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Authors examined the impact of neuropsychiatric symptoms in Alzheimer disease (AD) patients' and caregivers' quality of life (QOL) and assessed the relationship of caregiver distress to neuropsychiatric symptoms and caregiver QOL. Sixty-two patients with probable or possible AD and their caregivers participated. Neuropsychiatric symptoms of patients were assessed with the Neuropsychiatric Inventory (NPI). QOL of both patients and caregivers was assessed using the QOL–Alzheimer's Disease (QOL–AD) scale. Each patient and caregiver completed patient QOL ratings; caregivers also completed caregiver QOL assessments. Caregiver QOL–AD was negatively correlated with agitation/aggression, anxiety, disinhibition, irritability/lability, and total NPI score. Patient QOL on both patient and caregiver ratings was negatively correlated with depression. Patient-reported QOL–AD ratings at different levels of cognitive functioning were not correlated with caregiver-reported ratings. The lack of relationship between patient and caregiver assessments of patient QOL was evident in both mildly and moderately affected patients. Caregiver QOL was negatively correlated with distress related to agitation/aggression, disinhibition, irritability/lability, and total NPI distress. Neuropsychiatric symptoms of AD patients adversely affect both patient and caregiver QOL. These results suggest that identifying and treating neuropsychiatric symptoms in AD may improve both patient and caregiver QOL.

In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability progression, and better MRI features than interferon beta-1a. Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles. 1 – 3 B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation, 4 autoantibody production, 5 , 6 cytokine regulation, 4 and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration. 7 , 8 Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .

Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received placebo. The drug was associated with decreased lesion activity on MRI. Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis. 1 The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur. 1 Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful, 2 – 4 and no disease-modifying treatments have been approved. B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form. 5 Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) Diversity, Equity, and Inclusion Working Group (DE&I WG) was established to work with the ADNI3 Diversity Task Force to provide an industry perspective on increasing the representation of diverse participants in ADNI3 and to build precompetitive cross‐industry knowledge in engagement and recruitment of under‐represented participants (URPs). In this article, we review and highlight the role and ongoing activities within the ADNI PPSB DE&I WG and provide a cross‐industry perspective on areas where precompetitive collaboration can improve the inclusiveness in clinical trials, drawing on examples from ADNI4. Highlights New collaboration crosses boundaries to allow PPSB DE&I WG members to work together in a preproprietary way. When faced with the same challenges required by FDA combined with a growing prevalence of AD, the DE&I WG has drafted a range of initiatives that may benefit ADNI, AD patients, care partners, and respective companies involved in this work. In order to address the multifactorial problem of successfully enrolling representative populations in clinical trials, it will “take a village” to bring about sustainable changes.

Authors examined the impact of neuropsychiatric symptoms in Alzheimer disease (AD) patients' and caregivers' quality of life (QOL) and assessed the relationship of caregiver distress to neuropsychiatric symptoms and caregiver QOL.OBJECTIVEAuthors examined the impact of neuropsychiatric symptoms in Alzheimer disease (AD) patients' and caregivers' quality of life (QOL) and assessed the relationship of caregiver distress to neuropsychiatric symptoms and caregiver QOL.Sixty-two patients with probable or possible AD and their caregivers participated. Neuropsychiatric symptoms of patients were assessed with the Neuropsychiatric Inventory (NPI). QOL of both patients and caregivers was assessed using the QOL-Alzheimer's Disease (QOL-AD) scale. Each patient and caregiver completed patient QOL ratings; caregivers also completed caregiver QOL assessments.METHODSSixty-two patients with probable or possible AD and their caregivers participated. Neuropsychiatric symptoms of patients were assessed with the Neuropsychiatric Inventory (NPI). QOL of both patients and caregivers was assessed using the QOL-Alzheimer's Disease (QOL-AD) scale. Each patient and caregiver completed patient QOL ratings; caregivers also completed caregiver QOL assessments.Caregiver QOL-AD was negatively correlated with agitation/aggression, anxiety, disinhibition, irritability/lability, and total NPI score. Patient QOL on both patient and caregiver ratings was negatively correlated with depression. Patient-reported QOL-AD ratings at different levels of cognitive functioning were not correlated with caregiver-reported ratings. The lack of relationship between patient and caregiver assessments of patient QOL was evident in both mildly and moderately affected patients. Caregiver QOL was negatively correlated with distress related to agitation/aggression, disinhibition, irritability/lability, and total NPI distress.RESULTSCaregiver QOL-AD was negatively correlated with agitation/aggression, anxiety, disinhibition, irritability/lability, and total NPI score. Patient QOL on both patient and caregiver ratings was negatively correlated with depression. Patient-reported QOL-AD ratings at different levels of cognitive functioning were not correlated with caregiver-reported ratings. The lack of relationship between patient and caregiver assessments of patient QOL was evident in both mildly and moderately affected patients. Caregiver QOL was negatively correlated with distress related to agitation/aggression, disinhibition, irritability/lability, and total NPI distress.Neuropsychiatric symptoms of AD patients adversely affect both patient and caregiver QOL. These results suggest that identifying and treating neuropsychiatric symptoms in AD may improve both patient and caregiver QOL.CONCLUSIONNeuropsychiatric symptoms of AD patients adversely affect both patient and caregiver QOL. These results suggest that identifying and treating neuropsychiatric symptoms in AD may improve both patient and caregiver QOL.

