Seminars in clinical neuropsychiatry最新文献

Alzheimer's disease is a clinical syndrome reflecting the topography and rate of progression of amyloid-associated cell death and dysfunction. Abnormal processing of amyloid precursor protein or enhanced accumulation of brain amyloid incites multiple pathogenetic pathway including inflammation, oxidation, and tau protein hyperphosphorylation that lead to neuronal death. The molecular biology of Alzheimer's disease provides insight into the clinical phenotype. The steps of the amyloid cascade present multiple targets for drug development and identification of effective disease-modifying anti-Alzheimer's disease treatments.

The search for "reversible causes" in the patient presenting with dementia has become a routine part of medical care. This article reviews evidence as to the prevalence of reversibility and concludes that actual reversal of dementia by treatment is rare. In this context, the utility of specific laboratory investigations is discussed, and commonly sought conditions, such as normal-pressure hydrocephalus and B12 deficiency, are reviewed. Overemphasis on reversibility risks neglect of the assistance physicians can provide to patients suffering from irreversible conditions and their families.

This 2-part review of the frontotemporal lobar degeneration (FTLD) begins with an outline of clinical features, which differentiate FTLD from Alzheimer's disease, the more common cause of dementia. The second part describes interventions for FTLD. Although there is currently no disease-modifying therapeutic agent, symptomatic pharmacotherapy helps to control the marked mood and behavioral disturbances that may distinguish this syndrome from other causes of dementia.

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive neurodegenerative disorders that affect both animals and humans. These diseases take part of their name from a striking and common neuropathological feature: spongiform ("sponge-like") degeneration of the brain. As the name also implies, TSEs can literally be transmitted from one host to another much like any other infectious disease. In these situations, however, symptoms may take months or years to appear in the recipient host. Otherwise, TSEs either develop spontaneously or rarely arise through genetic mutation and therefore occur as familial disorders. Regardless of their origin, all TSEs progress over a period of months inevitably leading to the death of the affected individual. From a neuropsychiatric perspective, it is notable that the newly identified variant form of Creutzfeldt-Jakob disease (vCJD) typically occurs in younger adults causing prominent psychiatric and/or behavioral abnormalities as important early manifestations of disease. This has forced a heightened awareness of vCJD among mental health professionals throughout the United Kingdom where the disorder occurs. Relevant features of both the classic and variant forms of Creutzfeldt-Jakob disease (CJD) will be reviewed.

Continuing advances in neuroimaging technology as well as postmortem examinations have enabled researchers to begin to accumulate substantial evidence suggesting that chronic mood disorders may be associated with actual structural and neurochemical changes within the brain. There is emerging evidence to suggest that various treatment modalities may also induce measurable changes within the brain detectable with specialized neuroimaging techniques, which may be responsible for their clinical therapeutic effects. One such specialized neuroimaging technique, magnetic resonance spectroscopy (MRS), is briefly reviewed. Included is an overview of basic MRS technology and a review of its application in the study of chronic mood disorders to date. We review our recent studies investigating neurochemical changes induced by the mood stabilizer, lithium, in the treatment of bipolar disorder (BPD). Finally, in view of accumulating evidence suggesting a neuronal atrophy and cell death hypothesis for depression, we discuss the potential use of MRS to evaluate pharmacologic interventions for important potential neurotrophic and neuroprotective effects on the adult human brain.

In new, exciting, neuroanatomic studies on postmortem tissues from patients with mood disorders, quantitative cytomorphologic differences can be shown at the microscopic level. These investigations provide direct evidence that mood disorders are characterized by marked reductions in glial cell number and density in addition to subtle alterations in the density and size of cortical neurons in frontolimbic brain regions. Importantly, this corresponds with clinical neuroimaging studies and preclinical animal studies that suggest cell atrophy, cell loss, or impairments in neuroplasticity and cellular resilience may underlie the neurobiology of major depressive disorder and bipolar manic-depressive disorder. Because this represents a departure from modern efforts to understand mood disorders, published reports are scarce and based on rather small sample sizes. This article reviews the current findings from postmortem studies on glial and neuronal cell counts in primary mood disorders and discusses a possible link between cellular changes and the action of psychotherapeutic drugs.

Advances in understanding the functional and structural anatomy of depression outlined in this issue set the stage for attempting to manipulate implicated brain regions as potential antidepressant therapies. On the one hand, these circuit- and device-based approaches to treating depression are not new. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry with the discovery and rapid increase of first chemical (around 1910), and then later ECT. On the other hand, this area represents an important paradigm shift with treatments that are radical and different. A dizzying array of diverse technologies now allows researchers to stimulate the brain in undreamed of ways. However, the approaches described in this article are still considered experimental and are not approved for use in the United States by the Food and Drug Administration (FDA), except ECT, which predates the FDA. These device-based approaches to brain stimulation offer promise as potential acute and even longterm treatments. Additionally, the research determining whether and how these devices work to influence mood promises to help unravel the neurophysiology of mood regulation. These novel treatments are thus the translational tools to bridge from advances in brain imaging, into new treatments for depressed patients.

Of potential importance to the development and testing of novel and more effective antidepressant therapies is the noninvasive characterization of requisite brain changes mediating depression remission. A further clinical goal is the identification of pretreatment markers that might eventually inform optimal treatment selection. Toward these objectives, functional neuroimaging studies have described resting-state glucose metabolic and blood flow abnormalities in cortical, subcortical, and limbic regions, including changes with various antidepressant treatments. There is, however, variability in both site and direction of changes across published reports. In this article, a cortical-limbic network model of depression is used to explain this variability. In this approach, network dysfunction combined with ongoing intrinsic compensatory processes is seen to explain the heterogeneity of depressive symptoms observed clinically, as well as variations in pretreatment scan patterns. Furthermore, the synchronized modulation of these dysfunctional cortical-limbic pathways is considered critical for illness remission, regardless of treatment modality. Formal testing of disease-specific and response-specific functional interactions among regions in this depression network using multivariate approaches are discussed, with a perspective aimed at future studies examining treatment nonresponse, relapse risk, and disease vulnerability.