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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 68541

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Dr. Giulia Sita

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Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Interests: neuroprotection; neurodegeneration; Alzheimer’s disease; oxidative stress; aging; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most common neurodegenerative disease that represents the principal cause of dementia worldwide. The social and economic burden behind this disease affects families, caregivers and, obviously, patients. Numerous factors are involved in the onset and progression of AD, but the exact mechanisms leading to the accumulation of β-amyloid (Aβ) protein and the formation of neurofibrillary tangles of tau protein in the brain are still unresolved. In addition to the effort spent searching for new innovative treatments which are able to stop the progression of AD, to date, all treatments available are only applicable to symptomatic patients. Thus, the identification of modifications that accumulate with aging in the AD brain is certainly needed to discover new successful therapeutic approaches.

In this Special Issue, “Treatment of Alzheimer Disease”, we invite investigators to contribute original research articles and review articles regarding the novel therapeutic approaches to counteract AD progression.

Dr. Giulia Sita
Guest Editor

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Keywords

Alzheimer’s disease
oxidative stress
drug discovery
aging
neuoinflammation
mitochondria

Related Special Issue

Alzheimer's Disease Drugs in Pharmaceuticals (2 articles)

Published Papers (14 papers)

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Research

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19 pages, 3840 KiB

Open AccessArticle

Bezafibrate Exerts Neuroprotective Effects in a Rat Model of Sporadic Alzheimer’s Disease

by Li-Fan Lin, Yun-Ting Jhao, Chuang-Hsin Chiu, Lu-Han Sun, Ta-Kai Chou, Chyng-Yann Shiue, Cheng-Yi Cheng and Kuo-Hsing Ma

Pharmaceuticals 2022, 15(2), 109; https://doi.org/10.3390/ph15020109 - 18 Jan 2022

Cited by 8 | Viewed by 2583

Abstract

Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, reportedly attenuated tau pathology in a transgenic mouse model of primary tauopathy. Since tau pathology is a neuropathological hallmark of Alzheimer’s disease (AD), bezafibrate may be a potential drug for the treatment of AD. However, no study has investigated its effects in AD models. Thus, we aimed to evaluate whether bezafibrate has neuroprotective effects in a sporadic AD model induced by streptozotocin (STZ) intracerebroventricular (ICV) injection. Rats were administered STZ-ICV (3 mg/kg) followed by bezafibrate (50 mg/kg/day, intraperitoneal) for 4 weeks. Behavior tests and positron emission tomography (PET) were performed to evaluate longitudinal changes in cognitive function, tau pathology, and cerebral glucose metabolism. Immunofluorescence staining was performed to assess neuronal survival and microglial accumulation. STZ-ICV administration induced significant cognitive impairment and substantial neuronal loss, tau pathology, glucose hypometabolism, and microgliosis in the cortex and hippocampus, while bezafibrate effectively attenuated these abnormalities. This study demonstrated that bezafibrate has long-lasting neuroprotective effects in a sporadic AD model. Our data indicate that the neuroprotective effects of bezafibrate might be associated with its ability to ameliorate tau pathology, brain glucose hypometabolism, and neuroinflammation. These findings suggest that bezafibrate is a potential multi-target drug candidate for the treatment of AD. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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20 pages, 5675 KiB

Open AccessArticle

Effects of Magnesium Orotate, Benfotiamine and a Combination of Vitamins on Mitochondrial and Cholinergic Function in the TgF344-AD Rat Model of Alzheimer’s Disease

by Christian Viel, Adrian T. Brandtner, Alexander Weißhaar, Alina Lehto, Marius Fuchs and Jochen Klein

Pharmaceuticals 2021, 14(12), 1218; https://doi.org/10.3390/ph14121218 - 24 Nov 2021

Cited by 3 | Viewed by 2760

Abstract

Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer’s disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a “cocktail” containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the “cocktail” which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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14 pages, 2214 KiB

Open AccessArticle

A Novel Cardenolide Glycoside Isolated from Xysmalobium undulatum Reduces Levels of the Alzheimer’s Disease-Associated β-Amyloid Peptides Aβ42 In Vitro

by Anuradha Thakur, Phanankosi Moyo, Carl Johan van der Westhuizen, Hyun Ok Yang and Vinesh Maharaj

