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.

Trajectories of recovery in depressed Parkinson's disease patients treated with paroxetine or venlafaxine.

INTRODUCTION: Depression is considered a syndrome with a constellation of symptoms that are frequently categorized into 3 domains including affective, somatic and cognitive. There has been limited research into the domain specific magnitude or relative timing of treatment response in patients with Parkinson's disease (PD). In addition, antidepressant trials involving patients with PD have demonstrated a similar robust placebo response to that seen in other populations. However, the timing of the placebo response has not been carefully studied. METHODS: We studied differential responses to antidepressant treatment in affective, somatic and cognitive domains of depression. Patients were treated for twelve weeks with placebo, venlafaxine or paroxetine as part of the Study of Antidepressants in Parkinson's Disease (SAD-PD) randomized controlled trial. Depressive symptoms were evaluated with three commonly used rating scales. RESULTS: All symptom domains improved during the study period, There was a significant placebo effect, especially in the first two weeks that had diminished by week 12. Compared to placebo, the affective symptoms significantly improved during treatment as early as week 4, followed by the somatic symptoms of depression in week 6 and cognitive symptoms in week 8. The largest response was seen in the affective domain. CONCLUSION: In depressed PD patients treated with venlafaxine or paroxetine, affective symptoms improved first, followed by somatic symptoms and cognitive symptoms. These findings could guide patient counselling and increase patient compliance by informing about the expected treatment responses. The substantial placebo effect underlines the importance of a sufficiently long study period in future studies.

Pseudobulbar crying induced by stimulation in the region of the subthalamic nucleus.

We describe a case of pseudobulbar crying associated with deep brain stimulation (DBS) in the region of the subthalamic nucleus (STN). Patients with pseudobulbar crying show no other evidence of subjective feelings of depression such as dysphoria, anhedonia, or vegetative signs. This may be accompanied by other symptoms of pseudobulbar palsy and has been reported to occur with ischaemic or structural lesions in both cortical and subcortical regions of the brain. Although depression has been observed to result from DBS in the region of the STN, pseudobulbar crying has not been reported. A single patient who reported the symptoms of pseudobulbar crying after placement of an STN DBS was tested in the off DBS and on DBS conditions. The patient was tested using all four DBS lead contacts and the observations and results of the examiners were recorded. The Geriatric Depression Scale was used to evaluate for depression in all of the conditions. The patient exhibited pseudobulbar crying when on monopolar stimulation at all four lead contacts. The pseudobulbar crying resolved off stimulation. This case describes another type of affective change that may be associated with stimulation in the region of or within the STN. Clinicians should be aware of this potential complication, the importance of differentiating it from stimulation induced depression, and its response to a serotonin reuptake inhibitor, such as sertraline.

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Treatment of mania in dementia with electroconvulsive therapy.

Symptoms of mania have been given inadequate attention as a source of agitated behavior in the dementia patient. Characterized by elevation in mood or grandiosity, pressured speech, and impulsivity, mania is common among the elderly population, with a prevalence approaching 20% in some studies. Because it is so highly associated with behavioral agitation, mania has a significant impact on patient management, and can often lead to the institutionalization of difficult patients. Here we present a case series of three elderly individuals who had signs of mania in conjunction with dementia. Refractory to psychotropic medications, all were given an acute plus maintenance courses of right-unilateral electroconvulsive therapy (ECT). The patients achieved significant improvement in signs of mania and agitation, as well as in mental status scores. We conclude that a short course of ECT, followed by maintenance treatments every 2 weeks, can contribute significantly to the management of dementia patients whose behavioral agitation is associated with signs of mania.

Electroconvulsive therapy in the treatment of neuropsychiatric conditions and transcranial magnetic stimulation as a pathophysiological probe in neuropsychiatry.

It is a challenging task to review transcranial magnetic stimulation (TMS) studies in neuropsychiatric disorders alongside assessments of longstanding clinical applications of ECT as an empirical treatment. The task is challenging because TMS was developed as a probe of neural mechanisms, whereas, in marked contrast, ECT has been a clinical technique from its inception. Since the onset of modern psychopharmacology, the understanding of the potential applications of ECT to neuropsychiatric disorders is generally restricted to case reports of patients with intractable disease that have had at least a partial response to ECT. Studies of the possible efficacy of TMS in neuropsychiatric conditions have a significant advantage over ECT as the treatments are associated with less morbidity. The only serious known complication in TMS is a risk of seizures that may increase in patients with neuropsychiatric conditions such as course brain disease. Only cortical structures are themselves accessible to TMS using current technology. Present TMS techniques, however, seem capable of affecting activity in deeper brain structures that are functionally linked to cortical brain regions. TMS permits novel explorations of relationships between regional brain activity and symptoms of a number of neuropsychiatric disorders, as well as in research relating activity in functionally related brain regions to modulation of cognition and affective states in healthy individuals. This is particularly true at present because TMS and powerful neuroimaging and neuropsychological tools are all making rapid advances simultaneously.

