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New Advances in Alzheimer’s Disease and Other Associated Diseases

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neurodegenerative Diseases".

Deadline for manuscript submissions: closed (20 January 2024) | Viewed by 17712

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Dr. Genaro G. Ortiz

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Department of Philosophical and Methodological Disciplines and Molecular Biology in Medicine Service Hospital Civil, University Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
Interests: Alzheimer’s disease; basic and clinical studies; genetics; frontotemporal dementias; Parkinson’s disease; dementia; neuropsychiatry of neurodegenerative diseases; late onset dementia disorders; TDP-43 LATE

Dr. Ramiro Ruiz-Garcia

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Department of Scientific Publications, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, Tlalpan, Mexico City 14269, Mexico
Interests: frontotemporal dementia; Alzheimer’s disease; Parkinson’s disease; dementia; primary progressive aphasia; neuropsychiatry of neurodegenerative diseases; late onset psychiatric disorders; neuropsychiatry of epilepsy

Special Issue Information

Dear Colleagues,

The Alzheimer dementia (AD) is a neurodegenerative disorder that manifests with progressive cognitive impairment associated with a loss of functional autonomy. AD has traditionally been classified based on age of onset into "early-onset AD" (EOAD), which affects people younger than 65 years and accounts for 5-10% of all cases, and "late-onset AD" (LOAD), which occurs after the age of 65 and is the most frequent form. Furthermore, within the context of EOAD and LOAD, three different variants are recognized: autosomal dominant, familial, and sporadic AD. AD is a primary, irreversible and progressive neurodegenerative disease characterized by the loss of multiple cognitive functions typical of such an entity that interferes with the usual social activities of the patient. In addition to cognitive symptoms, especially in the moderate-advanced phases of the disease, there are alterations in the field of personality, affectivity, ideation, perception, vegetative functions, and behavior. The more or less rapid progression of cognitive deficits, behavior and functional deterioration leads to the loss of autonomy of self-sufficiency with varying degrees of disability and the consequent dependence on others, up to immobilization in bed. The disease initially manifests with mild memory problems, people start to forget some things to get to the point where they can no longer recognize even family members and need help with even the simplest daily activities. The speed with which symptoms appear varies from person to person, the course of the disease is slow and, on average, patients can live up to 8-10 years after diagnosis. From the moderate stage of Alzheimer's, the patient needs constant assistance, which becomes increasingly intense as the disease progresses. This pathology is strongly disabling and constantly increasing, due to the aging of the population, it is one of the priorities faced by social and health systems, due to the impact it has on health and social services.

Currently, the diagnosis of Alzheimer's disease (as well as other types of dementia) is based on symptoms and follow-up, with the important help of neuroimaging techniques and biochemical and molecular markers; however, dementias of various origins can manifest with clinical pictures that can often be confounding factors; Furthermore, the onset of clinical symptoms and signs represents a fairly late event in the natural history of the disease, since the pathological process remains for many years at the subclinical level. The instrumental tests available to date are very useful, but they are not endowed with absolute specificity. For these reasons, the diagnosis of these pathologies is usually carried out with a certain delay and diagnostic errors are not uncommon, especially in the initial stages of the disease; particularly difficult is the differential diagnosis between dementias that present with a similar clinical picture (eg, Alzheimer's disease and behavioral variant of frontotemporal dementia).

The prevalence of neurodegenerative disorders is increasing as our population gets older. Although current research biomarkers have been useful in the understanding of neurodegenerative diseases including Alzheimer’s Disease, more data is necessary to better characterize clinical phenotypes and comprehend the neurobiology of neurodegenerative diseases and further develop efficacious treatments.

This special issue of Brain Sciences aims to present a collection of studies detailing the most recent advances in the field of Alzheimer’s Disease and related diseases. Authors are invited to submit cutting edge research and reviews that address a range of topics in Alzheimer’s Disease and related diseases including the following: epidemiology, neurobiology, biomarkers, genetics, neuropsychiatry, pathology, clinical trials, including pharmacological and/or non-pharmacological treatment strategies. We aim to present advances in neurodegenerative diseases research.

