Victoria Johnson

This article was originally published in NeurologyLive.

New data shows patients with neurodegenerative diseases (NDD) treated with pimavanserin (Nuplazid) did not experience negative 

 with up to 9 months of treatment compared to placebo.

2021 American Academy of Neurology (AAN) Annual Meeting

, April 17-22, by Clive Ballard, MD, professor, age-related diseases, and pro-vice-chancellor and executive dean, University of Exeter Medical School. Ballard and colleagues sought to evaluate pimavanserin’s impact on cognition in patients with neuropsychiatric manifestations of NDD across multiple studies.

“Neuropsychiatric symptoms, including psychosis, are common among patients with dementia and are associated with poorer clinical outcomes. No therapies are approved in the United States for treating dementia-related psychosis (DRP). Off-label antipsychotic use is associated with significant adverse outcomes, including accelerated cognitive decline,” Ballard and colleagues wrote in the abstract.

The researchers analyzed cognitive function via the Mini-Mental State Examination (MMSE) that was an outcome in 3 parallel-arm, double-blind studies (019, 032, 046) that compared 34 mg of pimavanserin with placebo as well as the phase 3 randomized withdrawal HARMONY study. This study consisted of a 12-week open label phase followed by a randomized, double-blind period. There were 697 patients receiving pimavanserin across all studies, and 622 had DRP. Cognition related treatment-emergent adverse events (TEAEs) were also analyzed.

Ballard and colleagues found that the MMSE score least squares mean (LSMO change from baseline to week 12 was –0.25 (standard error [SE], 0.42) in study 019 and 0.0 (SE, 0.57) in study 032, and similar to placebo in both. LSM change from baseline to week 8 was 1.2 (SE, 0.21; n = 132) for pimavanserin and 0.5 (SE, 0.21; n = 128) for placebo in the interim analysis of study 046.

In the HARMONY study, the mean change from baseline to week 12 was 1.0 (SE, 0.22; n = 145). During the double-blind period, mean MMSE score with pimavanserin treatment did not decline and was similar to placebo. Patients treated with pimavanserin for the whole 9 months of the study (n = 46) had a mean change from baseline of 1.2 (SE, 0.51).

The researchers also found that confusion and memory impairment were the only cognition-related TEAEs reported. These TEAEs were infrequent and occurred at rates similar to placebo.

“Across studies, mean MMSE score changes in pimavanserin-treated patients with NDD were small and were similar to placebo. Cognition-related TEAEs were reported infrequently. Overall, pimavanserin did not have a negative impact on cognitive function with up to 9 months of treatment,” Ballard and colleagues concluded.

Pimavanserin, a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, was previously approved for the treatment of hallucinations and delusions associated with Parkinson disease psychosis in April 2016.

 to Acadia Pharmaceuticals due to deficiencies in their supplemental new drug application (sNDA) filing for pimavanserin for the treatment of DRP.

The FDA stated that the treatment cannot be accepted with the sNDA in its current form, citing a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.

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The study presented at the 2021 AAN Meeting follows the complete response letter issued by the FDA to Acadia Pharmaceuticals due to deficiencies in their sNDA.

Pimavanserin Doesn’t Cause Negative Cognition Treating Dementia-Related Psychosis

In a recent study, a research team evaluated several Alzheimer disease (AD) biomarkers, including cerebrospinal (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) to clarify how these markers are differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).

The research group found that higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and AD meta region of interest (ROI) cortical thickness.

“It is important to understand what information different neurodegenerative biomarkers provide to aid in both diagnosis and prognosis, especially because each marker is likely to be reflective of a different composite of pathological processes,” wrote first author Michelle M. Mielke, PhD, professor of epidemiology and neurology, and researcher, Mayo Clinic, and colleagues.

Mielke and colleagues analyzed data from 536 participants without dementia from the Mayo Clinic Study of Aging. CSF NfL, Ng, t-tau, amyloid beta (Aβ) 42 and longitudinal MRI scans were performed. They used linear mixed models to assess longitudinal associations between CSF markers and MRI changes.

