The role of neurotransmitters in the development of Parkinson's disease-related psychosis.

Psychotic symptoms are common, disabling non-motor features of Parkinson's disease (PD). Despite noted heterogeneity in clinical features, natural history and therapy response, current dogma posits that psychosis generally progresses in a stereotypic manner through a cascade of events that begins with minor hallucinations and evolves to severe hallucinations and delusions. Further, the occurrence of psychotic symptoms is believed to indicate a poor prognosis. Here we propose a classification scheme that outlines the pathogenesis of psychosis as it relates to dysfunction of several neurotransmitter systems. We hypothesize that several subtypes exist, and that PD psychosis is not consistently indicative of a progressive cascade and poor prognosis. The literature was reviewed from 1990 to 2017. An overview of the features of PD psychosis is followed by a review of data indicating the existence of neurotransmitter-related subtypes of psychosis. We found that ample evidence exists to demonstrate the presence of multiple subtypes of PD psychosis, which are traced to dysfunction of the following neurotransmitter systems: dopamine, serotonin and acetylcholine. Dysfunction of each of these systems is recognizable through their clinical features and correlates, and the varied long-term prognoses. Identifying which neurotransmitter system is dysfunctional may help to develop targeted therapies. PD psychosis has various subtypes that differ in clinical features, underlying pathology and pathophysiology, treatment response and prognosis. A novel classification scheme is presented that describes the clinical subtypes with different outcomes, which could lead to the development of targeted therapies. Future research should focus on testing the viability of this classification.

Cerebrospinal fluid biomarkers in Parkinson's disease with freezing of gait: an exploratory analysis.

We explore the association between three Alzheimer's disease-related and ten inflammation-related CSF markers and freezing of gait (FOG) in patients with Parkinson's disease (PD). The study population includes PD patients with FOG (PD-FOG, N = 12), without FOG (PD-NoFOG, N = 19), and healthy controls (HC, N = 12). Age and PD duration are not significantly different between groups. After adjusting for covariates and multiple comparisons, the anti-inflammatory marker, fractalkine, is significantly decreased in the PD groups compared to HC (P = 0.002), and further decreased in PD-FOG compared to PD-NoFOG (P = 0.007). The Alzheimer's disease-related protein, Aß42, is increased in PD-FOG compared to PD-NoFOG and HC (P = 0.001). Group differences obtained in individual biomarker analyses are confirmed with multivariate discriminant partial least squares regression (P < 0.001). High levels of Aß42 in PD-FOG patients supports an increase over time from early to advanced state. Low levels of fractalkine might suggest anti-inflammatory effect. These findings warrant replication.

Use of a novel technology for presenting screening measures to detect mild cognitive impairment in elderly patients.

BACKGROUND: Available screening tools for mild cognitive impairment (MCI), often a precursor to Alzheimer's disease, are insensitive or not feasible for administration in a busy primary care setting. Display Enhanced TEsting for Cognitive impairment and Traumatic brain injury (DETECT) addresses these issues by creating an immersive environment for the brief administration of neuropsychological (NP) measures. OBJECTIVE: The aim of this study was to determine if the DETECT cognitive subtests can identify MCI patients as accurately as standard pen and paper NP tests. METHODS: Twenty patients with MCI recruited from a memory disorders clinic and 20 age-matched controls were given both a full battery of NP tests (standard NP) and the DETECT screen. Logistic regression models were used to determine whether individual tests were predictive of group membership (MCI or control). Demographic variables including age, race, education and gender were adjusted as covariates. Selection methods were used to identify subset models that exhibited maximum discrimination between MCI patients and controls for both testing methods. RESULTS: Both the standard NP model (C-index = 0.836) and the DETECT model (C-index = 0.865) showed very good discrimination and were not significantly different (p = 0.7323). CONCLUSION: The DETECT system shows good agreement with standard NP tests and is capable of identifying elderly patients with cognitive impairment.

Diet as a Risk Factor for Cognitive Decline in African Americans and Caucasians with a Parental History of Alzheimer's Disease: A Cross-Sectional Pilot Study Dietary Patterns.

