Cognitive and behavioral assessment in the early stages of neurodegenerative extrapyramidal syndromes

Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration Syndrome (CBDS) are the most common neurodegenerative extrapyramidal syndromes. Beyond motor symptoms, cognitive dysfunctions and behavioral disturbances are reported. Neuropsychological and neuropsychiatry features in the early stages, however, are under-investigated, and few comparison studies are available yet. The aim of the present study was to evaluate the cognitive and behavioral profile in the early stages of neurodegenerative extrapyramidal syndromes. Thirty-nine PD, 27 DLB, 16 CBDS, and 24 PSP were recruited. Groups were matched for global cognitive and motor impairment. The overall sample showed a common neuropsychological core characterized by visuospatial deficits. Although in the early stage of the disease, a high presence of behavioral disturbances was detected, depression and anxiety were the most common disorders, followed by apathy and sleep disturbances. The observation of overlapping clinical entities points the attention on the need of adjunctive diagnostic markers for early differential diagnosis.     

Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population

OBJECTIVES: To evaluate the prevalence of silent stroke and its associated consequences on physical, cognitive, and emotional functioning in an elderly population. DESIGN: Population-based cross-sectional survey. SETTING: The Memory and Morbidity in Augsburg Elderly project in the Augsburg region of southern Germany. PARTICIPANTS: Two hundred sixty-seven community-dwelling persons aged 65 to 83. MEASUREMENTS: The presence of silent stroke was determined using magnetic resonance imaging brain scan and a single question asking for physician-diagnosed stroke in each participant. The health effect of silent stroke was assessed using rating scales for self-perceived health status (36-item short-form health survey), activities of daily living (ADLs) and instrumental ADLs, cognitive function, and depression (Center for Epidemiologic Studies Depression scale). RESULTS: Just fewer than 13% (12.7%) of participants were affected by silent stroke. Silent stroke was associated with a history of hypertension, heart surgery, and elevated C-reactive protein. Individuals with silent stroke showed impairments on the Mini-Mental State Examination test and in the cognitive domains of memory, procedural speed, and motor performance. CONCLUSION: The presence of silent stroke has a considerable effect on cognitive performance in those affected. Determining the presence of silent stroke using brain imaging may contribute to identifying individuals at risk for developing gradual neurological deficits.     

CNS dysfunction in the antiphospholipid syndrome

Though many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in this disease. We review clinical data obtained from a large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white matter disease and behavioral changes in APS or linked to laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with beta2-glycoprotein I, a central autoantigen in APS, which induces persistent high levels of aPL. These mice develop hyperactive behavior after a period of four to five months as well as deficits in learning and memory and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. Another model we have developed, in which IgG from APS patients induce depolarization of brain synaptoneurosomes, may serve as a model for the pathogenesis of epilepsy in APS.     

Peginterferon with or without ribavirin has minimal effect on quality of life, behavioral/emotional, and cognitive outcomes in children

The aim of this study was to prospectively assess the quality of life (QOL), behavioral/emotional functioning, and cognitive status of children undergoing treatment for hepatitis C virus (HCV) infection. In all, 114 children (5 to 18 years old) enrolled in a multisite randomized clinical trial (Peds-C) to evaluate peginterferon alpha 2a (PEG 2a) with ribavirin (RV) or with placebo (PL) completed several standardized measures prior to treatment and at 24 weeks, 48 weeks, 6 months following treatment, and at two annual follow-up visits. After 24 weeks of treatment, mean physical QOL scores declined significantly for both groups from baseline to 24 weeks of treatment (F = 5.8, P = 0.004), although scores remained in the average range. There were no significant time or group effects for behavioral/emotional or cognitive functioning. Three children (5%) in the PEG 2a + RV group and no children in the PEG 2a + PL group had a clinically significant increase in depression symptoms. For those children who received 48 weeks of treatment, there were no significant time or group effects on any of the outcome measures (P > 0.05). A majority of children in both the PEG 2a + RV and PEG 2a + PL groups experienced no clinically significant change in physical QOL, behavioral adjustment, depression, or cognitive functioning during or after treatment. CONCLUSION: Overall QOL and psychosocial functioning are not deleteriously impacted by PEG 2a + RV or PL treatment of children with HCV.     

