Martin Tolar

Spatial navigation testing discriminates two types of amnestic mild cognitive impairment

The hippocampus is essential for consolidation of declarative information and spatial navigation. Alzheimers disease (AD) diagnosis tends to be preceded by a long prodromal period and mild cognitive impairment (MCI). Our goal was to test whether amnestic MCI comprises two different subgroups, with hippocampal and non-hippocampal memory impairment, that vary with respect to spatial navigation ability. A total of 52 patients were classified into two subgroups: non-amnestic MCI (naMCI) (n=10) and amnestic MCI (aMCI) (n=42). The aMCI subgroup was further stratified into memory impairment of hippocampal type-hippocampal aMCI (HaMCI) (n=10) (potential preclinical AD) and isolated retrieval impairment-non-hippocampal (NHaMCI) (n=32). Results were compared to control (n=28) and AD (n=21) groups. We used the Hidden Goal Task, a human analogue of the Morris Water Maze, to examine spatial navigation either dependent (egocentric) or independent of individuals position (allocentric). Overall, the HaMCI group performed poorer on spatial navigation than the NHaMCI group, especially in the latter trials when the HaMCI group exhibited limited capacity to learn and the NHaMCI group exhibited a learning effect. Finally, the HaMCI group performed almost identically as the AD group. Spatial navigation deficit is particularly pronounced in individuals with hippocampus-related memory impairment and may signal preclinical AD.

Human Analogue of the Morris Water Maze for Testing Subjects at Risk of Alzheimer’s Disease

Background: Patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI) have difficulties with spatial orientation. Objective: To test hypothesis that spatial navigation is impaired early in MCI patients representing the presymptomatic stage of AD. Methods: We tested patients with probable AD (n = 21), MCI, further classified according to Petersen’s criteria as amnestic MCI (aMCI) single domain (n = 11), aMCI multiple domain (n = 31), or nonamnestic MCI (n = 7). The aMCI group was also stratified using cued recall according to Dubois’ criteria into memory impairment of the hippocampal type (n = 10) and isolated memory retrieval impairment-nonhippocampal (n = 32) and also according to ApoE4 status into E4+ (n = 12) and E4– (n = 30). These patients and controls (n = 28) were tested in the human variant of the Morris water maze. Depending on the subtest, the subjects could use the egocentric or allocentric (hippocampus-dependent) navigation. Results: The AD and aMCI multiple domain groups were impaired in all subtests. The aMCI single domain group was impaired in allocentric subtests. The hippocampal MCI group performed poorer than the nonhippocampal MCI group and similarly to the AD group. The ApoE4+ group was as bad as the AD group when compared with the E4– group. Conclusion: aMCI subjects represent a very heterogeneous population, and spatial memory or cued recall examination can add more value to aMCI classification. ApoE4+ patients are more impaired than ApoE4– patients.

Spatial Navigation and APOE in Amnestic Mild Cognitive Impairment

Background: The effect of APOE Ε4 allele (Ε4) on spatial navigation in amnestic mild cognitive impairment (aMCI) is unknown. Objective: Our purpose was to examine the characteristics of spatial navigation impairment in Ε4-positive (Ε4+) and Ε4-negative (Ε4–) aMCI subgroups. Methods: Blood samples were collected to determine the APOE genotype. A total of 34 aMCI patients were stratified into aMCI-Ε4– (n = 23) and aMCI-Ε4+ (n = 11) groups. Control (n = 28) and mild Alzheimer’s disease (AD; n = 16) groups were also used. We used a human analogue of the Morris water maze (enclosed arena 2.9 m in diameter) to examine body-centered (egocentric) and world-centered (allocentric) spatial navigation. Results: The aMCI-Ε4+ group performed poorer on spatial navigation than the aMCI-Ε4– group in both egocentric and allocentric tasks even though these 2 groups did not differ in global cognitive functioning or neuropsychological tests. The aMCI-Ε4+ and mild AD groups performed similarly on all Morris Water Maze tasks and were outperformed by the aMCI-Ε4– group, which also resembled the control group in performance on the egocentric tasks. The aMCI groups showed poor spatial navigation learning regardless of their Ε4 positivity. Conclusion: We found more profound deficits in spatial navigation in aMCI-Ε4+ relative to aMCI-Ε4– patients. The aMCI-Ε4+ group resembled the mild AD group in spatial navigation performance. Although the Ε4 genotype was indicative of spatial navigation performance, it was not indicative of the aMCI patients’ ability to learn the tasks. Spatial navigation testing represents a promising area with respect to identifying individuals at higher risk for AD among the heterogeneous MCI population.

PHASE 1 DEVELOPMENT OF ALZ-801, A NOVEL BETA AMYLOID ANTI-AGGREGATION PRODRUG OF TRAMIPROSATE WITH IMPROVED DRUG PROPERTIES, SUPPORTING BRIDGING TO THE PHASE 3 PROGRAM