Pharmaceuticals 2021, 14(8), 743; https://doi.org/10.3390/ph14080743 - 29 Jul 2021

Cited by 2 | Viewed by 2727

Abstract

Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer’s disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-d-glucopyranoside (2), and crotoxigenin 3-O-glucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD’s β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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22 pages, 5943 KiB

Open AccessArticle

Effects of the Hydroethanolic Extract of Lycopodium selago L. on Scopolamine-Induced Memory Deficits in Zebrafish

by Mihai-Vlad Valu, Catalin Ducu, Sorin Moga, Denis Negrea, Lucian Hritcu, Razvan Stefan Boiangiu, Emanuel Vamanu, Tudor Adrian Balseanu, Simone Carradori and Liliana Cristina Soare

Pharmaceuticals 2021, 14(6), 568; https://doi.org/10.3390/ph14060568 - 14 Jun 2021

Cited by 8 | Viewed by 3817

Abstract

This scientific research focused on the production of hydroethanolic extract of the plant species Lycopodium selago L. (L. selago) by the ultrasound-assisted extraction (USAE) and the identification of biocompounds with high antioxidant activity is of interest for possible phytotherapeutic treatment against Alzheimer’s disease (AD). The extract was phytochemically analyzed to investigate polyphenols, flavonoids, and identify the sesquiterpenoid alkaloid huperzine A (HupA), which is known in the literature for its great relevance in AD. Evaluation and comparison of the antioxidant activity of the extract were performed by four complementary spectrophotometric methods (DPPH, FRAP, ABTS, ORAC). In vitro tests of the extract showed an excellent reciprocal link between the concentration of polyphenols and the measurement of the antioxidant activity of the extract with the sesquiterpenoid HupA. To confirm the antioxidant activity, L. selago hydroethanolic extract was administered in vivo to zebrafish (Danio rerio) with a pattern of scopolamine-induced cognitive impairment. Moreover, this study explored a possible correlation between the expression of oxidative stress markers in the brain tissue with the behavior of the scopolamine zebrafish model. In vivo tests showed that this fern could be used as a nutritional supply and as a phytotherapeutic method to prevent or treat various neurodegenerative diseases that call for high-nutritive-value medications. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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Review

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15 pages, 1245 KiB

Open AccessReview

Antidepressants in Alzheimer’s Disease: A Focus on the Role of Mirtazapine

by Ana Salomé Correia and Nuno Vale

Pharmaceuticals 2021, 14(9), 930; https://doi.org/10.3390/ph14090930 - 16 Sep 2021

Cited by 17 | Viewed by 7534

Abstract

Mirtazapine belongs to the category of antidepressants clinically used mainly in major depressive disorder but also used in obsessive-compulsive disorders, generalized anxiety, and sleep disturbances. This drug acts mainly by antagonizing the adrenergic α2, and the serotonergic 5-HT2 and 5-HT3 receptors. Neuropsychiatric symptoms, such as depression and agitation, are strongly associated with Alzheimer’s disease, reducing the life quality of these patients. Thus, it is crucial to control depression in Alzheimer’s patients. For this purpose, drugs such as mirtazapine are important in the control of anxiety, agitation, and other depressive symptoms in these patients. Indeed, despite some contradictory studies, evidence supports the role of mirtazapine in this regard. In this review, we will focus on depression in Alzheimer’s disease, highlighting the role of mirtazapine in this context. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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34 pages, 373 KiB

Open AccessReview

Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

by Barbara Miziak, Barbara Błaszczyk and Stanisław J. Czuczwar

Pharmaceuticals 2021, 14(5), 458; https://doi.org/10.3390/ph14050458 - 13 May 2021

Cited by 19 | Viewed by 4534

Abstract

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

31 pages, 470 KiB

Open AccessReview

Sleep-Based Interventions in Alzheimer’s Disease: Promising Approaches from Prevention to Treatment along the Disease Trajectory

by Susanna Cordone, Serena Scarpelli, Valentina Alfonsi, Luigi De Gennaro and Maurizio Gorgoni

Pharmaceuticals 2021, 14(4), 383; https://doi.org/10.3390/ph14040383 - 19 Apr 2021