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer��s disease model

In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.     

Association of anti-ribosomal P protein antibodies with neuropsychiatric and other manifestations of systemic lupus erythematosus

The objective of our study was to determine the prevalence of neuropsychiatric manifestations and anti-ribosomal P antibodies (aRP) in SLE and to examine the diagnostic utility and associations of aRP with neuropsychiatric and other disease manifestations. Thirty two consecutive SLE patients, diagnosed according to the updated 1997 ACR criteria, were studied. A full medical history, rheumatological, neurological, psychiatric examination, and psychometric evaluation, including a battery of tests for cognitive dysfunction and the Symptom Checklist-90-Revised depression and anxiety scales were administered to all patients. Disease activity was scored using the SLEDAI. Neuropsychiatric manifestations were diagnosed and categorized according to the 1999 ACR case definitions for 19 NPSLE syndromes. Laboratory and serologic tests including ANA, anti-ds DNA, anti-cardiolipin antibodies (aCL) and aRP (ELISA) were also carried out. Twenty six (81.2%) patients had one or more NP manifestations. Depression (59.4%), headache (46.9%) and cognitive dysfunction (37.5%) were the commonest NPSLE syndromes. Other less commonly detected manifestations included seizures, anxiety, acute confusional state, stroke, and psychosis. aRP was positive in seven (21.9%) patients, all of whom had one or more NPSLE syndromes. Patients with psychiatric manifestations in general and mood disorders in particular had significantly higher mean titers of aRP than patients without these disorders (p < 0.05). aRP were found to be significantly associated with a younger age at the onset of SLE, with more severe articular manifestations and with the presence but not the severity of depression. aRP were highly specific for NPSLE and depression, and they were highly sensitive for psychosis. Neuropsychiatric manifestations are found in 81.2% of unselected Egyptian SLE patients. The presence of aRP antibodies positively predicts patients with psychiatric manifestations in general and mood disorders in particular, for which aRP is specific, but not sensitive. However, aRP is sensitive for psychosis, so that its absence in patients with SLE may help exclude Lupus psychosis. The authors have no conflicts of interest or disclosures.     

Emotional Disturbances after Stroke

Impairment after stroke may have acute and long-lasting psychological implications. Additionally, organic brain dysfunction also appears to play an important role in poststroke affective modifications. Emotional state is multidetermined and can be specifically modified by alteration of some brain networks. This article illustrates a certain number of acute and more chronic emotional disturbances after stroke, such as mood disorders, emotional dyscontrol, and modification of emotional experiences. Some neural mechanisms implicated in these modifications are discussed. The main modifications described are depression anxiety, psychosis, modification of emotional experience, and fatigue.     

Emotional disturbances after stroke

Impairment after stroke may have acute and long-lasting psychological implications. Additionally, organic brain dysfunction also appears to play an important role in poststroke affective modifications. Emotional state is multidetermined and can be specifically modified by alteration of some brain networks. This article illustrates a certain number of acute and more chronic emotional disturbances after stroke, such as mood disorders, emotional dyscontrol, and modification of emotional experiences. Some neural mechanisms implicated in these modifications are discussed. The main modifications described are depression anxiety, psychosis, modification of emotional experience, and fatigue.     

Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment

Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N-methyl-D-aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stress-induced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.     