Participants’ mean age was 74.9 years (standard deviation [SD], 7.3) and 304 (57%) were men. Out of all participants, 154 (29%) had an apolipoprotein E (APOE) ɛ4 allele and 70 (13%) had a clinical diagnosis of mild cognitive impairment (MCI). The participants had an average follow-up of 2.4 years (SD, 1.8) with 2.2 (SD, 1.0) visits.

Mielke and colleagues found that CSF Ng was strongly associated with t-tau (Spearman’s rho = 0.831; 

 <.0001) and t-tau (Spearman’s rho = 0.477; 

 <.0001). CSF NfL was moderately associated with Ng (Spearman’s rho = 0.321; 

Multivariable analyses revealed that that higher CSF NfL levels were cross-sectionally associated with lower AD meta- region of interest (ROI) cortical thickness (b, –0.149 [standard error (SE), 0.044]; 

 <.001) and with lower cortical thickness in the frontal (b, –0.224 [SE, 0.046]; 

 <.001), parietal (b, –0.163 [SE, 0.043]; 

 <.001), and temporal (b, –0.134 [SE, 0.042]; 

There were few cross-sectional associations between either CSF t-tau or Ng with most neuroimaging measures, with the exception that higher levels of t-tau (b, 0.209 [SE, 0.076]; 

 <.002) were associated with higher corpus callosum FA. Higher CSF t-tau levels were also associated with lower temporal lobe thickness in amyloid positive participants compared to amyloid negative in multivariable analyses (b, –0.215 [SE, 0.081]; 

Associations between CSF t-tau or Ng and neuroimaging markers did not differ in those with or without MCI after adjusting for age, sex, and CSF Aβ42. However, higher levels of CSF NfL were associated with reduced cortical thickness in participants with MCI in the frontal (b, –0.524 [SE, 0.131]; 

 <.001), parietal (b, –0.437 [SE, 0.125]; 

 <.001), and temporal lobes (b, -0.482 [SE, 0.121]; 

 <.001) and in an AD meta-ROI (b, –0.653 [SE, 0.125]; 

Higher CSF t-tau was longitudinally associated with declines in temporal lobe cortical thickness (b, –0.189 [SE, 0.068]; 

 = .006) and the AD signature region (b, –0.281 [SE, 0.073]; 

 <.001). Higher CSF NfL was associated with declines in the corpus callosum (b, – 0.283 [SE, 0.096]; 

 = .003) and cingulum (b, –0.308 [SE, 0.096]; 

 = .006) FA and WMH (b, 0.149 [SE, 0.055]; 

 = .007). No associations were seen between CSF Ng and longitudinal neuroimaging measures. Restricted analyses only including 268 participants with all neuroimaging modalities confirmed associations in all above analyses.

Mielke and colleagues found that associations between CSF t-tau or NfL and longitudinal neuroimaging markers did not differ by CSF Aβ42 status after adjusting for age and sex. Higher CSF Ng was associated with greater declines in temporal lobe thickness (b, –0.464 [SE, 0.140]; 

 <.001), AD meta-ROI thickness (b, –0.471 [SE, 0.151]; 

 = .002), and cingulum FA (b, –0.662 [SE, 0.240]; 

 = .006) in amyloid-positive individuals compared to amyloid-negative individuals. Restricting the analyses to participants with all neuroimaging modalities yielded similar results, with the exception that the interaction between CSF Ng and CSF Aβ42 for cingulum FA was no longer significant (

Lastly, increasing levels of CSF t-tau (b, –0.579 [SE, 0.218]; 

 = .008) and Ng (b, –0.664 [SE, 0.231]; 

 = .007) were associated with greater reduction in AD meta-ROI cortical thickness longitudinally in participants with MCI compared to those without. No differences were seen between CSF NfL and all neuroimaging outcomes between participants with or without diagnosed MCI.

“The present study contributes further insight regarding information each of these three candidate CSF markers may provide and how they can best be used for clinical and research purposes. Of the three, CSF Ng appears to be the best marker of AD-related pathological neurodegeneration (NfL, Ng, and t-tau) and will be most helpful for AD diagnosis and AD-related prognosis,” Mielke and colleagues wrote.