BACKGROUND: African Americans (AA) are more likely to develop Alzheimer's disease (AD) than Caucasians (CC). Dietary modification may have the potential to reduce the risk of developing AD. OBJECTIVE: The objective of this study is to investigate the relationship between Southern and Prudent diet patterns and cognitive performance in individuals at risk for developing AD. DESIGN: Cross-sectional observational study. PARTICIPANTS: Sixty-six cognitively normal AA and CC individuals aged 46-77 years with a parental history of AD were enrolled. MEASUREMENTS: Participants completed a Food Frequency questionnaire, cognitive function testing, which consisted of 8 neuropsychological tests, and cardiovascular risk factor assessments, including evaluation of microvascular and macrovascular function and ambulatory blood pressure monitoring. RESULTS: Results revealed a relationship between the Southern diet and worse cognitive performance among AAs. AAs who consumed pies, mashed potatoes, tea, and sugar drinks showed worse cognitive performance (p<0.05) compared with CCs. In addition, gravy (p=0.06) and cooking oil/fat (p=0.06) showed negative trends with cognitive performance in AAs. In both CC and AA adults, greater adherence to a Prudent dietary pattern was associated with better cognitive outcomes. Cardiovascular results show that participants are overall healthy. AAs and CCs did not differ on any vascular measure including BP, arterial stiffness and endothelial function. CONCLUSION: Research shows that dietary factors can associate with cognitive outcomes. This preliminary cross-sectional study suggests that foods characteristic of the Southern and Prudent diets may have differential effects on cognitive function in middle-aged individuals at high risk for AD. Results suggest that diet could be a non-pharmaceutical tool to reduce cognitive decline in racially diverse populations. It is possible that the increased prevalence of AD in AA could be partially reduced via diet modification.

The DETECT system: portable, reduced-length neuropsychological testing for mild traumatic brain injury via a novel immersive environment.

Undiagnosed mild traumatic brain injury (mTBI) often leads to poor patient management and significant morbidity. The lack of an efficient screening tool is especially apparent in the athletic setting, where repetitive injuries can lead to prolonged disability. We have developed the Display Enhanced Testing for Concussions and mTBI system (DETECT), in order to create a portable immersive environment that could eliminate visual and audio distractions. Neuropsychological tests sensitive to mTBI were modified for use with the system and allow rapid neurological assessment independent of the environment or trained personnel. We evaluated the immersive qualities of the DETECT system in 42 uninjured controls. The system was successful in blocking out external audiovisual stimuli. The neuropsychological test results obtained in a stimulus rich environment were equivalent to those obtained in a controlled quiet environment. The immersive environment, portability, and brevity of the DETECT system allow for real-time cognitive testing in situations previously deemed impractical or unavailable for mTBI patients.

Gist recall in multiple sclerosis.

This study examined gist recall (memory for important story ideas) in patients with multiple sclerosis. Twelve patients with clinically probable or definite multiple sclerosis and 10 neurologically intact control subjects were read prose passages from the Wechsler Memory Scale-Revised Logical Memory subtest. The idea units from these passages contained low, medium, and high information content to the stories. In comparison with the control subjects, the patients recalled fewer total elements over immediate and delayed conditions. However, similar to controls, they recalled more ideas that were of high rather than low or medium importance. These results suggest that semantic sensitivity to important ideas of narratives is a relatively preserved feature in multiple sclerosis.

Treatment trial of oxiracetam in Alzheimer's disease.

Twenty-four carefully assessed patients with probable Alzheimer's disease were enrolled in a double-blind, placebo-controlled treatment study of oxiracetam, a nootropic agent reported to improve memory performance in patients with dementia. A broad battery of neuropsychological tests failed to reveal any improvement in the treated group or in any treated patient when individual test scores were analyzed. These findings indicate that oxiracetam is ineffective in reducing cognitive impairment due to Alzheimer's disease.

Apolipoprotein E and age at onset of Alzheimer's disease in African American patients.

The authors examined whether the APOE-epsilon4 allele is associated with an earlier age at onset of AD in 71 African American patients with probable AD. The authors found a linear dose effect in which each copy of the epsilon4 allele was associated with a 3.6-year earlier onset of AD, indicating a dose-dependent relationship between APOE-epsilon4 and age at onset of AD in African Americans.

Functional outcome of cognitively impaired hip fracture patients on a geriatric rehabilitation unit.