Cognitive and Psycholologic Considerations in Pediatric Heart Failure

Because children with heart failure live longer both before and after cardiac transplantation, there is renewed focus on the quality and preservation of their intellectual functioning and psychosocial health. Children with chronic heart failure are at risk for delays in both cognitive development and psychologic functioning, though the extent and permanence of impairment is not well understood. Children with medically managed heart failure have been shown to be at increased risk for anxiety and depression, with a prevalence of emotional disorders similar to that of other children with congenital heart disease. The use of ventricular assist devices as a bridge to transplantation offers both risks and benefits for the preservation of intellectual and emotional function, with an increased risk for ischemic injury to the brain, but offers the advantage of allowing for cognitive stimulation and improved social interactions. A new population of children with heart failure, those outfitted with permanent ventricular assist devices in lieu of cardiac transplantation, may represent a particular risk group regarding social and cognitive function, but as of yet this is not well studied. Early intervention and school accommodations are recommended for those with cognitive, social, or emotional deficits, and brain imaging should be considered for those with persistent difficulties. Whenever possible, patients should be referred to psychologists and developmental specialists with experience in treating this patient population.     

Stroke and cognition

Several studies confirm cognitive impairment and dementia to be increased after stroke in the elderly. Although not necessarily involving memory deficits, the frequency of cognitive impairments may occur in up to 30% of stroke survivors at 3 months. This impairment may be confounded by preexisting cognitive decline or dementia. By contrast, cognitive changes and dementia are widely recognized in familial forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Several factors, including type of stroke, recurrent episodes, the site and laterality of the lesion(s), volume of cerebral infarction, medial temporal lobe atrophy, and coexistent neurodegenerative pathology predict the degree of impairment. Aphasia, diabetes mellitus, atrial fibrillation, and depression are listed among other biologic factors that further exacerbate cognition and affect long-term survival. There is no clear consensus whether genetic factors, such as the apolipoprotein E ε4 allele or angiotensin converting enzyme gene polymorphisms, modify cognitive changes or stroke outcome. Although several neurotransmitter systems may be affected in post-stroke dementia, the amelioration of cholinergic function is a worthy target.     

Neuropsychiatric assessment of Alzheimer's disease and related dementias.

Alzheimer's disease (AD) patients exhibit a variety of behavioral alterations including agitation, apathy, depression, anxiety, delusions, irritability and disinhibition. Most patients with AD exhibit neuropsychiatric symptoms, and behavioral changes become more frequent with advancing disease severity. The NPI is a valid and reliable means of assessing neuropsychiatric symptoms in patients with dementia. The NPI correlates with increasing disability in activities of daily living and increasing cognitive impairment. Physical illness contributes little to behavioral symptoms measured by the NPI. Reduced frontal lobe metabolism and perfusion have been identified in patients with apathy, agitation, psychosis and depression. Patients with elevated agitation scores on the NPI have a higher burden of frontal lobe neurofibrillary tangles than patients without agitation. The NPI is sensitive to behavioral improvements following treatment with cholinesterase inhibitors and psychotropic agents. Neuropsychiatric symptom profiles differ among dementia syndromes, and the NPI provides a means of assessing neuropsychiatric symptoms that may aid in differential diagnosis. Evaluation of neuropsychiatric symptoms is a critical aspect of dementia diagnosis and management.     

The stress response and the regulation of inflammatory disease.

The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.     

Diagnosing cognitive dysfunction in the elderly: primary screening tests.

The recognition of cognitive disturbances in geriatric patients has important clinical implications for the primary care physician. Commonly seen cognitive dysfunctions include dementia, pseudodementia, delirium, and frontal lobe syndrome; these may be confounded by overlapping depression. The cognitive examination covers such intellectual and behavioral functions as attention, memory, and language. As many psychiatric disorders result from neurologic brain disease, a psychiatric examination is essential. Mental status questionnaires are useful for screening of high-risk populations for dementia and to quantify the degree of cognitive dysfunction for purposes of management planning and surveillance.     