“Although CSF t-tau provides some indication of AD pathology, it appears to be less specific than Ng. Last, CSF NfL is non-specific to AD pathology. The measurement of CSF NfL has the added benefit of providing information regarding non-AD related pathologies, potentially due to vascular and other causes, and will add information about overall prognosis,” they concluded.

Researchers examine how biomarkers are differentially mapped to MRI measures of cortical thickness. 

Researchers Clarify Alzheimer Disease Biomarkers and MRI Measures

Visceral adiposity (VA) is strongly associated with obstructive sleep apnea (OSA) in elderly patients, while general adiposity is strongly associated with OSA in non-elderly patients, according to new research.

 resulted in an area under the curve (AUC) of 0.580 with a sensitivity of 0.382 and specificity of 0.790 in predicting moderate-to-severe-OSA in elderly patients. In non-elderly patients, body mass index (BMI) over 24.7 kg/m2 resulted in an AUC of 0.550 with a sensitivity of 0.883 and specificity of 0.484 in predictive power.

"Although some subjects may have never been clinically categorized as overweight or obese, if they have increased VA, they may be at increased risk of OSA and its adverse health outcomes. However, this hypothesis needs yet to be tested in the elderly,” wrote senior author Xinmin Liu, MD, president and respiratory specialist, Peking University First Hospital, and colleagues.

Liu and colleagues analyzed data from 169 patients aged at least 65 years (elderly) and 142 patients aged less than 65 years (non-elderly) referred for overnight polysomnography (PSG). More than 80% of participants were men (82.3% in elderly and 84.5% in non-elderly). Mild or no OSA was present in 69 participants (41% of total; 38 in elderly and 31 in non-elderly), moderate OSA was present in 104 (62% of total; 47 in elderly and 57 in non-elderly) and severe OSA was present in 138 (82% of total; 84 in elderly and 534 in non-elderly).

Patients reported smoking (25.1%) and drinking (23.2%), as well as comorbidities such as dyslipidemia (n = 263), hypertension (n = 229), thyroid diseases (n = 171), fatty liver (n =139), coronary heart disease (n = 122), diabetes (n = 105), gastroesophageal reflux disease (n = 69), hyperuricemia (n = 78), stroke (n = 66), chronic obstructive pulmonary disease (n = 25), cancer (n = 24), and chronic kidney disease (n = 20).

Increasing OSA severity was associated with increasing markers of obesity such as BMI, waist circumference (WC), hip circumference (HC), WC/HC ratio, NC/height (H) ratio, WC/H ratio, conicity index, SA, and VA (all P <.02) but was not associated with neck circumference (NC) and VA/subcutaneous adiposity (SA) ratio.

The researchers found a significant interaction between OSA severity and age only for VA/SA (

 <.005), which increased with OSA severity in the non-elderly and decreased in the elderly, although both VA and SA increased with OSA severity. Compared with the non-elderly, the elderly showed higher conicity index. VA/SA, lower BMI, NC, WC, HC and SA. WC/HC, NC/H, WC/H and VA increased with OSA severity across both groups (all 

Univariate analyses showed that BMI, WC, HC, WC/HC, WC/H, conicity index, VA and SA were significantly associated with apnea-hypopnea index (AHI) in the elderly, while BMI, NC, WC, HC, WC/HC, NC/H, WC/H, VA, SA and VA/SA were significantly associated with AHI in the non-elderly.

The strongest correlations were WC/H with AHI in the elderly (β = 0.296; 

 <.01) in the non-elderly. After adjusting for age, sex, cigarette smoking, alcohol drinking and main comorbidities, BMI, VA and VA/SA, explained 25.9% of AHI variability in the non-elderly and 17.2% variability in the elderly.

All told, Liu and colleagues found that VA over 128 cm

 resulted in an AUC of 0.580 with a sensitivity of 0.382 and specificity of 0.790 in predicting moderate-to-severe-OSA in elderly patients. In non-elderly patients, BMI over 24.7 kg/m2 resulted in an AUC of 0.550 with a sensitivity of 0.883 and specificity of 0.484 in predictive power.