OBJECTIVES: To compare outcomes (physical functions and discharge destinations) of cognitively impaired and intact older hip fracture patients, and to identify cognitive skills related to functional gains. DESIGN: Prospective longitudinal study of hip fracture patients treated on an acute inpatient rehabilitation service, with evaluation of functional performance and living status determined at admission and discharge. SETTING: A specialized inpatient geriatric rehabilitation program at Wesley Woods Geriatric Hospital, which is affiliated with Emory University School of Medicine. SUBJECTS: Fifty-eight hip fracture patients, 35 with and 23 without cognitive impairment. MEASUREMENTS: Cognitive functioning measured by the Mattis Dementia Rating Scale (MDRS); functional outcome assessed by the Functional Independence Measure (FIM); comparison of pre-fracture with discharge living environments. MAIN RESULTS: Both cognitively impaired and intact hip fracture patients exhibited similar overall FIM motor improvements as well as functional gains in specific FIM areas measuring self-care, sphincter control, and locomotion (e.g., walking). Cognitively intact patients, however, displayed significantly greater gains in mobility (e.g., transfers) at discharge. Cognitively impaired patients who lived in the community were as likely as intact patients to return to the community. Patients who entered the program at a modified dependence level (FIM 3-5) and achieved motor independence at discharge (FIM 6-7) had higher MDRS initiation/ perseveration and memory scores. CONCLUSIONS: Hip fracture patients with cognitive impairments can achieve positive outcomes as defined by functional improvement and discharge destination. Intensive post-fracture rehabilitation in the early phase of recovery may promote functional independence and a return to the community for older patients at risk for nursing home placement. Future research should examine the long-term maintenance of these improvements and explore how rehabilitation interventions can be altered to enhance outcome.

Infantile right hemisphere injury: a case report with MRI and 13 year follow-up.

Serial neuropsychological findings were obtained in a case of infantile right parietal injury who was studied over a 13 year follow-up period. Magnetic resonance imaging at age 13 years documented extensive injury to the right hemisphere, particularly the parietal region. Serial examinations at age 7 and 13 years showed intact visual attention, normal expression and processing of affect and variable visuospatial abilities. However, intellectual development was generally depressed. Implications of these findings for recovery from early brain injury are discussed.

Memory enhancement for emotional stimuli is impaired in early Alzheimer's disease.

Emotional arousal is associated with enhanced memory in neurologically intact individuals, but it is unknown whether this effect is obtained in Alzheimer's disease (AD). The current study compared emotional memory and emotional reactions in patients with early AD and in older controls. Participants viewed emotionally arousing (both pleasant and unpleasant) and neutral photographs while cognitive and electrophysiological reactions were assessed. Memory was tested by free recall and recognition. Emotional reactions were normal in the AD group, but the emotional memory effect (enhanced memory for emotional vs. neutral stimuli) was impaired. Recall results indicated that this effect was normal for pleasant stimuli but abnormal for unpleasant stimuli. These results suggest that the neural basis for the emotional memory effect may be disrupted in AD. Findings are discussed in terms of the role of the amygdala in mediating emotional memory.

The mere exposure effect in patients with Alzheimer's disease.

The mere exposure effect was examined in patients with mild to moderate Alzheimer's disease (AD). Twenty patients and 20 elderly controls judged the physical characteristics of faces. Implicit memory was tested later by presenting pairs of faces (old and new) and asking participants which faces they liked better. Patients and controls exhibited above chance preference for previously exposed faces. Experiment 2 evaluated whether the preserved implicit memory of patients was mediated by explicit memory. Patients and controls again judged faces but then later chose which faces they had seen before. Patients exhibited impaired recognition memory compared to controls. These findings suggest that a mere exposure effect for unfamiliar faces is present in mild to moderate AD. The results are discussed in terms of perceptual and conceptual priming and relatively spared occipital lobe functioning in early AD.

Conceptual encoding following severe closed head injury.

This investigation examined whether survivors of severe closed head injury encode semantic properties of to-be-remembered words and the relationship of such processing to frontal lobe functioning. Fourteen patients enrolled in rehabilitation and 12 controls were administered the Release from Proactive Inhibition paradigm involving trials of recalling words from the same category followed by a shift to a new category or continued presentation of identical material. Similar to the controls, patients demonstrated a facilitation in recall when the category shifted. An association between the amount of release and frontal lobe functioning (as evaluated by neuropsychological tests and magnetic resonance imaging) was not compelling and depended upon the particular measure of release that was utilized. Pending replication in a larger, more representative sample, we suggest that conceptual encoding is relatively preserved in long-term survivors. The failure to find a robust relationship between frontal lobe pathology and semantic encoding is discussed in light of other investigations suggesting an association.

Hemispheric disconnection syndrome persisting after anterior cerebral artery aneurysm rupture.

Hemispheric disconnection syndrome is a rarely reported sequela of aneurysm rupture. Serial neurobehavioral examinations of such a patient after clipping of a right pericallosal artery that had bled into a large portion of the corpus callosum disclosed defects in interhemispheric transfer of information and competitive movements between the left and right extremities. Although the patient's postoperative memory deficit subsequently resolved, his disconnection syndrome persisted and was primarily responsible for his disability despite otherwise normal neurological findings. We studied a second patient with a hematoma in the genu of the corpus callosum secondary to an arteriovenous malformation (AVM). Although the second patient also exhibited postoperative memory problems, her hemispheric disconnection symptoms were minimal and commensurate with a more circumscribed corpus callosum lesion. Neurobehavioral sequelae of aneurysm or AVM rupture involving the anterior circulation, which may be overlooked in the absence of a detailed examination, can produce persistent disability in many patients.