Sincerely:

Dr. Genaro G. Ortiz
Dr. Ramiro Ruiz-Garcia
Guest Editors

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Keywords

Alzheimer disease
biological markers
neurodegenerative dementias
frontotemporal
neuropsychology
TDP-43 LATE

Published Papers (10 papers)

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Research

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14 pages, 6299 KiB

Open AccessArticle

Modified RCTU Score: A Semi-Quantitative, Visual Tool for Predicting Alzheimer’s Conversion from aMCI

by Ari Chong, Jung-Min Ha, Ji Yeon Chung, Hoowon Kim and IL Han Choo

Brain Sci. 2024, 14(2), 132; https://doi.org/10.3390/brainsci14020132 - 27 Jan 2024

Viewed by 676

Abstract

This research evaluated the modified RCTU score, derived from amyloid PET scans, for predicting the progression from amnestic Mild Cognitive Impairment (aMCI) to Alzheimer’s Disease (AD). aMCI patients underwent baseline evaluations, including amyloid PET. AD conversion was identified through neuropsychological tests after observation. The RCTU was modified by segmenting frontal, parietal, and temporal lobes into left and right, resulting in seven areas. Scores from both modified and conventional RCTU were analyzed and compared. Among 45 patients, 12 progressed to AD (over 17.8 ± 6.8 months). AD converters showed higher scores in modified RCTU scores. Modified RCTU score had strong correlations with amyloid SUVR (r > 0.7). Modified RCTU sum score was the significant covariate of AD conversion. Modified RCTU could determine the asymmetry of amyloid deposits. We demonstrated that symmetric deposits of amyloid showed a higher risk for AD conversion when analyzed using modified RCTU. The modified RCTU score is a promising method for predicting AD conversion, correlating strongly with amyloid SUVR. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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15 pages, 1320 KiB

Open AccessArticle

Abnormalities of Hippocampal Subfield and Amygdalar Nuclei Volumes and Clinical Correlates in Behavioral Variant Frontotemporal Dementia with Obsessive–Compulsive Behavior—A Pilot Study

by Mu-N Liu, Li-Yu Hu, Chia-Fen Tsai, Chen-Jee Hong, Yuan-Hwa Chou, Chiung-Chih Chang, Kai-Chun Yang, Zi-Hong You and Chi Ieong Lau

Brain Sci. 2023, 13(11), 1582; https://doi.org/10.3390/brainsci13111582 - 11 Nov 2023

Cited by 1 | Viewed by 1163

Abstract

(1) Background: The hippocampus (HP) and amygdala are essential structures in obsessive–compulsive behavior (OCB); however, the specific role of the HP in patients with behavioral variant frontotemporal dementia (bvFTD) and OCB remains unclear. (2) Objective: We investigated the alterations of hippocampal and amygdalar volumes in patients with bvFTD and OCB and assessed the correlations of clinical severity with hippocampal subfield and amygdalar nuclei volumes in bvFTD patients with OCB. (3) Materials and methods: Eight bvFTD patients with OCB were recruited and compared with eight age- and sex-matched healthy controls (HCs). Hippocampal subfield and amygdalar nuclei volumes were analyzed automatically using a 3T magnetic resonance image and FreeSurfer v7.1.1. All participants completed the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS), Neuropsychiatric Inventory (NPI), and Frontal Behavioral Inventory (FBI). (4) Results: We observed remarkable reductions in bilateral total hippocampal volumes. Compared with the HCs, reductions in the left hippocampal subfield volume over the cornu ammonis (CA)1 body, CA2/3 body, CA4 body, granule cell layer, and molecular layer of the dentate gyrus (GC-ML-DG) body, molecular layer of the HP body, and hippocampal tail were more obvious in patients with bvFTD and OCB. Right subfield volumes over the CA1 body and molecular layer of the HP body were more significantly reduced in bvFTD patients with OCB than in those in HCs. We observed no significant difference in amygdalar nuclei volume between the groups. Among patients with bvFTD and OCB, Y-BOCS score was negatively correlated with left CA2/3 body volume (τ_b = −0.729, p < 0.001); total NPI score was negatively correlated with left GC-ML-DG body (τ_b = −0.648, p = 0.001) and total bilateral hippocampal volumes (left, τ_b = −0.629, p = 0.002; right, τ_b = −0.455, p = 0.023); and FBI score was negatively correlated with the left molecular layer of the HP body (τ_b = −0.668, p = 0.001), CA4 body (τ_b = −0.610, p = 0.002), and hippocampal tail volumes (τ_b = −0.552, p < 0.006). Mediation analysis confirmed these subfield volumes as direct biomarkers for clinical severity, independent of medial and lateral orbitofrontal volumes. (5) Conclusions: Alterations in hippocampal subfield volumes appear to be crucial in the pathophysiology of OCB development in patients with bvFTD. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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16 pages, 1062 KiB

