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Key Points Age-related hearing impairment (ARHI, also known as presbycusis) is the most common hearing disorder and a major cause of chronic disability in older age ARHI has an adverse effect on general health and quality of life; epidemiological studies have linked ARHI to incident cognitive impairment, accelerated cognitive decline and Alzheimer disease (AD) ARHI can cause difficulty in speech comprehension, thereby compromising communication skills and potentially leading to social isolation and loneliness Difficulty in verbal communication can exacerbate depletion of cognitive reserve, which might causally link ARHI to cognitive decline At present, control of modifiable risk factors for dementia and AD remains the most realistic preventive strategy for these disorders ARHI is a potentially a reversible risk factor for dementia and AD; timely diagnosis combined with hearing aids and cognitive training might delay or prevent cognitive deterioration Age related hearing impairment (ARHI, also known as presbycusis) is an important frailty marker, and could be a reversible risk factor for dementia and Alzheimer disease. Poor verbal communication and depletion of cognitive reserve might causally link ARHI to cognitive decline and frailty; hearing aids and cognitive training might, thus, provide a strategy to delay or prevent cognitive deterioration. In this Review, Panza and colleagues discuss the interplay between cognitive impairment, ARHI and frailty in older age. Age-related hearing impairment (ARHI, also known as presbycusis) is potentially a reversible risk factor for dementia and Alzheimer disease (AD). Social isolation, loneliness, poor verbal communication, and cognitive reserve depletion might causally link ARHI with cognitive impairment. ARHI is an important frailty marker, and several factors related to physical frailty could be associated with cognitive impairment. Such factors include inflammatory markers and vascular factors, which might also directly contribute to ARHI. Randomized controlled trials of potential interventions, and larger population-based studies, could facilitate further understanding of the interplay between cognitive impairment, ARHI and frailty in older age. Deficits in both peripheral hearing and central auditory processing (CAP) can contribute to ARHI. Impairments in peripheral hearing and CAP have been linked to accelerated cognitive decline, incident cognitive impairment and AD; moreover, CAP dysfunction is common in mild cognitive impairment (MCI) and AD. Assessment of CAP dysfunction in people with ARHI might, therefore, aid identification of older individuals with increased risk of MCI and AD.

Aging is often associated with a decline in physical function that eventually leads to loss of autonomy in activities of daily living (ADL). Walking is a very common ADL, important for main determinants of quality of life in older age, and it requires the integration of many physiological systems. Gait speed has been described as the ‘sixth vital sign’ because it is a core indicator of health and function in aging and disease. We reviewed original studies up to June 2020 that assessed frailty in both longitudinal and cross‐sectional observational studies, paying particular attention to how gait is measured in older population and how the gait parameter adopted may influence the estimated frailty models and the health‐related outcomes of the various studies (i.e. clinical, cognitive, physical, and nutritional outcomes). Eighty‐five studies met the search strategy and were included in the present systematic review. According to the frailty tools, more than 60% of the studies used the physical phenotype model proposed by Fried and colleagues, while one‐third referred to multi‐domain indexes or models and only 5% referred to other single‐domain frailty models (social or cognitive). The great heterogeneity observed in gait measurements and protocols limited the possibility to directly compare the results of the studies and it could represent an important issue causing variability in the different outcome measures in both clinical‐and population‐based settings. Gait appeared to be an indicator of health and function also in frail older adults, and different gait parameters appeared to predict adverse health‐related outcomes in clinical, cognitive, and physical domains and, to a lesser extent, in nutritional domain. Gait has the potential to elucidate the common basic mechanisms of cognitive and motor decline. Advances in technology may extend the validity of gait in different clinical settings also in frail older adults, and technology‐based assessment should be encouraged. Combining various gait parameters may enhance frailty prediction and classification of different frailty phenotypes.

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.

A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer’s disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.

A well-preserved oral function is key to accomplishing essential daily tasks. However, in geriatric medicine and gerodontology, as age-related physiological decline disrupts several biological systems pathways, achieving this objective may pose a challenge. We aimed to make a systematic review of the existing literature on the relationships between poor oral health indicators contributing to the oral frailty phenotype, defined as an age-related gradual loss of oral function together with a decline in cognitive and physical functions, and a cluster of major adverse health-related outcomes in older age, including mortality, physical frailty, functional disability, quality of life, hospitalization, and falls. Six different electronic databases were consulted by two independent researchers, who found 68 eligible studies published from database inception to September 10, 2022. The risk of bias was evaluated using the National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies. The study is registered on PROSPERO (CRD42021241075). Eleven different indicators of oral health were found to be related to adverse outcomes, which we grouped into four different categories: oral health status deterioration; decline in oral motor skills; chewing, swallowing, and saliva disorders; and oral pain. Oral health status deterioration, mostly number of teeth, was most frequently associated with all six adverse health-related outcomes, followed by chewing, swallowing, and saliva disorders associated with mortality, physical frailty, functional disability, hospitalization, and falls, then decline in oral motor skills associated with mortality, physical frailty, functional disability, hospitalization, and quality of life, and finally oral pain was associated only with physical frailty. The present findings could help to assess the contribution of each oral health indicator to the development of major adverse health-related outcomes in older age. These have important implications for prevention, given the potential reversibility of all these factors.

