Alzheimer’s disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies2. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels3, structural and functional magnetic resonance imaging4 and the recent use of brain amyloid imaging5 or inflammaging6, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer’s disease with the required sensitivity and specificity7. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer’s disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer’s disease within a 2–3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer’s disease.

Little axonal regeneration occurs after spinal cord injury in adult mammals. Regrowth of mature CNS axons can be induced, however, by altering the intrinsic capacity of the neurons for growth or by providing a permissive environment at the injury site. Fetal spinal cord transplants and neurotrophins were used to influence axonal regeneration in the adult rat after complete spinal cord transection at a midthoracic level. Transplants were placed into the lesion cavity either immediately after transection (acute injury) or after a 2-4 week delay (delayed or chronic transplants), and either vehicle or neurotrophic factors were administered exogenously via an implanted minipump. Host axons grew into the transplant in all groups. Surprisingly, regeneration from supraspinal pathways and recovery of motor function were dramatically increased when transplants and neurotrophins were delayed until 2-4 weeks after transection rather than applied acutely. Axonal growth back into the spinal cord below the lesion and transplants was seen only in the presence of neurotrophic factors. Furthermore, the restoration of anatomical connections across the injury site was associated with recovery of function with animals exhibiting plantar foot placement and weight-supported stepping. These findings suggest that the opportunity for intervention after spinal cord injury may be greater than originally envisioned and that CNS neurons with long-standing injuries can reinitiate growth, leading to improvement in motor function.

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The adult central nervous system is capable of considerable anatomical reorganization and functional recovery after injury. Functional outcomes, however, vary greatly, depending upon size and location of injury, type and timing of intervention, and type of recovery and plasticity evaluated. The present study was undertaken to assess the recovery of skilled and unskilled forelimb function in adult rats after a C5/C6 spinal cord over-hemisection and delayed intervention with fetal spinal cord transplants and neurotrophins. Recovery of forelimb function was evaluated during both target reaching (a skilled behavior) and vertical exploration (an unskilled behavior). Anatomical tracing and immunohistochemistry were used to assess the growth of descending raphespinal, corticospinal, and rubrospinal fibers at the injury site, tracts that normally confer forelimb function. Delayed intervention with transplants and either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) restored skilled left forelimb reaching to pre-injury levels. Animals showed recovery of normal reaching movements rather than compensation with abnormal movements. Transplants and NT-3 also improved right forelimb use during an unskilled vertical exploration, but not skilled right reaching. Intervention with fetal transplant tissue supported the growth of descending serotonergic, corticospinal, and rubrospinal fibers into the transplant at the lesion site. The addition of neurotrophins, however, did not significantly increase axonal growth at the lesion site. These studies suggest that the recovery of skilled and unskilled forelimb use is possible after a large cervical spinal cord injury following delayed intervention with fetal spinal cord and neurotrophins. Plasticity of both spared and axotomized descending pathways likely contributes to the functional recovery observed.

Several members of the family of guanine nucleotide-binding protein (G protein)-coupled receptors have recently been shown to induce agonist-dependent foci development in NIH 3T3 cells and tumors in nude mice. We selected the five subtypes of the muscarinic acetylcholine receptor family to investigate their role in tumor suppression. When transfected and expressed in CHO-Kl Chinese hamster ovary cells, ml, m3, and m5 muscarinic acetylcholine receptor activation resulted in a morphology change. Receptor activation did not slow or inhibit monolayer growth of CHOm5 cells in culture but markedly inhibited density-independent growth in soft agar and suppressed tumor formation in nude mice. Receptor-mediated tumor suppression was found to be agonistdependent and reversible and was blocked with a muscarinic receptor antagonist. Of the five signaling pathways associated with the ml, m3, and m5 receptors, only receptor-operated, and inositol trisphosphate-independent, calcium influx was found to correlate with inhibition of tumorigenicity. These data suggest a pivotal role for inositol trisphosphate-independent receptor-regulated calcium homeostasis in CHO-Kl tumor suppression.