.

Functional Magnetic Resonance Imaging Biomarkers Predicting Cognitive Progression in Parkinson Disease: Protocol for a Prospective Longitudinal Cohort Study.

BACKGROUND: Cardinal features of Parkinson disease (PD) are motor symptoms, but nonmotor features such as mild cognitive impairment (MCI) are common early in the disease process. MCI can progress and convert to dementia in advanced stages, creating significant disability and reduced quality of life. The primary pathological substrate for cognitive decline in PD is unclear, and there are no reliable biomarkers predicting the risk of conversion to dementia. A subgroup of PD patients with visual hallucinations may display more rapid conversion to dementia, suggesting that regional markers of visuoperceptual dysfunction may be sensitive to pathologic density in posterior cortical regions. OBJECTIVE: The purpose of this project is to characterize PD-MCI and evaluate the utility of genetic and neuroimaging biomarkers in predicting cognitive outcomes with a prospective longitudinal study. We will evaluate whether accelerated cognitive progression may be reflected in biomarkers of early posterior cortical changes reflective of α-synuclein deposition. METHODS: We will evaluate a cohort of early-stage PD patients with the following methods to predict cognitive progression: (1) serial neuropsychological evaluations including detailed visuoperceptual functioning across 4 years; (2) genetic analysis of SNCA (α-synuclein), MAPT (microtubule-associated tau), and APOE (apolipoprotein E); (3) an event-related functional magnetic resonance imaging paradigm of object recognition memory; and (4) anatomical and regional brain activation changes (resting-state functional magnetic resonance imaging) across 4 years. RESULTS: The project received funding from the National Institutes of Health in August 2017, and data collection began in February 2018. Enrollment is ongoing, and subjects will be evaluated annually for 4 years extended across a 5-year project including data analysis and image processing. CONCLUSIONS: Cognitive, genetic, and structural and functional magnetic resonance imaging will characterize neural network changes predictive of cognitive progression in PD across 4 years. Identification of biomarkers with sensitivity for early prediction and estimation of risk for conversion to dementia in PD will pave the way for effective intervention with neuroprotective therapies during the critical stage when treatment can have the greatest impact. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12870.

Audiovisual Lexical Retrieval Deficits Following Left Hemisphere Stroke.

Binding sensory features of multiple modalities of what we hear and see allows formation of a coherent percept to access semantics. Previous work on object naming has focused on visual confrontation naming with limited research in nonverbal auditory or multisensory processing. To investigate neural substrates and sensory effects of lexical retrieval, we evaluated healthy adults (n = 118) and left hemisphere stroke patients (LHD, n = 42) in naming manipulable objects across auditory (sound), visual (picture), and multisensory (audiovisual) conditions. LHD patients were divided into cortical, cortical⁻subcortical, or subcortical lesions (CO, CO⁻SC, SC), and specific lesion location investigated in a predictive model. Subjects produced lower accuracy in auditory naming relative to other conditions. Controls demonstrated greater naming accuracy and faster reaction times across all conditions compared to LHD patients. Naming across conditions was most severely impaired in CO patients. Both auditory and visual naming accuracy were impacted by temporal lobe involvement, although auditory naming was sensitive to lesions extending subcortically. Only controls demonstrated significant improvement over visual naming with the addition of auditory cues (i.e., multisensory condition). Results support overlapping neural networks for visual and auditory modalities related to semantic integration in lexical retrieval and temporal lobe involvement, while multisensory integration was impacted by both occipital and temporal lobe lesion involvement. The findings support modality specificity in naming and suggest that auditory naming is mediated by a distributed cortical⁻subcortical network overlapping with networks mediating spatiotemporal aspects of skilled movements producing sound.

Response shift - The experience of disease progression in Parkinson disease.

OBJECTIVE: To investigate response shift, the recalibration of perceived quality of life (QoL) relative to symptomatic changes in Parkinson disease (PD). BACKGROUND: Health-related QoL in PD is influenced by improvement vs. decline in disease severity. However, it is unclear how disease course changes internal standards of QoL over time. METHODS: 124 PD patients were subdivided based on Total UPDRS change over 1 year (stable, improved, declined). The EuroQol Visual Analog Scale assessed QoL at baseline (T1) and 1 year later (T2). At T2, patients rated current QoL (T2-current) and reappraised their T1 QoL (T2-retrospective). Recalibration response shifts were represented by the difference between T1 and T2-retrospective QoL ratings. RESULTS: At follow-up (T2), the total patient sample reported no difference between current (T2 current mean (M) = 76.3) and retrospective (T2-R M = 77.8) QoL ratings. While there was no significant difference between T1 (M = 79.2) and T2-R ratings 1 year later (M = 77.8) for the total sample, there was a change by group interaction (p < 0.005) which showed that retrospectively, decliners reduced ratings (M Δ = -9.0) and improvers increased ratings (M Δ = +6.4) while stable patients did not change. CONCLUSIONS: When PD patients consider their health status one year ago, decliners recalibrate and downgrade last year's health assessment, while improvers upgrade last year's assessment. Changes in internal calibrations cushion periods of decline or improvement in PD such that patients tend to "stabilize" their general disease course when recalling symptom trajectory, providing insight into the process of adaptation to the effects of disease progression and treatment over time.

