Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease.

BACKGROUND: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid ß-protein (Aß) deposits. METHODS: Burden, distribution, cellular layer, and structure of retinal Aß plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS: Histological examination uncovered classical and neuritic-like Aß deposits with increased retinal Aß42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aß plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aß assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

Alzheimer abnormalities of the amygdala with Klüver-Bucy syndrome symptoms: an amygdaloid variant of Alzheimer disease.

BACKGROUND: Neurofibrillary tangles and beta-amyloid plaques have been observed in the amygdala in Alzheimer disease. A disproportionate abundance of this abnormality in the amygdala may cause behavioral symptoms similar to Klüver-Bucy syndrome. OBJECTIVES: To describe an atypical behavioral presentation of Alzheimer disease and to review the literature on the subject. DESIGN: Case study. SETTING: Outpatient specialty clinic. PATIENT: A 70-year-old man with progressive behavioral symptoms of hyperorality, hypersexuality, hypermetamorphosis, visual agnosia, hyperphagia, and apathy who died at age 77 of asphyxiation on a foreign object. MAIN OUTCOME MEASURES: Clinical symptomatology, brain imaging, and neuropathology. RESULTS: The pathologic diagnosis was Alzheimer disease with abundant tangles and plaques in the lateral amygdala. CONCLUSIONS: This case represents a variant of Alzheimer disease with prominent amygdala abnormalities and a Klüver-Bucy phenotype that was misdiagnosed as frontotemporal dementia. Clinical and imaging findings that may aid in accurate diagnosis are reviewed.

Neuropsychiatric update: neuroimaging schizophrenia.

Neuroimaging has revitalized the quest for the neurobiology of schizophrenia. The various neuroimaging modalities used in research are described including CT, MRI, PET, SPECT, fMRI, and DTI. Prominent and consistent neuroanatomical findings in the neuroimaging literature of schizophrenia are outlined. These findings, including enlargement of the lateral ventricles, undersized superior temporal gyrus, and prefrontal abnormalities, are supported with neuropathological studies of schizophrenia. Additionally, these findings are correlated with the clinical symptoms of schizophrenia. Neurochemical imaging studies of schizophrenia are reviewed and noted to support dopaminergic dysregulation consistent with the dopamine hypothesis. Finally, current and near-future clinical uses of neuroimaging are described.

AMYLOID CLEARING IMMUNOTHERAPY FOR ALZHEIMER'S DISEASE AND THE RISK OF CEREBRAL AMYLOID ANGIOPATHY.

Immunization strategies which aid in the clearance of beta-amyloid (Aß) plaques have raised new hopes for the treatment of Alzheimer's disease (AD). Two particularly promising passive immunization therapies currently being investigated include intravenous immunoglobulins (IVIG) containing Aß antibodies and specifically developed monoclonal antibodies for Aß. These Aß antibodies may reduce amyloid accumulation in the brain by binding to the amyloid peptide and drawing it in through the blood-brain barrier for subsequent removal from the capillaries. However, as this strategy aims at removing extracellular amyloid through cerebral vessels, a redistribution of amyloid pathology may manifest as increased cerebral amyloid angiopathy (CAA). CAA occurs when Aß becomes embedded in the walls of cerebral vessels associated with weakening of the vessel walls. Antibody mediated Aß clearance from the parenchyma could significantly increase the Aß burden in the vessel lumen and wall, therefore increasing the risk of vessel rupture and hemorrhage. This chapter will review the current literature on Aß immunotherapy for AD and explore the mechanisms as well as possible risks of amyloid clearance treatment, particularly cerebral amyloid angiopathy.

Bithalamic lesions of butane encephalopathy.

Butane inhalation can cause serious medical complications and is particularly toxic to the nervous system. This is a report of an acutely encephalopathic youth with prominent abulia. MRI revealed severe bithalamic injury attributed to butane toxicity. Clinical issues, including particular radiologic findings, related to butane inhalation are reviewed.

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla.

Proton magnetic resonance spectroscopy ((1)H-MRS) studies showing increased lactate during neural activation support a broader role for lactate in brain energy metabolism than was traditionally recognized. Proton MRS measures of brain lactate responses have been used to study regional brain metabolism in clinical populations. This study examined whether variations in blood glucose influence the lactate response to visual stimulation in the visual cortex. Six subjects were scanned twice, receiving either saline or 21% glucose intravenously. Using (1)H-MRS at 1.5 Tesla with a long echo time (TE=288 ms), the lactate doublet was visible at 1.32 ppm in the visual cortex of all subjects. Lactate increased significantly from resting to visual stimulation. Hyperglycemia had no effect on this increase. The order of the slice-selective gradients for defining the spectroscopy voxel had a pronounced effect on the extent of contamination by signal originating outside the voxel. The results of this preliminary study demonstrate a method for observing a consistent activity-stimulated increase in brain lactate at 1.5 T and show that variations in blood glucose across the normal range have little effect on this response.

Neurodevelopmental pathways to aggression: a model to understand and target treatment in youth.

The authors describe a neurodevelopmentally relevant, clinically derived model for understanding and treating aggressive behavior in youth. Based on case experience and literature review, the authors divide aggressive behavior into five symptomatic domains with respective neurobiological/neurodevelopmental underpinnings. These five symptom domains (impulsivity, affective instability, anxious/hyperarousal, cognitive disorganization, and predatory aggression) emerge as logical and clinically useful targets for treatment. The authors aim to establish a relationship between these symptom domains and brain structure and function that offers a clinically relevant approach to the complexities of understanding aggression and its treatment.

Pharmacological intervention for cognitive deficits and aggression in frontal lobe injury.

We present a case that promotes early intervention and pharmacological treatment for the neuropsychiatric sequelae (frontal lobe syndrome, including cognitive impairment and aggressive behavior) associated with traumatic brain injury (TBI) and delirium. The patient, who sustained significant systemic complications related to his trauma, was previously diagnosed with alcohol and drug dependence and antisocial personality disorder. These antecedent conditions and prolonged systemic complications likely played a complicating role in his course of recovery.

Brain regions showing increased activation by threat-related words in panic disorder.

Threat-related stimuli consistently activate the posterior cingulate cortex in normal subjects and have exaggerated effects on memory in patients with panic disorder. We hypothesized that panic patients would show increased response to threat-related stimuli in the posterior cingulate cortex. While undergoing fMRI, six panic patients and eight healthy volunteers made valence judgements of threat-related and neutral words. Both groups showed threat-related activation in the left posterior cingulate and left middle frontal cortices, but the activation was significantly greater in panic patients. Panic patients also had more right>left asymmetry of activation in the mid-parahippocampal region. The increased responsivity observed in the posterior cingulate and dorsolateral prefrontal cortices is consistent with the hypothesis that panic disorder patients engage in more extensive memory processing of threat-related stimuli.