VA/SA ratio less than 0.41 resulted in an AUC of 0.553 with a sensitivity of 0.176 and specificity of 0.947 in predictive power in elderly patients. In non-elderly patients, WA/SA predicted moderate-to-severe OSA with an AUC of 0.667, sensitivity of 0.550, and specificity of 0.710.

The differences in OSA associations “may suggest the need for age-specific screening and therapeutic strategies. However, our results should be considered preliminary and point to the need for future prospective longitudinal studies in a large cohort to elucidate this issue and to explore possible etiological differences between the elderly and the non-elderly,” Liu and colleagues concluded.

Increasing OSA severity was associated with increasing markers of obesity.

Sleep Apnea Linked to Visceral Adiposity in Geriatric Patients

Stakeholders are moving forward with a new clinical trial for an investigational agent aimed at treating patients with early Alzheimer disease (AD).

Alector announced the first patient has been dosed in its randomized, double-blind, placebo-controlled, dose-ranging, phase 2 INVOKE-2 study evaluating AL002.

“Alzheimer’s is a devastating disease that robs a person of their identity, and a family of their loved one. We are hopeful that AL002 may one day be a treatment option for the millions of people diagnosed with this disease,” said Michael Gold, MD, vice president, Development Neurosciences, AbbVie, in a statement. “We are pleased that the study was initiated rapidly and look forward to data from the Phase 2 study that will inform a potential pivotal clinical development program for AL002.”

INVOKE-2 will enroll approximately 265 participants with early AD at up to 90 sites globally. Disease progression will be measured using the Clinical Dementia Rating Sum Boxes (CDR-SB), as well as fluid and imaging biomarkers.

AL002 Targets Alzheimer Disease-Linked Pathway, TREM2

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein expressed on some immune cells and microglia. Previous, large scale, genome-wide studies have demonstrated its genetic links to sporadic AD. Impacted function of TREM2 may lead to AD and dementia, previous research suggests. An effective therapeutic approach may be increasing TREM2 activity in the brain, which may activate the brain’s immune system to target multiple pathologies of AD.

“Loss of TREM2 activity has been shown through human genetics to be one of the notable risk factors for developing Alzheimer’s disease,” said Robert Paul, MD, PhD, chief medical officer, Alector, in the statement.

AL002 is an investigational, humanized monoclonal antibody that targets TREM2. The AL002 clinical program is being developed in collaboration with AbbVie. Paul noted that Alector believes that this first-in-class antibody may help slow the progression of AD by targeting the TREM2 receptor.

“Our ability to move quickly into a phase 2 study is based on compelling preclinical and phase 1 data showing that AL002 engages TREM2 on microglia cells in the brain, resulting in increased microglial activity. We look forward to efficiently enrolling the phase 2 study to better understand the potential clinical benefits of AL002,” Paul added to the statement.

INFRONT-3 Study to Evaluate AL001 for Frontotemporal Dementia

INFRONT-3 is a randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluating AL003 in people with or at risk for frontotemporal dementia due to progranulin gene mutation (FTD-GRN). The first patient was dosed in July 2020.

INFRONT-3 will enroll up to 180 patients with FTD-GRN mutations across approximately 50 sites in the US, Europe, and Australia. Symptomatic and presymptomatic patients will be randomized to receive AL001 or placebo intravenously every four weeks. The effect of AL001 on clinical decline will also be measured with CDR-SB.

AL001, also a monoclonal antibody, is designed to modulate progranulin. The treatment was developed in collaboration with Adimab. The FDA previously granted it orphan drug designation for FTD and fast track designation for FTD-GRN.

“The initiation of our global pivotal phase 3 trial of AL001 is a significant step towards achieving our mission of helping patients suffering from FTD and other neurodegenerative diseases,” Paul said in a statement on INFRONT-3.

Alector’s announcement about the INVOKE-2 study follows a similar update regarding its INFRONT-3 study for frontotemporal dementia.