Cited by 19 | Viewed by 5032

Abstract

The multifactorial nature of Alzheimer’s disease (AD) has led scientific researchers to focus on the modifiable and treatable risk factors of AD. Sleep fits into this context, given the bidirectional relationship with AD confirmed by several studies over the last years. Sleep disorders appear at an early stage of AD and continue throughout the entire course of the pathology. Specifically, sleep abnormalities, such as more fragmented sleep, increase in time of awakenings, worsening of sleep quality and primary sleep disorders raise with the severity and progression of AD. Intervening on sleep, therefore, means acting both with prevention strategies in the pre-clinical phase and with treatments during the course of the disease. This review explores sleep disturbances in the different stages of AD, starting from the pre-clinical stage. Particular attention is given to the empirical evidence investigating obstructive sleep apnea (OSA) disorder and the mechanisms overlapping and sharing with AD. Next, we discuss sleep-based intervention strategies in the healthy elderly population, mild cognitive impairment (MCI) and AD patients. We mention interventions related to behavioral strategies, combination therapies, and bright light therapy, leaving extensive space for new and raising evidence on continuous positive air pressure (CPAP) treatment effectiveness. Finally, we clarify the role of NREM sleep across the AD trajectory and consider the most recent studies based on the promising results of NREM sleep enhancement, which use innovative experimental designs and techniques. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

19 pages, 1736 KiB

Open AccessReview

Mild Cognitive Impairment and Mild Dementia: The Role of Ginkgo biloba (EGb 761^®)

by Carlo Tomino, Sara Ilari, Vincenzo Solfrizzi, Valentina Malafoglia, Guglielmo Zilio, Patrizia Russo, Stefania Proietti, Federica Marcolongo, Giovanni Scapagnini, Carolina Muscoli and Paolo Maria Rossini

Pharmaceuticals 2021, 14(4), 305; https://doi.org/10.3390/ph14040305 - 01 Apr 2021

Cited by 21 | Viewed by 7893

Abstract

Mild cognitive impairment (MCI) and dementia are clinically prevalent in the elderly. There is a high risk of cognitive decline in patients diagnosed with MCI or dementia. This review describes the effectiveness of Ginkgo biloba leaf special extract EGb 761^® for the treatment of dementia syndromes and EGb 761^® combination therapy with other medications for symptomatic dementia. This drug has shown convincing results, improving cognitive function, neuropsychiatric symptoms and consequent reduction of caregiver stress and maintenance of autonomy in patients with age-related cognitive decline, MCI and mild to moderate dementia. Currently, there is little evidence to support the combination therapy with anti-dementia drugs and, therefore, more evidence is needed to evaluate the role of EGb 761^® in mixed therapy. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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14 pages, 799 KiB

Open AccessReview

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

by Ernesto Fedele and Roberta Ricciarelli

Pharmaceuticals 2021, 14(1), 61; https://doi.org/10.3390/ph14010061 - 13 Jan 2021

Cited by 13 | Viewed by 3951

Abstract

Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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14 pages, 1024 KiB

Open AccessReview

The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease

by Kirsty Hamilton and Jenni Harvey

Pharmaceuticals 2021, 14(1), 52; https://doi.org/10.3390/ph14010052 - 11 Jan 2021

Cited by 18 | Viewed by 4726

Abstract

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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33 pages, 8977 KiB

Open AccessReview

Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease

by Marta Campora, Valeria Francesconi, Silvia Schenone, Bruno Tasso and Michele Tonelli

Pharmaceuticals 2021, 14(1), 33; https://doi.org/10.3390/ph14010033 - 05 Jan 2021

Cited by 46 | Viewed by 5041

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline leading to dementia and death. AD imposes neuronal death by the intricate interplay of different neurochemical factors, which continue to inspire the medicinal chemist as molecular targets for the development of new agents for the treatment of AD with diverse mechanisms of action, but also depict a more complex AD scenario. Within the wide variety of reported molecules, this review summarizes and offers a global overview of recent advancements on naphthoquinone (NQ) and anthraquinone (AQ) derivatives whose more relevant chemical features and structure-activity relationship studies will be discussed with a view to providing the perspective for the design of viable drugs for the treatment of AD. In particular, cholinesterases (ChEs), β-amyloid (Aβ) and tau proteins have been identified as key targets of these classes of compounds, where the NQ or AQ scaffold may contribute to the biological effect against AD as main unit or significant substructure. The multitarget directed ligand (MTDL) strategy will be described, as a chance for these molecules to exhibit significant potential on the road to therapeutics for AD. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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22 pages, 2344 KiB

