Neuropsychiatric symptoms (NPS) are very common and associated with high levels of distress, both in dementia patients and their caregivers. Especially at more advanced dementia disease stages, NPS rarely occur in isolation and the presence of two or more NPS may affect disease severity as well as the response to therapy. There is limited quantitative information on prevalence of specific symptom combinations in the general population, as well as in the populations recruited for symptom-specific investigations. We performed cross-sectional analyses of data from two longitudinal studies (Aging, Demographics, and Memory Study (ADAMS) and the National Alzheimer's Coordinating Center data (NACC)). In both studies and all Mini Mental State Examination (MMSE) strata, we observed every possible pair combination, from commonly recognized and discussed associations (e.g., hallucinations and delusions) to what might be seen as rather counter-intuitive patterns (e.g., apathy and agitation). In conclusion, prevalence of symptom pairs cannot be readily predicted based on prevalence of individual symptoms. Further, the presence of cognitive deficit and degree of cognitive impairment is associated with increased prevalence of all symptoms and symptom pairs, albeit to different degrees. The present study illustrates that, while there is the possibility of any combination of neuropsychiatric symptoms presenting during the course of dementia, their co-occurrence cannot be readily predicted based on the prevalence of individual symptoms. Thus, our study results serve as a source of reference information to inform the design and recruitment strategies for future clinical studies and epidemiological research on neuropsychiatric symptoms in people with dementia.

The study examines the behavioural and psychological symptoms (BPSs) associated with dementia and mild cognitive impairment (MCI), highlighting the prevalence and impact of these symptoms on individuals with varying levels of cognitive function, particularly in the context of the increasing incidence of dementia among the ageing population.

To explore the BPSs among out-patients with different cognitive statuses.

This cross-sectional study enrolled out-patients who attended the cognitive assessment out-patient clinic at our hospital between January 2018 and October 2022. The patients' cognitive status was evaluated using the Neuropsychiatric Inventory (NPI), Activities of Daily Living and the Montreal Cognitive Assessment-Basic scales.

The study enrolled 3273 out-patients, including 688 (21%) with cognitively unimpairment, 1831 (56%) with MCI and 754 (23%) with dementia. The NPI score, the percentage of patients with BPSs and the number of BPSs increased with decreasing cognition level. Unordered logistic regression analysis showed that after adjustment of confounding variables, delusions, depression, euphoria and psychomotor alterations were independently associated with MCI. Delusions, agitation, euphoria, apathy, psychomotor alterations and sleep change were independently associated with dementia.

NPI scores, the percentage of patients with BPSs and the numbers of BPSs increased with declining cognitive function.

Neuropsychiatric symptoms (NPS) are common throughout the Alzheimer's disease (AD) continuum and profoundly affect patients, caregivers, and health-care systems. This review synthesizes key research presented in the 2022 and 2023 Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes-Professional Interest Area (NPS-PIA) Year-In-Reviews, emphasizing six critical areas: (1) diversity and disparities, (2) diagnostic frameworks, (3) neurobiology of NPS, (4) NPS as a disease marker, (5) the impact of COVID-19, and (6) interventions. NPS accelerates AD progression, increases functional decline, diminishes quality of life, and heightens caregiver burden and institutionalization rates. Current treatments primarily rely on psychotropics, which offer limited efficacy and raise safety concerns. This review aims to inform clinicians and researchers about recent NPS advancements while identifying gaps for future studies to improve outcomes for individuals with AD. HIGHLIGHTS: Research in Alzheimer's disease-related neuropsychiatric symptoms has rapidly increased, indicating heightened interest. Key areas include: diversity, diagnostics, markers, COVID-19 impact, and treatments. A road map for future studies, based on the key areas of research, is provided. This road map includes considerations to improve study applicability and validity.

Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI). However, knowledge is limited about the relationship of NPS, clinical factors, and cognition in MCI.

A total of 1099 dementia, 1323 MCI and 377 cognitively normal (CN) were selected from the Tongji Cohort Study of Aging. All participants underwent comprehensive clinical and neuropsychological assessment. NPS were evaluated by the Neuropsychiatric Inventory Questionnaire (NPI-Q). Logistic regression analyses were conducted to investigate the relationship between clinical factors, cognition and NPS.