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.

Post-stroke lower limb spasticity impairs balance and gait leading to reduced walking speed, often increasing wheelchair use and caregiver burden. Several studies have shown that appropriate treatments for lower limb spasticity after stroke include injections of botulinum toxin type A (BoNT-A), phenol or alcohol, surgical correction and a rehabilitation program. In the present article, we review the safety and effectiveness of BoNT-A for the treatment of lower limb spasticity after stroke, with a focus on higher doses of BoNT-A. The cumulative body of evidence coming from the randomized clinical trials and open-label studies selected in the article suggest BoNT-A to be safe and efficacious in reducing lower limb spasticity after stroke. Studies of high doses of BoNT-A also showed a greater reduction of severe post-stroke spasticity. In stroke survivors with spasticity of the ankle plantar-flexor muscles, a combined approach between surgery and BoNT-A can be indicated. However, controversy remains about improvement in motor function relative to post-stroke spasticity reduction after BoNT-A treatment.

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

Vascular contribution to cognitive impairment and dementia (VCID) is a clinical label encompassing a wide range of cognitive disorders progressing from mild to major vascular cognitive impairment (VCI), which is also defined as vascular dementia (VaD). VaD diagnosis is mainly based on clinical and imaging findings. Earlier biomarkers are needed to identify subjects at risk to develop mild VCI and VaD. In the present meta-analysis, we comprehensively evaluated the role of inflammatory biomarkers in differential diagnosis between VaD and Alzheimer’s disease (AD), and assessed their prognostic value on predicting VaD incidence. We collected literature until January 31, 2021, assessing three inflammatory markers [interleukin(IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α] from blood or cerebrospinal fluid (CSF) samples. Thirteen cross-sectional and seven prospective studies were included. Blood IL-6 levels were cross-sectionally significantly higher in people with VaD compared to AD patients (SMD: 0.40, 95% CI: 0.18 to 0.62) with low heterogeneity ( I 2 : 41%, p  = 0.13). Higher IL-6 levels were also associated to higher risk of incident VaD (relative risk: 1.28, 95% CI: 1.03 to 1.59, I 2 : 0%). IL-6 in CSF was significantly higher in people with VaD compared to healthy subjects (SMD: 0.77, 95% CI: 0.17 to 1.37, I 2 : 70%), and not compared to AD patients, but due to limited evidence and high inconsistency across studies, we could not draw definite conclusion. Higher blood IL-6 levels might represent a useful biomarker able to differentiate people with VaD from those with AD and might be correlated with higher risk of future VaD.

Age-related hearing loss (ARHL), also called presbycusis, is a progressive disorder affecting hearing functions and among the elderly has been recognized as the third most frequent condition. Among ARHL components, the age-related central auditory processing disorder (CAPD) refers to changes in the auditory network, negatively impacting auditory perception and/or the speech communication performance. The relationship between auditory-perception and speech communication difficulties in age-related CAPD is difficult to establish, mainly because many older subjects have concomitant peripheral ARHL and age-related cognitive changes. In the last two decades, the association between cognitive impairment and ARHL has received great attention. Peripheral ARHL has recently been defined as the modifiable risk factor with the greatest impact on the development of dementia. Even if very few studies have analyzed the relationship between cognitive decline and age-related CAPD, a strong association was highlighted. Therefore, age-related CAPD could be a specific process related to neurodegeneration. Since these two disorders can be concomitant, drawing causal inferences is difficult. The assumption that ARHL, particularly age-related CAPD, may increase the risk of cognitive impairment in the elderly remains unchallenged. This review aims to summarize the evidence of associations between age-related CAPD and cognitive disorders and to define the diagnostic procedure of CAPD in the elderly. Finally, we highlight the importance of tailoring the rehabilitation strategy to this relationship. Future longitudinal studies with larger sample sizes and the use of adequate assessment tools that can disentangle cognitive dysfunction from sensory impairments are warranted.