Open AccessArticle

Poor Oral Health Linked with Higher Risk of Alzheimer’s Disease

by Mihir S. Kulkarni, Brandi C. Miller, Manan Mahani, Rahul Mhaskar, Athanasios Tsalatsanis, Shalini Jain and Hariom Yadav

Brain Sci. 2023, 13(11), 1555; https://doi.org/10.3390/brainsci13111555 - 07 Nov 2023

Viewed by 2281

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease characterized by cognitive and behavioral changes in older adults. Emerging evidence suggests poor oral health is associated with AD, but there is a lack of large-scale clinical studies demonstrating this link. Herein, we used the TriNetX database to generate clinical cohorts and assess the risk of AD and survival among >30 million de-identified subjects with normal oral health (n = 31,418,814) and poor oral health (n = 1,232,751). There was a greater than two-fold increase in AD risk in the poor oral health cohort compared to the normal oral health group (risk ratio (RR): 2.363, (95% confidence interval: 2.326, 2.401)). To reduce potential bias, we performed retrospective propensity score matching for age, gender, and multiple laboratory measures. After matching, the cohorts had no significant differences in survival probability. Furthermore, when comparing multiple oral conditions, diseases related to tooth loss were the most significant risk factor for AD (RR: 3.186, (95% CI: 3.007, 3.376)). Our results suggest that oral health may be important in AD risk, regardless of age, gender, or laboratory measures. However, more large-scale cohort studies are necessary to validate these findings and further evaluate links between oral health and AD. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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17 pages, 1208 KiB

Open AccessArticle

Detection of Alzheimer’s Disease Using Logistic Regression and Clock Drawing Errors

by Sophia Lazarova, Denitsa Grigorova, Dessislava Petrova-Antonova and for the Alzheimer’s Disease Neuroimaging Initiative

Brain Sci. 2023, 13(8), 1139; https://doi.org/10.3390/brainsci13081139 - 29 Jul 2023

Cited by 1 | Viewed by 1565

Abstract

Alzheimer’s disease is an incurable disorder that accounts for up to 70% of all dementia cases. While the prevalence of Alzheimer’s disease and other types of dementia has increased by more than 160% in the last 30 years, the rates of undetected cases remain critically high. The present work aims to address the underdetection of Alzheimer’s disease by proposing four logistic regression models that can be used as a foundation for community-based screening tools that do not require the participation of medical professionals. Our models make use of individual clock drawing errors as well as complementary patient data that is highly available and easily collectible. All models were controlled for age, education, and gender. The discriminative ability of the models was evaluated by area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow test, and calibration plots were used to assess calibration. Finally, decision curve analysis was used to quantify clinical utility. We found that among 10 possible CDT errors, only 3 were informative for the detection of Alzheimer’s disease. Our base regression model, containing only control variables and clock drawing errors, produced an AUC of 0.825. The other three models were built as extensions of the base model with the step-wise addition of three groups of complementary data, namely cognitive features (semantic fluency score), genetic predisposition (family history of dementia), and cardio-vascular features (BMI, blood pressure). The addition of verbal fluency scores significantly improved the AUC compared to the base model (0.91 AUC). However, further additions did not make a notable difference in discriminatory power. All models showed good calibration. In terms of clinical utility, the derived models scored similarly and greatly outperformed the base model. Our results suggest that the combination of clock symmetry and clock time errors plus verbal fluency scores may be a suitable candidate for developing accessible screening tools for Alzheimer’s disease. However, future work should validate our findings in larger and more diverse datasets. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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16 pages, 2016 KiB