The NPS presented in 56.39% of MCI participants, and the NPI-Q scores of MCI was intermediate between CN and dementia. The most common NPS in MCI were depression (30.76%), anxiety (25.09%), apathy (19.43%), and irritability (12.02%). MCI patients with NPS showed worse performance in global, memory, language, and attention than those without NPS. Additionally, Logistic regression analyses revealed that MCI patients with ischemic heart disease (OR = 1.41; 95%CI 1.050-1.897; P = 0.022) were more likely to have NPS, but MCI patients with increased memory domain Z score (OR = 0.847, 95%CI = 0.720-0.996, p = 0.044), and language domain Z score (OR = 0.801, 95%CI = 0.682-0.941, p = 0.007) were less likely to have NPS.

Neuropsychiatric symptoms occur commonly in MCI participants, and are mainly related to defect of language and memory function. A better understanding of the relationship between specific cognition and NPS may alert clinicians to pay close attention to the NPS in MCI patient, which may need early intervention.

Higher physical activity (PA) is associated with better neuropsychiatric health, but prior studies have been limited by cross-sectional designs, self-reported PA measures, and small numbers of older individuals. We examined associations between baseline and changes in accelerometer-measured moderate-vigorous PA (MVPA) with neuropsychiatric health among individuals aged ≥ 70 years in the National Health and Aging Trends Study.

We used the average daily minutes of accelerometer-measured MVPA above a validated threshold of 2184 counts per minute as a continuous measure at baseline for the exposure variable. For longitudinal analyses, we categorized change in MVPA as follows: an increase of > 20 min/day over 1 year, a decrease of > 20 min/day over 1 year, and staying within 20 min/day over 1 year. Our outcomes were possible/probable dementia and anxiety or depression. Associations were estimated using confounder-adjusted logistic regressions.

In our survey-weighted analytic sample of 639 individuals aged ≥ 70 years, 56% were ≥ 75 years, and 53% were female. After adjusting for confounders, a 20-min/day higher baseline MVPA was significantly associated with lower odds of possible/probable dementia 1 year later (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.83-0.96) but not with depression and anxiety symptoms. Compared to no change in PA over 1 year, an increase in MVPA by > 20 min/day was associated with decreased odds of depression and anxiety symptoms (OR = 0.06, 95% CI = 0.03-0.14) but not with possible/probable dementia. Compared to no change in MVPA over 1 year, a decrease in MVPA by > 20 min/day was associated with higher odds of possible/probable dementia (OR = 3.82, 95% CI = 1.34-10.87) but not with depression and anxiety symptoms.

Higher and increasing MVPA over time is associated with better neuropsychiatric health in individuals aged ≥ 70 years. Future studies should prioritize evaluating detailed PA trajectories to better understand how different doses, intensities, and modalities of PA impact neuropsychiatric decline in older adults.

Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25-80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, β-amyloid, and TDP-43. To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tauDRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. A significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.

The aim of this study was to examine the potential added value of including neuropsychiatric symptoms (NPS) in machine learning (ML) models, along with demographic features and Alzheimer's disease (AD) biomarkers, to predict decline or non-decline in global and domain-specific cognitive scores among community-dwelling older adults.

To evaluate the impact of adding NPS to AD biomarkers on ML model accuracy in predicting cognitive decline among older adults.

The study was conducted in the setting of the Mayo Clinic Study of Aging, including participants aged ≥ 50 years with information on demographics (i.e., age, sex, education), NPS (i.e., Neuropsychiatric Inventory Questionnaire; Beck Depression and Anxiety Inventories), at least one AD biomarker (i.e., plasma-, neuroimaging- and/or cerebrospinal fluid [CSF]-derived), and at least 2 repeated neuropsychological assessments. We trained and tested ML models using a stepwise feature addition approach to predict decline versus non-decline in global and domain-specific (i.e., memory, language, visuospatial, and attention/executive function) cognitive scores.

