Laura Marsh

Diagnostic criteria for psychosis in Parkinson's disease: Report of an NINDS, NIMH work group

There are no standardized diagnostic criteria for psychosis associated with Parkinsons disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV‐TR. PDPsy has a well‐characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinsons disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Age-related decline in MRI volumes of temporal lobe gray matter but not hippocampus

The effect of normal aging on the volume of the hippocampus and temporal cortex was assessed cross-sectionally with quantitative Magnetic Resonance Imaging (MRI) in 72 healthy men, spanning 5 decades of the adult age range (21 to 70 years). Neither the hippocampal nor cortical white matter volumes were significantly correlated with age. By contrast, left and right temporal lobe gray matter volumes, exclusive of the hippocampal measures, each decreased with age (p < 0.01). Volumes of temporal lobe sulcal CSF and the ventricular system (temporal horns and lateral and third ventricles) significantly increased with age. Measures of verbal and nonverbal working memory showed age-related declines and were related to enlargement of the three ventricular regions, which may be indicative of age-related atrophy of the adjacent cortex but not the hippocampus, at least up to age 70 years.

Provisional diagnostic criteria for depression in Parkinson's disease: Report of an NINDS/NIMH Work Group

Mood disorders are the most common psychiatric problem associated with Parkinsons disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH‐sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD‐associated depression.

Volumetric MRI assessment of temporal lobe structures in schizophrenia

This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

Fatigue in Parkinson's disease: A review

Fatigue is a common problem in Parkinsons disease (PD), often the most troubling of all symptoms. It is poorly understood, generally under‐recognized, and has no known treatment. This article reviews what is known about the symptom, putting it into the context of fatigue in other disorders, and outlines a program for developing better understanding and therapy.

The impact of depressive symptoms in early Parkinson disease

Background: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. Methods: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. Results: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). Conclusions: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease

Objective: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). Methods: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. Results: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. Conclusions: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. Classification of Evidence: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Cortical and Hippocampal Volume Deficits in Temporal Lobe Epilepsy

Summary: Purpose: To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization‐related epilepsy of temporal lobe origin (TLE).

Cognitive performance of GBA mutation carriers with early-onset PD The CORE-PD study

Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration–matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. Results: Demographics, UPSIT, and Unified Parkinsons Disease Rating Scale–III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). Conclusion: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged.

Event-related potentials (ERPs) and brain magnetic resonance images (MRIs) were acquired from 28 normal men, age 21-60 years. ERPs were recorded during 3 paradigms designed to elicit automatic or effortful attention, and a combination of both. MRI-derived measures of brain gray matter, white matter and cerebral spinal fluid (CSF) volumes were computed from frontal, parietal and temporal lobes. P300 amplitude correlated significantly with gray matter volumes but not with white matter or CSF volumes. Furthermore, the relationships between P300 amplitude and gray matter volumes reflected functional rather than direct topographical relationships: P300 recorded at Pz during automatically elicited attention correlated significantly with frontal but not parietal lobe gray matter volumes, P300 recorded during effortful attention correlated significantly with parietal but not frontal lobe gray matter volumes, and P300 recorded when both types of attention were invoked correlated significantly with both frontal and parietal gray matter volumes. Startle blinks, also elicited during automatic attention-engaging paradigms, were significantly correlated with frontal but not parietal lobe gray matter volumes. There was no evidence for a direct spatial relationship between P300 amplitude and the gray matter volumes underlying the recording electrode.