Open AccessArticle

Neuropsychological Evaluation and Quantitative EEG in Patients with Frontotemporal Dementia, Alzheimer’s Disease, and Mild Cognitive Impairment

by Letteria Tomasello, Leonardo Carlucci, Angelina Laganà, Santi Galletta, Chiara Valeria Marinelli, Massimo Raffaele and Pierluigi Zoccolotti

Brain Sci. 2023, 13(6), 930; https://doi.org/10.3390/brainsci13060930 - 08 Jun 2023

Viewed by 1675

Abstract

This study analyzed the efficacy of EEG resting state and neuropsychological performances in discriminating patients with different forms of dementia, or mild cognitive impairment (MCI), compared with control subjects. Forty-four patients with dementia (nineteen patients with AD, and seven with FTD), eighteen with MCI, and nineteen healthy subjects, matched for age and gender, underwent an extensive neuropsychological test battery and an EEG resting state recording. Results showed greater theta activation in posterior areas in the Alzheimer’s disease (AD) and Fronto-Temporal Dementia (FTD) groups compared with the MCI and control groups. AD patients also showed more delta band activity in the temporal-occipital areas than controls and MCI patients. By contrast, the alpha and beta bands did not discriminate among groups. A hierarchical clustering analysis based on neuropsychological and EEG data yielded a three-factor solution. The clusters differed for several neuropsychological measures, as well as for beta and theta bands. Neuropsychological tests were most sensitive in capturing an initial cognitive decline, while increased theta activity was uniquely associated with a substantial worsening of the clinical picture, representing a negative prognostic factor. In line with the Research Domains Framework (RDoC) perspective, the joint use of cognitive and neurophysiological data may provide converging evidence to document the evolution of cognitive skills in at-risk individuals. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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16 pages, 2235 KiB

Open AccessArticle

Retinal Alterations as Potential Biomarkers of Structural Brain Changes in Alzheimer’s Disease Spectrum Patients

by Zheqi Hu, Lianlian Wang, Dandan Zhu, Ruomeng Qin, Xiaoning Sheng, Zhihong Ke, Pengfei Shao, Hui Zhao, Yun Xu and Feng Bai

Brain Sci. 2023, 13(3), 460; https://doi.org/10.3390/brainsci13030460 - 08 Mar 2023

Cited by 4 | Viewed by 1840

Abstract

Retinal imaging being a potential biomarker for Alzheimer’s disease is gradually attracting the attention of researchers. However, the association between retinal parameters and AD neuroimaging biomarkers, particularly structural changes, is still unclear. In this cross-sectional study, we recruited 25 cognitively impaired (CI) and 21 cognitively normal (CN) individuals. All subjects underwent retinal layer thickness and microvascular measurements with optical coherence tomography angiography (OCTA). Gray matter and white matter (WM) data such as T1-weighted magnetic resonance imaging and diffusion tensor imaging, respectively, were also collected. In addition, hippocampal subfield volumes and WM tract microstructural alterations were investigated as classical AD neuroimaging biomarkers. The microvascular and retinal features and their correlation with brain structural imaging markers were further analyzed. We observed a reduction in vessel density (VD) at the inferior outer (IO) sector (p = 0.049), atrophy in hippocampal subfield volumes, such as the subiculum (p = 0.012), presubiculum (p = 0.015), molecular_layer_HP (p = 0.033), GC-ML-DG (p = 0.043) and whole hippocampus (p = 0.033) in CI patients. Altered microstructural integrity of WM tracts in CI patients was also discovered in the cingulum hippocampal part (CgH). Importantly, we detected significant associations between retinal VD and gray matter volumes of the hippocampal subfield in CI patients. These findings suggested that the retinal microvascular measures acquired by OCTA may be markers for the early prediction of AD-related structural brain changes. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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Review

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24 pages, 1370 KiB

Open AccessReview

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

by Valeria Santillán-Morales, Norberto Rodriguez-Espinosa, Jesús Muñoz-Estrada, Salvador Alarcón-Elizalde, Ángel Acebes and Gloria Benítez-King

Brain Sci. 2024, 14(1), 46; https://doi.org/10.3390/brainsci14010046 - 02 Jan 2024

