Cerebral deposition of the amyloid ␤ protein (A␤), an invariant feature of Alzheimer's disease, reflects an imbalance between the rates of A␤ production and clearance. The causes of A␤ elevation in the common late-onset form of Alzheimer's disease (LOAD) are largely unknown. There is evidence that the A␤-degrading protease neprilysin (NEP) is down-regulated in normal aging and LOAD. We asked whether a decrease in endogenous NEP levels can prolong the halflife of A␤ in vivo and promote development of the classic amyloid neuropathology of Alzheimer's disease. We examined the brains and plasma of young and old mice expressing relatively low levels of human amyloid precursor protein and having one or both NEP genes silenced. NEP loss of function 1) elevated whole-brain and plasma levels of human A␤ 40 and A␤ 42 , 2) prolonged the half-life of soluble A␤ in brain interstitial fluid of awake animals, 3) raised the concentration of A␤ dimers, 4) markedly increased hippocampal amyloid plaque burden, and 5) led to the development of amyloid angiopathy. A ϳ50% reduction in NEP levels, similar to that reported in some LOAD brains, was sufficient to increase amyloid neuropathology. These findings demonstrate an important role for proteolysis in determining the levels of A␤ and A␤-associated neuropathology in vivo and support the hypothesis that primary defects in A␤ clearance can cause or contribute to LOAD pathogenesis. (Am J Pathol

Distal symmetric polyneuropathy (DSP) related to human immunodeficiency virus (HIV) is one of the most common neurologic complications of HIV, possibly affecting as many as 50% of all individuals infected with HIV. Two potentially neurotoxic mechanisms have been proposed to play a crucial role in the pathogenesis of HIV DSP: neurotoxicity resulting from the virus and its products; as well as adverse neurotoxic effects of medications used in the treatment of HIV. Clinically, HIV DSP is characterized by a combination of signs and symptoms that include decreased deep tendon reflexes at the ankles and decreased sensation in the distal extremities as well as paresthesias, dysesthesias, and pain in a symmetric stocking–glove distribution. These symptoms are generally static or slowly progressive over time, and depending on the severity, may interfere significantly with the patient’s daily activities. In addition to the clinical picture, nerve conduction studies and skin biopsies are often pursued to support the diagnosis of HIV DSP. Anticonvulsants, antidepressants, topical agents, and nonspecific analgesics may help relieve neuropathic pain. Specifically, gabapentin, lamotrigine, pregabalin, amitriptyline, duloxetine, and high-dose topical capsaicin patches have been used in research and clinical practice. Further research is needed to elucidate the pathogenesis of HIV DSP, thus facilitating the development of novel treatment strategies. This review discusses the epidemiology, pathophysiology, clinical findings, diagnosis, and management of DSP in the setting of HIV.

In recent years, a large body of data has surfaced reporting the therapeutic benefit of botulinum toxin injection in multiple conditions. The aim of this review is: to summarize the highest quality literature pertaining to clinical application of botulinum toxin in neuropathic pain conditions including postherpetic neuralgia, trigeminal neuralgia, diabetic polyneuropathy, post-traumatic neuralgia, carpal tunnel syndrome, complex regional pain syndrome, phantom limb and stump pain, and occipital neuralgia; to provide an overview of the clinical trials using botulinum toxin in adult spasticity; and to assign levels of evidence according to the American Academy of Neurology guidelines. In summary, there is level A evidence for established efficacy in postherpetic neuralgia and adult spasticity; level B evidence for probable efficacy in trigeminal neuralgia and post-traumatic neuralgia; level B evidence for probable lack of efficacy in carpal tunnel syndrome; level C evidence for possible efficacy in diabetic polyneuropathy; and level U (insufficient) evidence in complex regional pain syndrome, phantom limb and stump pain, and occipital neuralgia.

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