The Blood–Brain Barrier: Geriatric Relevance of a Critical Brain–Body Interface

The blood–brain barrier (BBB) represents the interface between the brain and other body tissues. Its ability to protect the brain from harmful compounds has attracted the attention of clinicians and investigators, but far from being a simple physical barrier, the BBB is a complex, heterogeneous, and dynamic tissue. The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells (BMECs), cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity. Based on the published literature, this study proposes that age‐ and disease‐related BBB alterations play a key role in diminishing the ability of older patients to recover from acute ischemic stroke. Evidence linking deficits in the cerebral microvasculature and BBB integrity to dementia, medication‐related cognitive decline, white matter disease (WMD or leukoaraiosis), and related geriatric syndromes including delirium, gait disorders, and urinary incontinence is also reviewed. Priority areas for a future research agenda include strategies to improve clinicians' ability to diagnose, prevent, and manage BBB abnormalities. In future years, in vivo measures such as functional and contrast‐enhanced neuroimaging will be used to evaluate BBB integrity in older adults while also assessing the effectiveness of interventions, some targeting inflammatory pathways known to disrupt the BBB, for their ability to prevent or slow the progression of these complex multifactorial geriatric syndromes.     

Prenatal alcohol exposure affects frontal-striatal BOLD response during inhibitory control

BACKGROUND: Prenatal alcohol exposure can lead to widespread cognitive impairment and behavioral dysregulation, including deficits in attention and response inhibition. This study characterized the neural substrates underlying the disinhibited behavioral profile of individuals with fetal alcohol spectrum disorders (FASD). METHODS: Children and adolescents (ages 8-18) with (n=13) and without (n=9) histories of heavy prenatal alcohol exposure underwent functional magnetic resonance imaging while performing a response inhibition (go/no-go) task. RESULTS: Despite similar task performance (mean response latency, performance accuracy, and signal detection), blood oxygen level-dependent (BOLD) response patterns differed by group. Region-of-interest analyses revealed that during portions of the behavioral task that required response inhibition, alcohol-exposed participants showed greater BOLD response across prefrontal cortical regions (including the left medial and right middle frontal gyri), while they showed less right caudate nucleus activation, compared with control participants. CONCLUSIONS: These data provide an account of response inhibition-related brain functioning in youth with FASD. Furthermore, results suggest that the frontal-striatal circuitry thought to mediate inhibitory control is sensitive to alcohol teratogenesis.     

Apathy in Alzheimer's disease

Apathy, or loss of motivation, is arguably the most common change in behavior in Alzheimer's disease (AD) but is underrecognized. Apathy represents a form of executive cognitive dysfunction. Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks. Despite the profound effects of this common syndrome, only a few instruments have been designed to specifically assess apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of ability due to cognitive decline. Although apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome. Distinguishing apathy from depression has important treatment implications, because these disorders respond to different interventions. Further research is required to clarify the specific neuroanatomical and neuropsychological correlates of apathy and to determine how correct diagnosis and treatment of apathy may improve patient functioning and ease caregiver burden.     

Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease

Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Aß plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Aß or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.     

Activation of memory circuits during cue-elicited cocaine craving.

Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.     

Cognitive Correlates of Single Neuron Activity in Task-Performing Animals: Application to Ethanol Research

The deleterious effects of ethanol on cognitive processes result from an interaction between ethanol and the neural structures that are critical for executing those cognitive functions. Results from studies that employ contemporary behavioral neuroscience techniques are beginning to elucidate the neural circuits that underlie specific cognitive processes, and the stage is set for rigorous investigations into the neural basis for ethanol-induced cognitive impairments. In this article, the application of single neuron recording techniques to the study of the memory and attentional deficits produced by acute exposure to low levels of ethanol are described, with an emphasis on the advantages of combining physiological techniques with operant behavioral procedures in rats. After reviewing background information on the basic neurophysiological and behavioral techniques, empirical results from this laboratory will be used to illustrate how single-unit analysis can be applied to the study of ethanol-induced cognitive impairments.