ObjectivesTo assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with no evidence of progression or active disease (NEPAD) in the Phase III, placebo-controlled ORATORIO study in primary progressive multiple sclerosis (PPMS). PPMS is characterised by steadily increasing neurologic disability. The analysis of accompanying inflammatory disease activity in PPMS, including brain MRI activity and relapses, has to date been limited. NEPAD is a novel composite endpoint that assesses the combined absence of disease progression and active disease in patients with PPMS.MethodsIn a post-hoc exploratory analysis of the ORATORIO trial, 234 placebo- and 465 ocrelizumab-treated patients were evaluated to assess the proportion of patients with NEPAD, defined as having no evidence of progression (no 12 weeks confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12 weeks confirmed progression of ≥20% on the timed 25 foot walk test and 9-hole peg test), no brain MRI activity (no new/enlarging T2 lesions and no T1 Gd+ lesions), and no protocol-defined relapse. Brain MRI assessments were conducted at baseline and weeks 24, 48, and 120.ResultsCompared with placebo, ocrelizumab increased the proportion of patients with NEPAD at Week 120 (9.4% vs 29.9%; risk ratio ocrelizumab vs placebo (95% CI): 3.15 (2.07 to 4.79); p<0.0001). A consistent effect of ocrelizumab was also observed on all three components of NEPAD. Sensitivity analyses will also be presented.ConclusionsIn the ORATORIO trial, ocrelizumab increased by approximately 3-fold the proportion of patients with NEPAD vs placebo, as measured by the combination of no evidence of progression, no relapse and no MRI activity. NEPAD may represent a useful composite outcome to assess the absence of clinical and MRI features of disease progression and activity in patients with PPMS.

Background The deposition of amyloid-β (Aβ) in the human brain is a hallmark of Alzheimer’s disease and is associated with cognitive decline. Aβ pathology is traditionally assessed at the whole-brain level across neocortical regions using positron emission tomography (PET). However, these measures often show weak associations with future cognitive impairment. A more sensitive pathology metric is needed to quantify early Aβ burden and better predict cognitive decline. Here, we aim to develop a network-based metric of Aβ burden to improve early prediction of cognitive decline in aging populations. Methods We integrated subject-specific brain connectome information with Aβ-PET measures to construct a network-based metric of Aβ burden. Cross-validated predictive modeling was used to evaluate the performance of this metric in predicting longitudinal cognitive decline. Furthermore, we identified a neuropathological signature pattern linked to future cognitive decline, and we validated this pattern in an independent cohort. Results Our results demonstrate that incorporating individualized structural connectome, but not functional connectome, information into Aβ measures enhances predictive performance for prospective cognitive decline. The identified neuropathological signature pattern is reproducible across cohorts. Conclusion These findings advance our understanding of the spatial patterns of Aβ pathology and its relationship to brain networks, highlighting the potential of connectome-informed network-based metrics for Aβ-PET imaging in identifying individuals at higher risk of cognitive decline. Plain language summary Amyloid-β peptide is a molecule that is known to accumulate in the brains of people with Alzheimer’s disease. This accumulation starts to occur many years before the symptoms of Alzheimer’s disease, such as memory problems. Current methods to image the brain for amyloid-β peptide usually measure the overall level across the whole brain. In this study, we developed a more sensitive and personalized measure of amyloid-β by also considering how the different parts of a person’s brain are connected. We found that this approach improves the ability to predict future changes in cognition compared to the standard method. Our method might enable earlier identification of people at risk of developing Alzheimer’s disease, which could improve monitoring and treatment. He et al. develop a network-based metric of amyloid-β burden by integrating individualized brain connectomes with amyloid-PET imaging. This approach improves prediction of future cognitive decline in older adults and may support earlier identification of individuals at risk of dementia.

The development of a maturing T-cell-mediated immune response was characterized in Parkinson's disease subjects receiving recombinant human glial-derived neurotrophic factor (r-metHuGDNF) via continuous bilateral intraputaminal infusion. Eighteen of 34 subjects tested positive for anti-r-metHuGDNF-binding antibodies. Four subjects developed neutralizing activity, three of which demonstrated classic immunoglobulin class switching from IgM to IgG. An increase of anti-r-metHuGDNF IgG-binding antibodies correlated with the development of neutralizing activity. All serum samples from two subjects with neutralizing activity were characterized for IgG subclasses. These data revealed an initial anti-r-metHuGDNF IgG population where IgG1 >> IgG2 >> IgG4, and IgG3 concentrations were negligible. However, continued antigenic stimulation resulted in concentration changes where IgG4 > IgG1> IgG2, indicating a mature immune response. In addition, using in silico techniques, two immunodominant MHC class II T-cell epitopes were predicted for the native GDNF sequence. These data demonstrate development of a mature T-cell-mediated immune response in these subjects.

Objective: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine. Methods: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer’s disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale. Results: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups. Conclusions: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism.

Behavioural disturbances are common in Alzheimer's disease and may be affected by medications being developed to enhance cognition or slow disease progression as well as by psychotropic agents developed specifically to affect behaviour. In many cases, Alzheimer's disease patients included in clinical trials are not selected for behavioural attributes and the patient population is heterogeneous at baseline with regard to these symptoms. Analyses of the behavioural data should include assessment of the effects of the agent on patients who were symptomatic at baseline as well as on the incidence of new behaviours in those without symptoms at the time of study initiation. Analyses may focus on symptomatic patients exhibiting specific degrees of improvement (e.g. 50% reduction in symptom severity). The analytic strategy chosen to characterize the behavioural changes occurring in clinical trials involving Alzheimer's disease patients will depend on the hypotheses being explored, the characteristics of the patients at baseline, the size of the population studied, the assessment methodology, and the outcomes of interest.