Variability in the anatomy of the planum temporale and posterior ascending ramus: do right- and left handers differ?

The anatomy of the planum temporale (PT) and posterior ascending ramus (PAR) was studied in vivo in 67 healthy right- and left-handed adults using MRI-based morphometry. The left PT was significantly larger than the right, and there was a weakly significant effect of the right PAR larger than the left. A leftward PT asymmetry was found in 72%, and a rightward PAR asymmetry was found in 64% of the sample. The "typical" configuration of a larger left PT and larger right PAR co-occurred in 56% of the subjects studied, which was only slightly more often than predicted by chance. Eight of 67 subjects had "reversed" PT and PAR asymmetries, with consistent left and mixed handers over-represented in this group. Right PAR size was the only variable that predicted writing hand, and left PT size was the only measure that differed by sex. The left PT was expanded relative to the left PAR in 93% of the sample, suggesting that this configuration may be developmentally regulated and may be a critical substrate for the development of language. These findings demonstrate that important relationships exist between hand preference, and the anatomy of posterior cortical language areas.

Predictors of mild cognitive impairment in early-stage Parkinson's disease.

AIM: The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles. METHODS: Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states. RESULTS: Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state. CONCLUSION: Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD.

Recent and past musical activity predicts cognitive aging variability: direct comparison with general lifestyle activities.

Studies evaluating the impact of modifiable lifestyle factors on cognition offer potential insights into sources of cognitive aging variability. Recently, we reported an association between extent of musical instrumental practice throughout the life span (greater than 10 years) on preserved cognitive functioning in advanced age. These findings raise the question of whether there are training-induced brain changes in musicians that can transfer to non-musical cognitive abilities to allow for compensation of age-related cognitive declines. However, because of the relationship between engagement in general lifestyle activities and preserved cognition, it remains unclear whether these findings are specifically driven by musical training or the types of individuals likely to engage in greater activities in general. The current study controlled for general activity level in evaluating cognition between musicians and nomusicians. Also, the timing of engagement (age of acquisition, past versus recent) was assessed in predictive models of successful cognitive aging. Seventy age and education matched older musicians (>10 years) and non-musicians (ages 59-80) were evaluated on neuropsychological tests and general lifestyle activities. Musicians scored higher on tests of phonemic fluency, verbal working memory, verbal immediate recall, visuospatial judgment, and motor dexterity, but did not differ in other general leisure activities. Partition analyses were conducted on significant cognitive measures to determine aspects of musical training predictive of enhanced cognition. The first partition analysis revealed education best predicted visuospatial functions in musicians, followed by recent musical engagement which offset low education. In the second partition analysis, early age of musical acquisition (<9 years) predicted enhanced verbal working memory in musicians, while analyses for other measures were not predictive. Recent and past musical activity, but not general lifestyle activities, predicted variability across both verbal and visuospatial domains in aging. These findings are suggestive of different use-dependent adaptation periods depending on cognitive domain. Furthermore, they imply that early age of musical acquisition, sustained and maintained during advanced age, may enhance cognitive functions and buffer age and education influences.

The relation between instrumental musical activity and cognitive aging.

OBJECTIVE: Intensive repetitive musical practice can lead to bilateral cortical reorganization. However, whether musical sensorimotor and cognitive abilities transfer to nonmusical cognitive abilities that are maintained throughout the life span is unclear. In an attempt to identify modifiable lifestyle factors that may potentially enhance successful aging, we evaluated the association between musical instrumental participation and cognitive aging. METHOD: Seventy older healthy adults (ages 60-83) varying in musical activity completed a comprehensive neuropsychological battery. The groups (nonmusicians, low and high activity musicians) were matched on age, education, history of physical exercise, while musicians were matched on age of instrumental acquisition and formal years of musical training. Musicians were classified in the low (1-9 years) or high (>10 years) activity group based on years of musical experience throughout their life span. RESULTS: The results of this preliminary study revealed that participants with at least 10 years of musical experience (high activity musicians) had better performance in nonverbal memory (η2 = .106), naming (η2 = .103), and executive processes (η2 = .131) in advanced age relative to nonmusicians. Several regression analyses evaluated how years of musical activity, age of acquisition, type of musical training, and other variables predicted cognitive performance. CONCLUSIONS: These correlational results suggest a strong predictive effect of high musical activity throughout the life span on preserved cognitive functioning in advanced age. A discussion of how musical participation may enhance cognitive aging is provided along with other alternative explanations.

Age-related deficits in auditory confrontation naming.

The naming of manipulable objects in older and younger adults was evaluated across auditory, visual, and multisensory conditions. Older adults were less accurate and slower in naming across conditions, and all subjects were more impaired and slower to name action sounds than pictures or audiovisual combinations. Moreover, there was a sensory by age group interaction, revealing lower accuracy and increased latencies in auditory naming for older adults unrelated to hearing insensitivity but modest improvement to multisensory cues. These findings support age-related deficits in object action naming and suggest that auditory confrontation naming may be more sensitive than visual naming.