In spite of advances in neuroimaging and other brain biomarkers to assess preclinical Alzheimer’s disease (AD), cognitive assessment has relied on traditional memory paradigms developed well over six decades ago. This has led to a growing concern about their effectiveness in the early diagnosis of AD which is essential to develop preventive and early targeted interventions before the occurrence of multisystem brain degeneration. We describe the development of novel tests that are more cognitively challenging, minimize variability in learning strategies, enhance initial acquisition and retrieval using cues, and exploit vulnerabilities in persons with incipient AD such as the susceptibility to proactive semantic interference, and failure to recover from proactive semantic interference. The advantages of various novel memory assessment paradigms are examined as well as how they compare with traditional neuropsychological assessments of memory. Finally, future directions for the development of more effective assessment paradigms are suggested.

The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.

OBJECTIVE To examine the utility of a novel “cognitive stress test” to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. DESIGN Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI) and pre-clinical mild cognitive impairment (PreMCI) were administered the LASSI-L, a sensitive test of proactive semantic interference (PSI), retroactive semantic interference and uniquely, the ability to recover from the effects of PSI. SETTING Ninety-three subjects (31 males and 62 females) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent F-18 Florbetapir PET scanning. MEASURES Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by chi-square and Fisher's Exact Test. Spearman's rho was employed to examine associations between amyloid load, and different cognitive measures. RESULTS LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI and 13% of those classified as CN. CN subjects had no difficulties with recovery from PSI while SMI, preMCI and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from theeffects of PSI and amyloid load in the brain. CONCLUSIONS Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

OBJECTIVE To determine the degree to which susceptibility to different types of semantic interference may reflect the earliest manifestations of early Alzheimer disease (AD) beyond the effects of global memory impairment. METHODS Normal elderly (NE) subjects (n= 47), subjects with amnestic mild cognitive impairment (aMCI: n=34) and 40 subjects with probable AD were evaluated using a unique cued recall paradigm that allowed for an evaluation of both proactive and retroactive interference effects while controlling for global memory impairment (LASSI-L procedure). RESULTS Controlling for overall memory impairment, aMCI subjects had much greater proactive and retroactive interference effects than NE subjects. LASSI-L indices of learning using cued recall evidenced high levels of sensitivity and specificity with an overall correct classification rate of 90%. These provided better discrimination than traditional neuropsychological measures of memory function. CONCLUSION The LASSI-L paradigm is unique and unlike other assessments of memory in that items presented for cued recall are explicitly presented, and semantic interference and cuing effects can be assessed while controlling for initial level of memory impairment. This represents a powerful procedure allowing the participant to serve as his or her own control. The high levels of discrimination between subjects with aMCI and normal cognition that exceeded traditional neuropsychological measures makes the LASSI-L worthy of further research in the detection of early AD.

SIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy- participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.