Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.

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Alzheimer's disease, the most common neurodegenerative dementia in the elderly, affects cognition, behavior and functioning, and a prominent neuroinflammatory component likely contributes to disease pathogenesis. The epidemiology of AD has previously shown that NSAID use decreases the incidence of AD, and evidence from tissue culture, in vivo models, and Alzheimer brain tissue studies indicate that inflammation in AD is mediated by the production of proinflammatory molecules, leading to microglial activation and neuronal damage. Preliminary clinical drug trials of anti-inflammatory agents, such as indomethacin, suggest slowing of cognitive decline in AD, further supporting a role for inflammation. The basic mechanisms underlying the AD neuroinflammatory cascade, which might accelerate the development of AD neuropathology, are poorly understood, but several recent studies implicate a number of established signaling pathways in this process. Microglial activation might involve beta-amyloid binding and activation of cell surface immune and adhesion molecules such as CD45, CD40, CD36 and integrins, with the subsequent recruitment of Src family tyrosine kinases such as Fyn, Lyn and Syk kinases. ERK and MAPK pathways are then activated, which induces proinflammatory gene expression and leads to the production of cytokines and chemokines. These molecules may then contribute to synaptic pruning, damage and loss, while TNFalpha can induce neuronal apoptosis and injury. The production of interleukins and other cytokines and chemokines also may lead to microglial activation, astrogliosis, and further secretion of proinflammatory molecules and amyloid, thus perpetuating the cascade. Simultaneously, direct neuronal injury from amyloid-induced signaling also contributes to neurodegeneration. Of clinical relevance, components of these pathways may be suitable targets for therapeutic modulation in AD and for the development of novel disease-modifying anti-inflammatory therapy.

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The aggregation of a-synuclein (a-syn) is believed to play a critical role in the pathogenesis of disorders such as dementia with Lewy bodies and Parkinson's disease. The function of asyn remains unclear, although several lines of evidence suggest that a-syn is involved in synaptic vesicle trafficking, probably via lipid binding, and interactions with lipids have been shown to regulate a-syn aggregation. In this context, the main objective of this study was to determine whether methylb-cyclodextrin (MbCD), a cholesterol-extracting agent, interfered with a-syn accumulation in models of synucleinopathy. For this purpose, we studied the effects of MbCD on the accumulation of a-syn in a transfected neuronal cell line and in transgenic mice. Immunoblot analysis showed that MbCD reduced the level of a-syn in the membrane fraction and detergent-insoluble fraction of transfected cells. In agreement with the in vitro studies, treatment of mice with MbCD resulted in decreased levels of a-syn in membrane fractions and reduced accumulation of a-syn in the neuronal cell body and synapses. Taken together, these results suggest that changes in cholesterol and lipid composition using cholesterol-lowering agents may be used as a tool for the treatment of synucleinopathies.