Background:ALZ-801 is a novel, orally bioavailable, small-molecule prodrug of tramiprosate with improved pharmacokinetics and oral tolerability. The initial tramiprosate Phase 3 program in mild-to-moderate Alzheimer’s disease (AD) included two studies with >2,000 patients but did not show significant separation on co-primary outcomes. In these studies,w60% of patients were carriers of the e4 allele of the apolipoprotein E gene (APOE4), and w14% were homozygous for APOE4. A subgroup intention-totreat analysis of APOE4/4 patients showed that tramiprosate 150mg BID produced a significant and clinically meaningful improvement on cognition (ADAS-cog), and a positive trend on function (CDR-SB), at 65 and 78 weeks, on top of standard of care symptomatic therapy. Tramiprosate also showed a favorable safety profile: the most common AE was nausea. Safety data from Phase 3 tramiprosate studies support bridging to the ALZ801 safety database, based on bioequivalence.Methods: To advance the clinical development of ALZ-801 into Phase 3, we have completed single dose and 14-day multiple ascending dose Phase 1 bridging studies in healthy elderly volunteers to evaluate safety, tolerability and pharmacokinetics. Results: Compared with oral tramiprosate, oral ALZ-801 delivered an equivalent plasma exposure of tramiprosate with over 50% lower inter-subject variability. Oral ALZ-801 also prolonged plasma tramiprosate terminal half-life to w24 hours. Administration of ALZ-801 with food markedly reduced the incidence of GI symptoms as compared to the fasted state, while maintaining plasma tramiprosate exposure. An immediate release tablet formulation of ALZ-801 was developed, which displayed exposure and low variability similar to the loose filled capsule formulation. ALZ-801 also showed excellent dose proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Conclusions: Based on the single and multiple dose pharmacokinetics of ALZ-801, the steady-state plasma exposure of the active drug tramiprosate following oral BID dosing of ALZ-801 immediate release tablet has been determined. The data indicate that 265mg BID of ALZ-801 will achieve a steady-state tramiprosate exposure that is equivalent to 150mg BID of oral tramiprosate. These bridging data will support the Phase 3 development of ALZ-801, an optimized prodrug of tramiprosate with improved GI toleration and low inter-subject pharmacokinetic variability, in APOE4/4 homozygous AD subjects.

APOE E4 affects spatial working memory and attention in patients with amnestic mild cognitive impairment

6 3.8, namci-s: 179.6 6 11.2, namci-m: 143.6 6 19.9). There were significant differences on the scores of SNSB-D and several cognitive domains of language, visuospatial function, memory and frontal executive function among the subtypes of MCI. According to post-hoc analysis, the subtypes of amnestic and non-amnestic multi-domian MCI showed more deficits in all cognitive domains compared with other types of MCI. Conclusions: Our study shows characteristic and different pattern of cognitive deficits in patients with MCI, and these results may be helpful to predict the conversion tendency to dementia conditions according to subtypes of MCI.

NOVEL ENVELOPING MECHANISM OF ACTION OF ALZ-801: CONFORMATIONAL STABILIZATION OF BETA AMYLOID BY A SMALL MOLECULE RESULTS IN ANTI-OLIGOMER ACTIVITY

Background: Soluble forms of Ab are in equilibrium between the CSF and the ISF. This poster poses a new hypothesis: that Ab can be cleared from the brain with interventions where Ab is continuously removed from the CSF. All clinical trials with peripheral immunotherapy have failed to date. Also, the benefits of central immunotherapy in animal models are transient since pulsatile immune reactions lead to alternate shifts in the balance in/out from the ISF to the CSF. We expect continuous depletion of Ab in the CSF would produce a steady clearance of Ab in the ISF. Methods: Today, we can conceive several ways of removing Ab continuously from the CNS by accessing the CSF and debugging it. For instance, Ab can be targeted either by size -particularly the aggregated forms(this would be made by filtering the CSF) or by epitopes (this would be made by permanent immunotherapy on the CSF) or by a combination of both. The first pilot studies testing this strategy are currently underway.Results:This poster presents a new therapeutic hypothesis with the aim of discussing it and promoting exploratory studies. Conclusions: We conclude that continuous clearance of beta-amyloid from the CSF may represent a new therapeutic strategy in AD.

Spatial navigation computer test can discriminate two types of amnestic mild cognitive impairment

Participants (n 1⁄4 300) included cognitively normal community volunteers and patients with mild cognitive complaints, all of whom were not demented at baseline, had been clinically evaluated, and were followed annually as part of a longitudinal study of Mild Cognitive Impairment (MCI) at the Joseph and Kathleen Bryan ADRC at Duke (18% African American; mean age 1⁄4 75 [8.8sd]). Diagnoses for prAD, functional MCI (CDR 1⁄4 0.5) and revised prAD were algorithmically applied retrospectively, as was done in previous work. Diagnostic stability, assessed by positive and negative predictive values (PPV, NPV) and reversion rates over three years of follow-up, was examined in the AfAm and Caucasian subgroups. Results: At baseline, approximately half of the participants met criteria for prAD and fMCI, while only 9% met criteria for revised prAD. The reversion rate to cognitively normal status in each impaired group was low (1016%), though substantially higher in AfAms (30%). Prediction of later dementia at one year was highest for the revised prAD criteria (ppv 1⁄4 0.32) compared to fMCI (ppv 1⁄4 .09) and the original formulation of prAD (ppv 1⁄4 0.08). NPVs were consistently high across all diagnostic entities (.961.0). Conclusions: Current results suggest that diagnosing early AD in its prodromal stage across diverse groups is facilitated by clinical criteria which require objective evidence of both memory disorder and either executive dysfunction or functional decline. However, there is a higher degree of diagnostic instability in AfAm using this approach, possibly due to cultural differences in psychometric test performance or due to other variables that may be changing with time (e.g. disease co-morbidities). The findings require further investigation in a larger sample before applied as a screening method.