Viewed by 1226

Abstract

Alzheimer’s disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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28 pages, 6805 KiB

Open AccessReview

Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach

by Genaro Gabriel Ortiz, Javier Ramírez-Jirano, Raul L. Arizaga, Daniela L. C. Delgado-Lara and Erandis D. Torres-Sánchez

Brain Sci. 2023, 13(10), 1474; https://doi.org/10.3390/brainsci13101474 - 18 Oct 2023

Viewed by 1431

Abstract

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system, which is crucial for memory, emotions, and learning. However, distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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14 pages, 1820 KiB

Open AccessReview

The Association between Pesticide Exposure and the Development of Fronto-Temporal Dementia-Cum-Dissociative Disorders: A Review

by Carlos Alfonso Flores-Gutierrez, Erandis Dheni Torres-Sanchez, Emmanuel Reyes-Uribe, Juan Heriberto Torres-Jasso, Mireya Zoila Reyna-Villela, Daniel Rojas-Bravo and Joel Salazar-Flores

Brain Sci. 2023, 13(8), 1194; https://doi.org/10.3390/brainsci13081194 - 12 Aug 2023

Viewed by 1373

Abstract

Pesticides are chemicals used in agricultural fields for the prevention or destruction of pests. Inappropriate use of these substances, as well as handling them without using personal protective equipment, may result in serious health problems such as neurodegenerative diseases and mental disorders. Previous studies have demonstrated the adverse effects of pesticides on brain function. However, some researchers have associated pesticide poisoning with the development of disorders such as dissociative amnesia, multiple personality disorders, and depersonalization disorder. The objective of this work was to perform a bibliographic review of the relationship between pesticide poisoning and the development of dissociative disorders. Previous studies suggest that the duration of pesticide exposure is a major determinant in the development of dissociative diseases and disorders. The information obtained in this review suggests that there is no specific relationship between dissociative disorders and pesticide poisoning. However, these results point to associating the most representative symptoms of dissociative disorder (such as amnesia and memory loss) with pesticide exposure. Based on the bibliographic search, possible mechanisms of action were suggested in an attempt to explain a possible association between exposure to pesticides and the appearance of dissociative disorders. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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26 pages, 2983 KiB

Open AccessEditor’s ChoiceReview

Neurocognitive Psychiatric and Neuropsychological Alterations in Parkinson’s Disease: A Basic and Clinical Approach

by Héctor Alberto González-Usigli, Genaro Gabriel Ortiz, Claudia Charles-Niño, Mario Alberto Mireles-Ramírez, Fermín Paul Pacheco-Moisés, Blanca Miriam de Guadalupe Torres-Mendoza, José de Jesús Hernández-Cruz, Daniela Lucero del Carmen Delgado-Lara and Luis Javier Ramírez-Jirano

Brain Sci. 2023, 13(3), 508; https://doi.org/10.3390/brainsci13030508 - 18 Mar 2023

Cited by 7 | Viewed by 3605

Abstract

The main histopathological hallmarks of Parkinson’s disease (PD) are the degeneration of the dopaminergic neurons of the substantia nigra pars compacta and the loss of neuromelanin as a consequence of decreased dopamine synthesis. The destruction of the striatal dopaminergic pathway and blocking of striatal dopamine receptors cause motor deficits in humans and experimental animal models induced by some environmental agents. In addition, neuropsychiatric symptoms such as mood and anxiety disorders, hallucinations, psychosis, cognitive impairment, and dementia are common in PD. These alterations may precede the appearance of motor symptoms and are correlated with neurochemical and structural changes in the brain. This paper reviews the most crucial pathophysiology of neuropsychiatric alterations in PD. It is worth noting that PD patients have global task learning deficits, and cognitive functions are compromised in a way is associated with hypoactivation within the striatum, anterior cingulate cortex, and inferior frontal sulcus regions. An appropriate and extensive neuropsychological screening battery in PD must accurately assess at least five cognitive domains with some tests for each cognitive domain. This neuropsychological screening should consider the pathophysiological and clinical heterogeneity of cognitive dysfunction in PD. Full article

(This article belongs to the Special Issue New Advances in Alzheimer’s Disease and Other Associated Diseases)

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