Trial of Solanezumab in Preclinical Alzheimer's Disease.

BACKGROUND: Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results. METHODS: We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. RESULTS: A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. CONCLUSIONS: Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Targeting amyloid ß in Alzheimer's disease: Meta-analysis of low-dose solanezumab in Alzheimer's disease with mild dementia studies.

INTRODUCTION: Solanezumab is a monoclonal antibody that binds to the mid-domain of soluble amyloid ß peptide. This meta-analysis evaluated the effect of low-dose solanezumab on clinical progression in three phase 3 studies. METHODS: The population comprised patients aged ≥55 years with Alzheimer's disease (AD) with mild dementia, randomized to 400 mg solanezumab or placebo every 4 weeks for 80 weeks. Frequentist mixed-model repeated-measures (MMRM) and Bayesian disease progression model (DPM) longitudinal analyses were conducted. RESULTS: Pooled MMRM analyses showed a statistically significant effect of solanezumab across cognitive and functional outcome measures. DPM results were generally consistent with MMRM results, ranging from 15% to 30% slowing of clinical progression. DISCUSSION: These analyses suggest low-dose solanezumab slows clinical progression of AD with mild dementia. The ongoing A4 solanezumab study in participants with preclinical AD will ascertain the effect of a higher dose of solanezumab in an earlier disease stage. HIGHLIGHTS: Individual EXPEDITION studies were negative but suggest low-dose solanezumab had an effect in slowing the clinical progression of Alzheimer's disease (AD) with mild dementia. At 80 weeks, mixed-model repeated-measures analyses showed numeric reductions in measures of clinical decline in solanezumab-treated arms compared with placebo across almost every outcome measure, and statistical significance in multiple outcome measures in each study. Pooled analyses suggest a high probability that low-dose solanezumab has at least some effect on slowing the clinical progression of AD with mild dementia. Across cognitive and functional outcome measures, estimates from disease progression model analyses range from 15% to 30% slowing of decline with low-dose solanezumab in AD with mild dementia.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Validation and diagnostic accuracy of the Alzheimer's questionnaire.

BACKGROUND: accurately identifying individuals with cognitive impairment is difficult. Given the time constraints that many clinicians face, assessment of cognitive status is often not undertaken. The intent of this study is to determine the diagnostic accuracy of the Alzheimer's questionnaire (AQ) in identifying individuals with mild cognitive impairment (MCI) and AD. METHODS: utilising a case-control design, 300 [100 AD, 100 MCI, 100 cognitively normal (CN)] older adults between the ages of 53 and 93 from a neurology practice and a brain donation programme had the AQ administered to an informant. Diagnostic accuracy was assessed through receiver-operating characteristic analysis, which yielded sensitivity, specificity and area under the curve (AUC). RESULTS: the AQ demonstrated high sensitivity and specificity for detecting MCI [89.00 (81.20-94.40)]; [91.00 (83.60-65.80)] and AD [99.00 (94.60-100.00)]; [96.00 (90.10-98.90)]. AUC values also indicated high diagnostic accuracy for both MCI [0.95 (0.91-0.97)] and AD [0.99 (0.96-1.00)]. Internal consistency of the AQ was also high (Cronbach's alpha = 0.89). CONCLUSION: the AQ is a valid informant-based instrument for identifying cognitive impairment, which could be easily implemented in a clinician's practice. It has high sensitivity and specificity in detecting both MCI and AD and allows clinicians to quickly and accurately assess individuals with reported cognitive problems.

Magnetic resonance imaging measures of brain volumes across the EXPEDITION trials in mild and moderate Alzheimer's disease dementia.

Introduction: Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low-dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods: Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor-based morphometry (EXPEDITION3). Results: The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) ε4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all P-values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change. Discussion: Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low-dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken.

Avoid or Embrace? Practice Effects in Alzheimer's Disease Prevention Trials.

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer's disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed "practice effects"). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies.

Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.

Brain amyloid burden, sleep, and 24-hour rest/activity rhythms: screening findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Studies.

STUDY OBJECTIVES: To examine in a subsample at the screening phase of a clinical trial of a ß-amyloid (Aß) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer's disease (AD). METHODS: Overall, 26 Aß-positive (Aß+) and 33 Aß-negative (Aß-) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR]). RESULTS: We were unable to detect any differences between Aß+ and Aß- participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aß+ participants had lower activity levels than Aß- participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aß+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05). CONCLUSIONS: Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally "local" RAR alterations in preclinical AD.

Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals.

Importance: The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid. Objective: To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function. Design, Setting, and Participants: This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]). Main Outcomes and Measures: Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aß+) or not having elevated amyloid (Aß-). Results: Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aß+. Aß+ participants were slightly older than Aß-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aß+ participants were more likely to have a family history of dementia (3320 Aß+ [74%] vs 3050 Aß- [68%]) and at least 1 APOE ε4 allele (2602 Aß+ [58%] vs 1122 Aß- [25%]). Aß+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index. Conclusions and Relevance: Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

Medical management of frontotemporal dementia.

