How can we manage progressive supranuclear palsy syndrome with pharmacotherapy?

INTRODUCTION: Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions. AREAS COVERED: In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS). EXPERT OPINION: Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could be also viable targets.

The epigenetics of frailty.

The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.

The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) ε4 allele have a 4-fold increased AD risk, while APOE ε4/ε4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE ε3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.

Which Came First, Age-Related Hearing Loss with Tinnitus or Cognitive Impairment? What are the Potential Pathways?

Research on the causal relationship between age-related hearing loss (ARHL) and/or tinnitus and dementia is an important and fast-moving field. In this opinion paper, the up-to-date evidence and potential mechanisms for the bidirectional relationship are reviewed. We also present several critical factors that increase the challenges of understanding the causal relationship. These factors include common causes (such as aging, frailty, vascular impairment, and chronic inflammation), auditory and cognitive reserves, and the difficulty in distinguishing central auditory processing disorder (CAPD) from cognitive impairment. Finally, based on cumulative evidence, we propose an integrated mechanism in which the central auditory system might be the common target of both peripheral auditory impairment and dementia or its precursor. There is a bidirectional interaction between the peripheral and central auditory systems and between the central auditory systems and the cognitive brain. CAPD causes the depletion of auditory and cognitive reserves, and indirectly affects the peripheral auditory system via the auditory efferent system. According to the proposal, multimodal intervention might be beneficial for patients with ARHL and/or tinnitus and cognitive impairment, apart from hearing restoration by hearing aids or cochlear implants.

The Relationship between Oral Health-Related Quality of Life and Body Mass Index in an Older Population from Southern Italy: The Salus in Apulia Study.

BACKGROUND: The assessment of oral health-related quality of life (OHRQoL) evaluated the impact of an individual's oral health on the patient's physical and psychosocial status. We evaluated the association between subjective OHRQoL, measured with the Oral Health Impact Profile-14 (OHIP-14) questionnaire, and unfavorable body mass index (BMI) (i.e., too high or too low) in a large population-based study on older adults from Southern Italy. Moreover, we assessed which of the seven OHIP-14 domains was the most strongly associated with an unfavorable BMI. METHODS: We used data on a subpopulation of the Salus in Apulia Study, including 216 older adults. BMI < 18.4 kg/m2 and >30 kg/m2 were classified as unfavorable, while values between 18.5 and 30 kg/m2 were classified as ideal. RESULTS: A higher OHIP-14 total score increased the risk of an unfavorable BMI (odds ratio (OR): 1.08, 95% confidence interval (CI): 1.01-1.15). In the model adjusted for age, sex, education, hypertension, carbohydrate consumption, and alcohol consumption, this finding was confirmed with a higher OHIP-14 total score increasing the risk of an unfavorable BMI (OR: 1.10, 95% CI: 1.01-1.22), and higher age linked to a decreased risk of an unfavorable BMI (OR: 0.89, 95% CI: 0.82-0.97). In a random forest regression model, the most important predictive domains/sub-scales of OHIP-14 in the mean decrease in the Gini coefficient for unfavorable BMI were, in order of decreasing importance, physical pain, functional limitation, psychological discomfort, physical disability, social disability, psychological disability, and handicap. CONCLUSIONS: In older age, negative OHRQoL, particularly linked to the physical pain domain, increased the risk of being underweight or overweight and obesity.

Passive tau-based immunotherapy for tauopathies.

Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. In secondary tauopathies, i.e., Alzheimer's disease (AD), tau deposition can be observed, but tau may coexist with another protein, i.e., amyloid-ß. In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. Treatments are being developed to interfere with the aggregation process or to promote the clearance of tau protein. Several tau-targeted passive immunotherapy approaches are in development for treating tauopathies. At present, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005). However, none of these seven agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab and tilavonemab. Further evidence will come from ongoing Phase I/II trials on passive immunotherapeutics for treating primary and secondary tauopathies.

Nutritional patterns as machine learning predictors of liver health in a population of elderly subjects.

BACKGROUND AND AIMS: Non-alcoholic hepatic steatosis affects 25% of adults worldwide and its prevalence increases with age. There is currently no definitive treatment for NAFLD but international guidelines recommend a lifestyle-based approach, including a healthy diet. The aim of this study was to investigate the interactions between eating habits and the risk of steatosis and/or hepatic fibrosis, using a machine learning approach, in a non-institutionalized elderly population. METHODS AND RESULTS: We recruited 1929 subjects, mean age 74 years, from the population-based Salus in Apulia Study. Dietary habits and the risk of steatosis and hepatic fibrosis were evaluated with a validated food frequency questionnaire, the Fatty Liver Index (FLI) and the FIB-4 score, respectively. Two dietary patterns associated with the risk of steatosis and hepatic fibrosis have been identified. They are both similar to a "western" diet, defined by a greater consumption of refined foods, with a rich content of sugars and saturated fats, and alcoholic and non-alcoholic calorie drinks. CONCLUSION: This study further supports the concept of diet as a factor that significantly influences the development of the most widespread liver diseases. However, longitudinal studies are needed to better understand the causal effect of the consumption of particular foods on fat accumulation in the liver.

Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies.

INTRODUCTION: Tauopathies are clinicopathological entities with increased and pathological deposition in glia and/or neurons of hyperphosphorylated aggregates of the microtubule-binding protein tau. In secondary tauopathies, i.e. Alzheimer's disease (AD), tau deposition can be observed, but tau coexists with another protein (amyloid-ß). In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. AREAS COVERED: The present review summarized recent advances about the development and challenges in treatments for primary and secondary tauopathies, with a focus on passive tau-based immunotherapy. EXPERT OPINION: Several tau-targeted passive immunotherapeutics are in development for treating tauopathies. At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for progressive supranuclear palsy syndrome and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005). However, none of these nine agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Further evidence on passive immunotherapeutics for treating primary and secondary tauopathies will come from ongoing Phase I/II trials.

Exploring the Association of Burning Mouth Syndrome with Depressive and Anxiety Disorders in Middle-Aged and Older Adults: A Systematic Review.

BACKGROUND: Burning Mouth Syndrome (BMS) is an idiopathic condition mainly affecting middle-aged and older individuals with hormonal disturbances or psychiatric disorders and is characterized by chronic pain. The etiopathogenesis of this multifactorial syndrome is largely unknown. The objective of the present systematic review was therefore to evaluate the relationship of BMS with depressive and anxiety disorders in middle-aged and older individuals. METHODS: We selected studies evaluating BMS and depressive and anxiety disorders assessed with validated tools, published from their inception up to April 2023, using PubMed, MEDLINE, EMBASE, Scopus, Ovid, and Google Scholar databases and adhering to the PRISMA 2020 guidelines/PRISMA 2020 27-item checklist. This study is registered on PROSPERO (CRD42023409595). The National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies were used to examine the risk of bias. RESULTS: Two independent investigators rated 4322 records against the primary endpoint and found 7 records meeting the eligibility requirements. Anxiety disorders were found to be the most common psychiatric disorders related to BMS (63.7%), followed by depressive disorders (36.3%). We found a moderate association of BMS with anxiety disorders, with multiple studies included (n = 7). Moreover, we found a low association of BMS with depressive disorders (included studies, n = 4). The role of pain appeared to be controversial in explaining these associations. CONCLUSIONS: In middle-aged and older subjects, anxiety and depressive disorders may be potentially related to the development of BMS. Furthermore, also in these age groups, females showed higher risk of developing BMS than males, even when taking into account multimorbidity such as sleep disorders, personality traits, and biopsychosocial changes as suggested by study-specific findings.

Temporomandibular Disorders as Contributors to Primary Headaches: A Systematic Review.

AIMS: To systematically review the literature assessing associations between TMDs and primary headaches. METHODS: Using validated clinical criteria, studies on TMDs and primary headaches published up to January 10, 2023 were identified using six electronic databases. This review adhered to the PRISMA 2020 guidelines and 27-item checklist and is registered on PROSPERO (CRD42021256391). Risk of bias was evaluated using the National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies. RESULTS: Two independent investigators rated 7,697 records against the primary endpoint and found 8 records meeting the eligibility requirements. Migraine was found to be the most common primary headache related to TMDs (61.5%), followed by episodic tension-type headache (ETTH; 38.5%). A moderate association was found for mixed TMDs with migraine and ETTH, with a large sample size and multiple studies included (n = 8). A very low-quality association was found for myalgia-related TMDs with migraine and ETTH (included studies, n = 2). CONCLUSION: The association between TMDs and primary headaches is of great interest given the possible effectiveness of TMD management in reducing headache intensity/frequency in patients with TMDs and headache comorbidity. A moderate association was found for mixed TMDs with primary headaches, in particular migraine and ETTH. However, owing to the overall moderate certainty of evidence of the present findings, further longitudinal studies with larger samples investigating possible associated factors and using accurate TMD and headache category assignment are needed.

Depressive and Biopsychosocial Frailty Phenotypes: Impact on Late-life Cognitive Disorders.

In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer's disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality.

Dementia, infections and vaccines: 30 years of controversy.

This paper reports the proceedings of a virtual meeting convened by the European Interdisciplinary Council on Ageing (EICA), to discuss the involvement of infectious disorders in the pathogenesis of dementia and neurological disorders leading to dementia. We recap how our view of the infectious etiology of dementia has changed over the last 30 years in light of emerging evidence, and we present evidence in support of the implication of infection in dementia, notably Alzheimer's disease (AD). The bacteria and viruses thought to be responsible for neuroinflammation and neurological damage are reviewed. We then review the genetic basis for neuroinflammation and dementia, highlighting the genes that are currently the focus of investigation as potential targets for therapy. Next, we describe the antimicrobial hypothesis of dementia, notably the intriguing possibility that amyloid beta may itself possess antimicrobial properties. We further describe the clinical relevance of the gut-brain axis in dementia, the mechanisms by which infection can move from the intestine to the brain, and recent findings regarding dysbiosis patterns in patients with AD. We review the involvement of specific pathogens in neurological disorders, i.e. SARS-CoV-2, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1), and influenza. Finally, we look at the role of vaccination to prevent dementia. In conclusion, there is a large body of evidence supporting the involvement of various infectious pathogens in the pathogenesis of dementia, but large-scale studies with long-term follow-up are needed to elucidate the role that infection may play, especially before subclinical or clinical disease is present.

