Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; H&Y = Hoehn and Yahr; MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

Imaging amyloid deposition in Lewy body diseases

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of patients. There are various descriptive hypotheses regarding the causes of AD, including the cholinergic hypothesis, amyloid hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, inflammatory hypothesis, metal ion hypothesis, and lymphatic system hypothesis. However, the ultimate etiology of AD remains obscure. In this review, we discuss the main hypotheses of AD and related clinical trials. Wealthy puzzles and lessons have made it possible to develop explanatory theories and identify potential strategies for therapeutic interventions for AD. The combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD. We further propose that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD.

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History and progress of hypotheses and clinical trials for Alzheimer’s disease

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Alzheimer's disease and its treatment by different approaches: A review.

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2-production

Dear Editors, Alzheimer’s disease (AD) and vascular dementia (VaD) are two of the most common forms of dementia, resulting in increased disability and mortality, impaired quality of life, and serious burdens on society and caregivers. However, the presently available drugs can only alleviate symptoms for a short time without delaying the progression of the cognitive disorders. Since 2003, no new drugs have been approved by the US Food and Drug Administration for the treatment of AD. In 2019, phase III clinical trials of crenezumab and aducanumab, two anti-amyloid beta monoclonal antibodies, were terminated. The scant progress in clinical trials urges efforts towards an alternative therapeutic strategy for dementia. Approximately half of dementia patients suffered from depression. Physicians tend to prescribe selective serotonin reuptake inhibitors (SSRIs) for depression-complicating dementia. SSRIs have effects on brain function associated with neuronal plasticity, neurogenesis, and neuronal differentiation in rodents and may contribute to cognitive performance. However, the role of SSRIs in the cognitive function of dementia patients has not yet reached a consensus. Therefore, we conducted the present meta-analysis to review and quantify the effects of SSRIs, especially fluoxetine, on cognitive function in AD and VaD patients, with the intention to provide useful advice for clinical practice. The literature search initially identified 854 citations, and 14 randomized controlled trials (RCTs) published between 2000 and 2018 remained in the final analysis (Supplementary Fig. 1), of which five compared fluoxetine with a placebo. A total of 1091 patients (550 received SSRIs and 541 received the placebo) were followed from 8 to 12 weeks. The baseline information and quality assessment results of the included studies are presented in Supplementary Table 1 and Supplementary Fig. 2. The mean difference (MD) with 95% confidence intervals (CIs) was used as the effect size. No significant heterogeneity was detected for age, and there was no age difference (Fig. 1a) between the SSRI group and the control group. The effect of SSRIs on cognitive function as assessed by the Mini-Mental State Examination (MMSE) was the primary outcome of interest in this study. The MMSE scores differed between the SSRI and placebo groups, indicating a significantly beneficial influence of SSRIs on cognitive disorders compared with placebo (MD= 0.84, 95% CI: 0.32–1.37, P= 0.002) (Fig. 1b). Two subgroups (fluoxetine and nonfluoxetine) of SSRIs were further analyzed. Five studies provided data for the fluoxetine subgroup comparison, showing a statistically significant difference in the MMSE scores between the fluoxetine and placebo groups (MD= 1.16, 95% CI: 0.41–1.90, P= 0.002) (Fig. 1c). Nine studies showed no significant difference between the nonfluoxetine SSRI and placebo groups with regard to the MMSE scores (MD= 0.58, 95% CI: −0.17–1.33, P= 0.13) (Fig. 1d). The present meta-analysis explored the effectiveness of SSRIs with regard to the amelioration of cognitive performance in people with AD and VaD. All participants had a standardized diagnosis of dementia that was restricted to AD and VaD. Some, but not all, studies required participants to have depression at the point of entry. Our pooled meta-analysis is the first to support that SSRIs (mainly fluoxetine) exert beneficial effects on cognition compared with a placebo. Previously, three meta-analyses investigated whether SSRIs influence cognitive performance in dementia patients and showed either a disadvantage or no benefit in the SSRI group. 8 Previous studies recruited both AD and frontotemporal dementia patients and calculated the overall effects of SSRIs. Here, we focused on the effect of fluoxetine on AD and VaD, two of the most common types of dementia. Based on these meta-analyses, short-term SSRI treatment (<30 days) was significantly associated with increased risks of dementia compared with the placebo. Another study found increased rates of dementia during the initial prescription periods and then reductions in the rate of dementia during continued long-term antidepressant treatment. However, our meta-analysis demonstrates that fluoxetine treatment for 8–12 weeks is associated with improved MMSE performance (Fig. 1c). Interestingly, this conclusion is consistent with and supported by the fact that fluoxetine can trigger neurogenesis and synapse formation in the rat hippocampus and enlarge hippocampal volume in female patients; more detailed potential mechanisms are discussed in our accompanying review. As depression impairs cognitive function, improved cognition might be expected after the remission of depression due to SSRI treatment; however, this is unlikely to be the underlying mechanism because only fluoxetine and no other SSRIs exerted a beneficial influence on cognition compared with the placebo in our meta-analysis. Our study had several strengths. To minimize variations in types of cognition tests, we only calculated the MDs of the MMSE and avoided mixing different types of tests together. With the available evidence and the enlarged number of RCTs studies to date, we have enhanced statistical power to quantify the effects of SSRI antidepressants on cognition in dementia patients. In addition, the quality of the included studies was generally high, and subgroup analyses were carried out to reduce heterogeneity. The sensitivity analysis showed that the estimates were relatively stable. Limitations should be considered. Although strict inclusion