There are no Food and Drug Administration (FDA)-approved medications for the medical management of frontotemporal dementia and its related disorders, so all management recommendations are necessarily off-label and borrowed from experience with Alzheimer's disease, psychiatric disease, and related medical illnesses. Six areas of pharmacotherapeutic consideration are prevention (primary and secondary), intellectual decline, behavioral disorders (such as depression, anxiety, and psychosis), sleep disorders, frequently associated disorders (including motor neuron disease), and abrupt decline. In addition to pharmacotherapy, important lifestyle issues confronting the clinician include driving cessation, securing any weapons maintained at home, assisted living, and caregiver burnout.

Utility of the telephone interview for cognitive status for enrollment in clinical trials.

BACKGROUND: The modified Telephone Interview for Cognitive Status (TICS-m) assesses cognitive status via the telephone and has been used to recruit for clinical trials by screening for amnestic mild cognitive impairment (aMCI). The utility of screening for aMCI has not been validated, and it is unknown which questions best predict aMCI. METHODS: The Alzheimer's Disease Cooperative Study (ADCS) used the TICS-m to recruit for an aMCI clinical trial. If telephone respondents screened positive for aMCI on the TICS-m, they were referred to a clinical site where they were assessed for the operational criteria of aMCI. Univariate analyses identified the TICS-m questions that best predicted aMCI, creating a final model using forward stepwise logistic regression. RESULTS: Of 52,722 calls, 16,312 were screened for trial entry. Of these, 4,883 received the TICS-m. The 2,431 that screened positive for aMCI were referred to a clinic, and 527 arrived for clinical assessment. Of these, 266 met operational criteria for aMCI. The positive predictive value of the TICS-m in this population is 50.9% (95% confidence interval [CI], 46.2% to 54.8%). The final model included 5 variables: (1) 10-word list delayed recall (p < 0.001), (2) day of month (p = 0.002), (3) season (p = 0.009), (4) last name of current president (p = 0.020), and (5) month (p = 0.036). This model has a predictive accuracy of 0.61 (95% CI, 0.51 to 0.71) which is similar to the entire TICS-m. The predictive accuracy of the 10-word list delayed recall alone was 0.63 (95% CI, 0.54 to 0.72). CONCLUSION: The TICS-m is not optimally efficient for recruitment of subjects for aMCI clinical trials. The 10-word delayed recall has a predictive accuracy similar to that of the entire TICS-m.

Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD.

We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK- 0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological-Test-Battery (CNTB) summary score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB summary score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score s -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2) versus placebo (18/70; 25.7%). Adverse events in > 5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment. (ClinicalTrials.gov trial registration, NCT00420420).

Reversible dementia and gait disturbance after prolonged use of valproic acid.

Valproic acid (VPA) has been reported to cause cognitive decline and parkinsonism that are reversed with cessation of medication. Common imaging findings among these reports demonstrate reversible cortical pseudoatrophy and enlargement of the lateral ventricles. This case exemplifies these adverse effects of VPA which can cause reversible neurological symptoms even in long-term treated patients and can present as dementia syndromes such as normal pressure hydrocephalus.

The Alzheimer's questionnaire: a proof of concept study for a new informant-based dementia assessment.

The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer's disease (AD) that can be administered in a primary care setting. The Alzheimer's Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.

Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene.

In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-ß, histologic amyloid-ß, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology.

Non-cholinergic drug development for Alzheimer's disease.

BACKGROUND: Recent advances in the understanding of the pathobiology of Alzheimer's disease have led to a large number of non-cholinergic targets for the development of therapeutic agents. These include, for example, neurotransmitter-based, anti-amyloid, antitangle, antioxidant, anti-excitotoxic, and growth factor strategies. There are several hundred agents in, or approaching, clinical trials. Some hold promise for treatment of those affected, some may have potential for prevention, some for both. OBJECTIVES: Key examples of each of these development approaches will be summarized. CONCLUSIONS: It is too soon to predict which, if any, of these approaches will bear fruit. At the moment, it appears that the amyloid-based therapies are the farthest along in development, and have shown in some cases that the amyloid dysregulation cascade can be interrupted. It is unknown, however, whether altering this aspect of the pathobiology of Alzheimer's will actually yield clinical benefit. Efforts to affect tangle development would appear to be a fruitful approach, although these efforts lag behind the anti-amyloid efforts. The same is essentially true for the other approaches reviewed as well. Given the fact that many new interventions target specific pathways that can be measured biologically in go-no go proof of concept studies, the opportunity exists to capitalize on biomarkers in earlier stages of development. The same can be said for evolving imaging techniques. Given the number of agents in development, we offer the provocative suggestion that the biggest threat to identifying effective therapies may prove to be the implementation of enough treatment trials, and applying out-of-the-box prevention methodologies, rather than the discovery of promising candidates. This prediction may or may not hold true.