Memory functioning during the first year after closed head injury in children and adolescents.

Effects of the severity of closed head injury (CHI) on verbal learning and memory and visual recognition memory were studied at base line and on a 1-year follow-up examination in 58 pediatric admissions sampled from three age ranges, 6-8, 9-12, and 13-15 years. Within each age range, recovery of memory was compared in patients with mild to moderate CHI and survivors of severe injury. Consistent with previous findings obtained in head-injured children sampled from a wide age range, the present study confirms that memory deficit persists at least 1 year after severe CHI. Impairment of visual recognition memory was directly related to severity of CHI in all three age ranges. The severity of CHI was directly related to initial and residual verbal memory deficit in adolescents, but this effect was inconsistent in children. We suggest that the cerebral substrate for visual recognition memory was well established in all three age ranges and thus was vulnerable to the effects of injury. In contrast, verbal memory skills were undergoing rapid development in the adolescents, but were still immature in children. Extended follow-up could conceivably demonstrate the late appearance of verbal memory deficit in the children who had apparent sparing of function.

Dysnomia in Alzheimer's disease: an evaluation of neurobehavioral subtypes.

The relative influence of perceptual and semantic features on naming performance was investigated with reference to the neurobehavioral profiles displayed by patients with Alzheimer's disease (AD). Forty-one patients were classified as manifesting a verbal, visual, or global subtype based upon their pattern of neuropsychological functioning. Perceptual characteristics of to-be-named pictures were varied by manipulating the amount of line detail, whereas semantic qualities were varied by altering word frequency norms. All AD subtypes were less accurate than normal elderly controls in naming low frequency pictures. Patients and controls took longer to name low frequency and high complexity pictures, and this effect was comparable across the AD groups. Patients with predominantly visual deficits were significantly slower in naming than controls, and those with verbal impairments made a higher proportion of semantic naming errors when compared to patients displaying visual or severe global impairments. These results suggest that deficits in semantic processing contribute to naming dysfunction in AD, and they highlight the importance of examining dissociations among neurobehavioral subtypes.

Neurobehavioral and magnetic resonance imaging findings in two cases of decompression sickness.

Two divers underwent neurobehavioral examinations and magnetic resonance imaging (MRI) while hospitalized during the first 2 weeks after sustaining decompression sickness (DCS). Their neurologic findings included a Brown-Séquard Syndrome consistent with spinal cord lesion, and focal deficits consistent with cerebral lesion(s). MRI revealed subcortical white matter lesions in the brains of both divers, whereas no lesion of the spinal cord was demonstrated. The patients exhibited neurobehavioral sequelae including disturbances of memory, divergent thinking, and visuospatial and motor functioning. Focal neurologic deficits resolved in both patients, and their cognitive and memory problems improved slowly. Findings in these two divers raise the possibility that cerebral insult more frequently accompanies spinal cord injury in DCS than previously thought.

Freezing of gait subtypes have different cognitive correlates in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major concern for Parkinson's disease (PD) patients because it is a leading cause of falls and is associated with poor quality of life. The pathophysiology is unknown but it is hypothesized that it relates to cognitive abnormalities; particularly executive and visuospatial dysfunction. However, prior results have been discrepant. Pharmacologic subtypes of FOG include those that are responsive and unresponsive to levodopa. OBJECTIVE: To determine whether executive and visuospatial dysfunction are associated specifically with the levodopa unresponsive subtype of FOG. METHODS: 135 PD subjects completed a single assessment included FOG questionnaire, UPDRS motor scale, comprehensive cognitive battery and measure of hallucinations. Analyses compared unresponsive (n = 16), responsive (n = 20) and no FOG (n = 99) subtypes. RESULTS: The unresponsive subtype had a significantly older age of onset of PD than the responsive group (p = .03) and had worse motor scores (p = .003) than the no FOG group. Longer disease duration was associated with the responsive group compared to the no FOG group (p = .002). The unresponsive FOG group had significantly poorer visuospatial ability (p = .001) and executive functioning (p = .02) than both the no and responsive FOG subgroups. These latter groups were not significantly different. The responsive FOG group was associated with the presence of hallucinations. CONCLUSION: Aside from pharmacological differences, unresponsive FOG is associated with executive and visuospatial dysfunction implicating frontostriatal pathways while responsive FOG is associated with hallucinations suggesting involvement of posterior cortical regions. Further study and treatment of FOG should include appropriate subtype classification.