Processed foods and diet quality in pregnancy may affect child neurodevelopment disorders: a narrative review.

OBJECTIVE: To review the evidence on the association between maternal exposure to ultra-processed food (UPF) categories, UPF diet items, and overall diet quality, as assessed by recognized dietary indices, and neurodevelopmental outcomes in offspring. METHODS: PubMed, MEDLINE, EMBASE, Scopus, Ovid, and Scholar databases were searched for original articles on female gestational exposure to UPF categories, individual elements of the UPF diet, or indices of diet quality, in relation to outcomes regarding their offspring's neurocognitive development, according to neuropsychometric and behavioral scales, anthropometric/psychomotor indices, and symptoms/diagnosis of neurodevelopmental disorders (NDDs). RESULTS: Fourteen articles were selected and underwent the quantitative analysis. Six of these examined diet quality, and eight exposure to UPF categories or specific UPF foods. The maternal population was adult (18+). Child cognitive development was negatively impacted by a diet featuring many processed foods, saturated fats, and sugars. Conversely, a Med-diet led to better neurodevelopment, particularly verbal intelligence and executive functions, in middle childhood. DISCUSSION: A maternal diet with many UPFs, saturated fats, and total sugars (especially those added or hidden in packaged carbonated beverages) can adversely affect a child's cognitive development. Knowledge needs to be further extended and managed from a prevention perspective in light of the well-known negative effects of UPFs on human health in all age groups.

The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies.

INTRODUCTION: Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins. AREAS COVERED: The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies. EXPERT OPINION: ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.

Associations of a biopsychosocial frailty phenotype with all-cause dementia, Alzheimer's disease, vascular dementia, and other dementias: the Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA).

Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty construct, estimating its impact on the odds of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and other dementias in 2838 older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA). Biopsychosocial frailty operationalization was based on the results of a previous comprehensive geriatric assessment and the presence of physical frailty. In this cross-sectional study, participants with biopsychosocial frailty showed an increased odds ratio of all-cause dementia [odds ratio (OR): 5.55, 95% confidence interval (CI): 3.72-8.28, p < 0.001], in particular for probable AD (OR: 3.62, 95% CI: 1.55-8.45, p < 0.001), probable VaD (OR: 10.05, 95% CI: 5.05-19.97, p < 0.001), and possible VaD (OR: 17.61, 95% CI: 6.42-48.32, p < 0.001). No statistically significant association was found between this biopsychosocial frailty phenotype and possible AD (OR: 2.84, 95% CI: 0.81-9.97, p = 0.09) or other dementias (OR: 1.77, 95% CI: 0.75-0.21, p = 0.19). In conclusion, in a large cohort of Italian older individuals, a biopsychosocial frailty model was associated to all-cause dementia, probable AD, and probable and possible VaD. In the next future, other large and prospective population-based studies evaluating the association between the biopsychosocial frailty phenotype and incident all-cause dementia, AD, and VaD are needed, addressing also potential bias and confounding sources.

Prevalence of Sarcopenia in Liver Cirrhosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chronic liver disease is often combined with a morbidity burden that strongly affects the functional domain. In liver cirrhosis (LC), qualitative and quantitative muscle wasting, known as sarcopenia, poses an added clinical burden, together with comorbidities and a poor quality of life. METHODS: We conducted a systematic review and meta-analysis of the prevalence of sarcopenia in LC. The literature was screened through 6 electronic databases from the study's inception to January 2023. No exclusion criteria were applied to language, operative tools for diagnosing sarcopenia, population age, general health status, country, and study setting (cohort or cross-sectional). Two independent researchers applied the inclusion criteria in parallel to evaluate the eligibility of the 44 retrieved articles; only 36 met the eligibility requirements. RESULTS: The total sample (N = 8,821) was slightly dominated by men (N = 4,941). The cross-sectional design predominated over the longitudinal, and the hospital setting was prevalent. The pooled prevalence of sarcopenia across the selected studies was 33% (95% confidence interval [CI] 0.32-0.34), with high heterogeneity ( I2 = 96%). A further meta-analysis using the Child-Pugh (CP) score to stage LC was conducted on 24 entries, and the results showed that for the LC populations classified with the CP-A, CP-B, and CP-C staging, respectively, the overall mean prevalence was 33% (95% CI 0.31-0.35), 36% (95% CI 0.34-0.39) and 46% (95% CI 0.43-0.50). The risk of bias was moderate. In LC, 1 in 3 patients suffers sarcopenia. DISCUSSION: Poor management of muscle mass loss plays a role in the prognosis of death and quality of life of patients with LC. Clinicians in the field are recommended, when screening for sarcopenia, to pay close attention by carefully assessing body composition as part of the monitoring scheme.