Treatment of advanced Parkinson's disease by unilateral posterior GPi pallidotomy: 4-year results of a pilot study.

To assess the long-term outcome following unilateral pallidotomy for advanced Parkinson's disease, we performed nonblinded Core Assessment Program for Intracerebral Transplantations protocol assessments in 10 of the original 15 patients in our pilot study for 4 years following surgery. Although Unified Parkinson's Disease Rating Scale motor examination scores returned to baseline levels at 3 and 4 years, most patients continued to show sustained improvements in contralateral tremor, akinesia, and drug-induced dyskinesias. Contralateral tremor was absent at 4 years in all seven patients with preoperative tremor. Contralateral "off" arm movement times (averaged for three tasks) decreased by 37% at 1 year and by 30% at 4 years. Contralateral dyskinesia scores improved by 82% at 1 year and by 64% at 4 years. In contrast, after reaching speeds equal to the contralateral side at 1 year, ipsilateral "off" movement times increased by 13% over baseline levels at 4 years. Although most gait and postural stability measures showed modest initial improvement followed by a return to baseline values, "on" stand-walk-sit task performance declined significantly at 4 years. Despite the restriction of our surgeries to one side and the expected natural progression of Parkinson's disease, the results of patient self-assessments suggest that 4 years after unilateral pallidotomy, most patients continue to experience a quality of life above preoperative levels.

Epidemiology, etiology, and treatment of geriatric mania.

Few prospective studies have focused on elderly patients with mania, despite the rapidly aging population and the difficulties encountered in treating older patients with manic symptoms. Retrospective studies generally have found that the number of new cases of mania and the prevalence of mania in the population decrease with age, although there is evidence to contradict this widely held belief. The diagnosis of mania in the elderly is confounded by the overlap of manic symptoms with other syndromes that occur with aging, including dementia, delirium, and medical illnesses. The treatment of mania is more difficult in the elderly, and new treatments such as the atypical antipsychotics and the anticonvulsants take on a more important role in treatment regimens for older patients.

Hyperintense lesions on magnetic resonance images in bipolar disorder.

BACKGROUND: To examine the magnetic resonance (MR) images of bipolar patients across a wide age range for the presence of hyperintense lesions compared to age- and gender-matched control subjects. METHODS: Consecutive admissions to a mood disorders unit over a 2-year period were evaluated retrospectively for the presence of bipolar disorder by DSM-III-R criteria and whether they received an MR scan. Bipolar patients (n = 70, mean age = 49.9 +/- 19.7 years) were age- and gender-matched to control subjects (n = 70, mean age = 53.2 +/- 18.1 years) and the MR scans were rated to assess for the presence of hyperintensites. RESULTS: Compared to control subjects, the bipolar patients demonstrated hyperintense lesions in the subependymal region, subcortical gray nuclei, and the deep white matter. CONCLUSIONS: Hyperintense lesions in bipolar patients are found in both the subcortical white matter and gray nuclei and may play an important role in the etiology of bipolar illness.

Magnetic resonance imaging correlates of depression in early- and late-onset Alzheimer's disease.

BACKGROUND: Depressive symptoms are frequent complications of Alzheimer's disease (AD). We hypothesized that AD patients with depression would be more likely than nondepressed AD patients to show deep white-matter, subcortical gray-matter, and periventricular hyperintensities on magnetic resonance imaging (MRI). METHODS: In a retrospective study of 31 AD patients, depression was characterized by clinical diagnosis (DSM-III-R major depression, depressive symptoms, or no depression), a clinician-rated depression scale, and informant ratings of premorbid (before memory disorder) as well as current depression using the NEO Personality Inventory (NEO-PI), and related to qualitative and quantitative ratings of MRI hyperintensities. RESULTS: In contrast to reports in nondemented elderly patients, there was no relationship between clinical diagnosis of major depressive episode and hyperintensities; however, clinician-rated depressive symptoms were higher in subjects with large anterior hyperintensities. In the early-onset AD group only, MRI abnormalities were related to greater premorbid depression, and less increase in depression after the onset of dementia, as rated by informants on the NEO-PI. CONCLUSIONS: Results highlight the need to consider early- and late-onset AD separately when assessing relationships between personality and MRI abnormalities, and to consider premorbid personality style when drawing conclusions about the etiology of depressive features seen in AD.