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The effect of selective serotonin reuptake inhibitors on cognitive function in patients with Alzheimer's disease and vascular dementia: focusing on fluoxetine with long follow-up periods.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Author Correction: History and progress of hypotheses and clinical trials for Alzheimer’s disease

In a recent paper published in Nature, Gate et al. reported adaptive immune changes in Alzheimer’s disease (AD), discovered CD8 T effector memory CD45RA (TEMRA) cells with proinflammatory and cytotoxic functions in AD patients, and identified two TEMRA cell-recognized antigens of human herpesvirus 4 (HHV-4), also known as Epstein–Barr virus (EBV). The findings suggested that adaptive immunity might have a role in AD progression. In this article, the authors performed comprehensive analyses of four cohorts to explore the adaptive immunity in AD. In the first cohort, using mass cytometry to study the peripheral blood mononuclear cells (PBMCs) of patients with mild cognitive impairment (MCI) or AD, the authors detected an increased population of CD3CD8CD27CD45RA TEMRA cells. In the second cohort, a negative correlation was revealed between TEMRA cells and cognition in MCI and AD patients. By stimulating PBMCs with phorbol 12-myristate 13-acetate and ionomycin, TEMRA cells from patients with MCI or AD demonstrated potent effector functions, such as secreting proinflammatory cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor (TNF), which was consistent with the upregulated T cell receptor (TCR) and cytokine signaling in TEMRA cells. In the third cohort, the authors detected the increased localization of TEMRA cells adjacent to amyloid-β (Aβ) plaques in the leptomeninges adjacent to the hippocampus and in the cerebrospinal fluid (CSF) of patients with AD. In the fourth cohort, the authors revealed the cytotoxic function of clonal TEMRA cells from the CSF of patients with AD, including high expression levels of cytotoxic effectors (granule protein 7, NKG7 and granzymes A, GZMA) and the pro-aging factor (beta-2-microglobulin, B2M). Therefore, the authors demonstrated the proinflammatory (IFN-γ and TNF) and cytotoxic functions (NKG7, GZMA and B2M) of TEMRA cells from patients with AD. Since T effector memory cells are associated with immunological memory, the authors further determined the antigens that caused specific clonal expansion of TEMRA cells in AD, including Herpesviridae EB nuclear antigen 3 (EBNA3A) and the EBV/HHV-4 trans-activator protein BZLF1.

Pei-Pei Liu

Papers

History and progress of hypotheses and clinical trials for Alzheimer’s disease

The effect of selective serotonin reuptake inhibitors on cognitive function in patients with Alzheimer's disease and vascular dementia: focusing on fluoxetine with long follow-up periods.

Author Correction: History and progress of hypotheses and clinical trials for Alzheimer’s disease

Human herpesvirus 4 and adaptive immunity in Alzheimer's disease.