Open AccessReview

Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer’s Disease

by José J. Jarero-Basulto, Martha C. Rivera-Cervantes, Deisy Gasca-Martínez, Francisco García-Sierra, Yadira Gasca-Martínez and Carlos Beas-Zárate

Pharmaceuticals 2020, 13(12), 424; https://doi.org/10.3390/ph13120424 - 26 Nov 2020

Cited by 23 | Viewed by 3176

Abstract

Substantial evidence in the literature demonstrates the pleiotropic effects of the administration of recombinant human erythropoietin (rhEPO) and its molecular variants in different tissues and organs, including the brain. Some of these reports suggest that the chemical properties of this molecule by itself or in combination with other agents (e.g., growth factors) could provide the necessary pharmacological characteristics to be considered a potential protective agent in neurological disorders such as Alzheimer’s disease (AD). AD is a degenerative disorder of the brain, characterized by an aberrant accumulation of amyloid β (Aβ) and hyperphosphorylated tau (tau-p) proteins in the extracellular and intracellular space, respectively, leading to inflammation, oxidative stress, excitotoxicity, and other neuronal alterations that compromise cell viability, causing neurodegeneration in the hippocampus and the cerebral cortex. Unfortunately, to date, it lacks an effective therapeutic strategy for its treatment. Therefore, in this review, we analyze the evidence regarding the effects of exogenous EPOs (rhEPO and its molecular variants) in several in vivo and in vitro Aβ and tau-p models of AD-type neurodegeneration, to be considered as an alternative protective treatment to this condition. Particularly, we focus on analyzing the differential effect of molecular variants of rhEPO when changes in doses, route of administration, duration of treatment or application times, are evaluated for the improved cellular alterations generated in this disease. This narrative review shows the evidence of the effectiveness of the exogenous EPOs as potential therapeutic molecules, focused on the mechanisms that establish cellular damage and clinical manifestation in the AD. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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25 pages, 1862 KiB

Open AccessReview

Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery

by William M. Pardridge

Pharmaceuticals 2020, 13(11), 394; https://doi.org/10.3390/ph13110394 - 16 Nov 2020

Cited by 83 | Viewed by 10956

Abstract

Despite the enormity of the societal and health burdens caused by Alzheimer’s disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood–brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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Other

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8 pages, 254 KiB

Open AccessCase Report

Dementia and COVID-19: A Case Report and Literature Review on Pain Management

by Damiana Scuteri, Marianna Contrada, Paolo Tonin, Maria Tiziana Corasaniti, Pierluigi Nicotera and Giacinto Bagetta

Pharmaceuticals 2022, 15(2), 199; https://doi.org/10.3390/ph15020199 - 04 Feb 2022

Cited by 9 | Viewed by 2190

Abstract

The coronavirus disease 2019 (COVID-19) pandemic imposes an unprecedented lifestyle, dominated by social isolation. In this frame, the population to pay the highest price is represented by demented patients. This group faces the highest risk of mortality, in case of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, and they experience rapid cognitive deterioration, due to lockdown measures that prevent their disease monitoring. This complex landscape mirrors an enhancement of neuropsychiatric symptoms (NPSs), with agitation, delirium and reduced motor performances, particularly in non-communicative patients. Due to the consistent link between agitation and pain in these patients, the use of antipsychotics, increasing the risk of death during COVID-19, can be avoided or reduced through an adequate pain treatment. The most suitable pain assessment scale, also feasible for e-health implementation, is the Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID-2) pain scale, currently under validation in the Italian real-world context. Here, we report the case of an 85-year-old woman suffering from mild cognitive impairment, subjected to off-label treatment with atypical antipsychotics, in the context of undertreated pain, who died during the pandemic from an extensive brain hemorrhage. This underscores the need for appropriate assessment and treatment of pain in demented patients. Full article

(This article belongs to the Special Issue Treatment of Alzheimer Disease)

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