The use of rapid-rate transcranial magnetic stimulation (rTMS) in refractory depressed patients.

Rapid-rate transcranial magnetic stimulation (rTMS) allows for the noninvasive examination of the cerebral cortex. Recent studies have begun to investigate whether rTMS may be therapeutic for the treatment of depression. In the present study, the authors report on the safety and efficacy of rTMS in treating 50 patients with refractory depression. Overall, there were 21 responders (42%). Interestingly, 56% of the young patients responded, but only 23% of the elderly patients responded to rTMS. Overall, rTMS was well tolerated in all patients. Specifically, no patient developed a new onset of seizures during rTMS. The authors discuss the extant literature on rTMS for the treatment of depression along with future areas of research.

Magnetic resonance imaging changes in putamen nuclei iron content and distribution in normal subjects.

To study patterns of iron deposition in the putamen in aging, we reviewed brain magnetic resonance imaging (MRI) scans of 56 normal subjects. We developed the Signal Hypointensity in the Putamen (SHIP) Scale, a semiquantitative measure, to evaluate putamen nuclei for extent of iron deposition relative to the globus pallidus. The SHIP score was highly reliable (kappa = 0.76) and significantly correlated with age (P < 0.0001). We found that age-related iron deposition in putamen nuclei follows a characteristic pattern along a posterolateral-to-anteromedial gradient. This gradient may be related to the microvasculature of the putamen. Other studies are needed to replicate our findings in patients with affective and other neuropsychiatric disorders and to clarify the pathophysiological mechanisms that govern these changes.

Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: 1-year results of a pilot study.

The effects of posterior internal pallidal ablation (GPi pallidotomy) on parkinsonian signs and symptoms were studied in 15 patients with medically intractable Parkinson's disease (PD). The sensorimotor territory of the internal portion of the globus pallidus and the adjacent optic tract and internal capsule were identified with microelectrode recording and stimulation. Radiofrequency lesions were then created in the identified sensorimotor territory. Pallidotomy significantly improved all cardinal parkinsonian motor signs (tremor, rigidity, akinesia/bradykinesia, and gait dysfunction) and reduced drug-induced motor fluctuations and dyskinesias. The improvements occurred predominately contralateral to the lesion, but were also present ipsilaterally. Early postoperative (3-month), mean total United Parkinson's Disease Rating Scale scores improved by 30.1% from preoperative values. Mean combined "on/off" Schwab and England Scale scores, a measure of functional independence, increased from 48.8% to 73.0% postoperatively. The mean total United Parkinson's Disease Rating Scale and Schwab and England scores did not show a statistically significant decline over the 1-year postoperative period. Surgery resulted in little morbidity, including a lack of significant deficits on neuropsychological and psychiatric testing. Physical and social functioning and vitality measures on the Medical Outcome Scale also showed significant improvement over the postoperative period. The findings of this pilot study demonstrate that ablation of the sensorimotor portion of the internal pallidum is a highly effective treatment for advanced PD, with benefits sustained at 1 year.

The diagnosis and treatment of mania in the elderly.

Mania in late life is often complicated by comorbid medical conditions, medication intolerance, and inadequate medication response. Lithium remains the primary medication in the acute and prophylactic treatment of mania in the elderly. However, certain anticonvulsants (valproic acid and carbamazepine) have a number of advantages, including a more tolerable side effect profile and increased efficacy in subgroups of patients, such as patients with secondary mania due to neurological and other medical disorders. Future research is needed to focus on the double-blind trials of somatic treatments, including ECT, in the elderly.

Alzheimer's disease in the National Academy of Sciences-National Research Council Registry of Aging Twin Veterans. III. Detection of cases, longitudinal results, and observations on twin concordance.

OBJECTIVES: To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE). SETTING: Nationwide survey. DESIGN: Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts. PARTICIPANTS: Membership in 1990-1991 of intact pairs in the National Academy of Sciences--National Research Council Registry of veteran twins, then aged 62 to 73 years. MAIN OUTCOME MEASURES: Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method. RESULTS: Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their co-twins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r = .86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no epsilon 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years. CONCLUSIONS: The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Arteriosclerotic depression.

Depression is a psychiatric syndrome seen in about 1-2% of elderly patients. When depression is seen for the first time late in life, genetic and psychosocial factors appear to be less important. Structural changes in the brain appear to be more important. In this paper the author presents the concept of arteriosclerotic depression and relates the occurrence of structural changes in the brain to atherosclerosis and the structural changes to the occurrence of depression. Evidence in support of this concept is presented.