ML models had better performance when NPS were included along with a) neuroimaging biomarkers for predicting decline in global cognition, as well as language and visuospatial skills; b) plasma-derived biomarkers for predicting decline in visuospatial skills; and c) CSF-derived biomarkers for predicting decline in attention/executive function, language, and memory.

NPS, added to ML models including demographic and AD biomarker data, improves prediction of downward trajectories in global and domain-specific cognitive scores among community-dwelling older adults, albeit effect sizes are small. These preliminary findings need to be confirmed by future cohort studies.

Neuropsychiatric symptoms (NPS) such as depression, anxiety, and apathy are present in mild cognitive impairment (MCI) and are risk factors for cognitive decline. However, the relationship between NPS and specific cognitive domains is less clear.

This study aimed to assess whether there is a correlation between NPS and specific cognitive domains.

A cross-sectional study which included 174 participants with MCI, aged 55 years or older. Differences in sociodemographic profile, neuroimaging, and neuropsychological tests between MCI participants with and without NPS were measured.

Participants with NPS had lower education and worse performance in attention tests and executive functions. Psychotic symptoms were correlated with deficits in visuospatial functions; irritability and agitation with inattention and deficit of inhibitory control; and depression with inattention.

Correlations were found between some NPS with specific cognitive domains, especially psychotic symptoms, but also agitation, irritability, apathy, and depression.

Elevated plasma homocysteine (Hcy) has been reported as a risk factor for cognitive impairment in the general population. However, there are conflicting results regarding the relationship between Hcy and cognitive impairment across various cognitive domains in Parkinson's disease (PD).

This study aims to explore the association between plasma Hcy levels, cognitive impairment, and dysfunction in various cognitive domains among PD patients with and without mild cognitive impairment (MCI).

A total of 101 PD patients underwent plasma Hcy measurement, comprising 50 PD-MCI patients and 51 patients with normal cognition (PD-NC). A battery of neuropsychological tests was administered to assess different cognitive domains. Adjusted generalized linear models were used to assess the correlations between Hcy levels and cognitive functions.

As anticipated, PD-MCI patients demonstrated a significant decline in cognitive function across all five cognitive domains (memory, executive function, attention/working memory, language, and visuospatial function). Elevated plasma Hcy levels (≥ 10 μmol/L) were associated with a higher odds of PD-MCI, even within the normal range of Hcy levels (< 15 μmol/L). After adjusting for confounding factors, a negative correlation was observed between plasma Hcy levels and the performance on specific cognitive tests evaluating executive functions in PD, such as the Stroop Color-Word Test-C (β = -1.123, 95% CI = -1.845 ∼-0.401, p = 0.0023).

This study underscores a significant link between plasma Hcy levels and PD-MCI, particularly concerning executive dysfunction, even within the normal range of Hcy levels (< 15 μmol/L).

Dementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear.

The objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status.

Higher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20-2.27] in T + , 2.6 [1.06-6.59] in A-T-, and 1.6 [1.15-2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07-2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06-2.02]. No significant associations were found in the CU biomarker subgroups.

Addressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.

Neuropsychiatric symptoms may impact prognosis in individuals with mild cognitive impairment (MCI); however, data on frequency of psychotic symptoms are sparse.

We searched MEDLINE, EMBASE, PsychoINFO from inception to June 2023. We included studies reporting patients with MCI prevalence of (delusions and/or hallucinations. Random effects model were performed to estimate the prevalence, and subgroup and meta-regression analyses were performed to explore heterogeneity.

Of 3145 records identified, 36 studies were included, enrolling 20,426 patients. Overall prevalence of hallucinations was 1.78 % (95 % CI, 1.17 - 2.71) and delusions 3.84 % (95 % CI, 2.71 - 5.42), both with significant heterogeneity (/2 = 90 %). Prevalence of hallucinations and delusions were lower when measured by NPI scales and in population-based samples.

Delusions and hallucinations occur in MCI patients at low rates. Prevalence can be partially explained by the assessment method, sample source and study heterogeneity.

Anxiety is a neuropsychiatric symptom (NPS) of Alzheimer disease (AD) patients which has been studied primarily in prospective and retrospective studies of clinically diagnosed AD. However, this can be confounded by other primary etiologies. Moreover, anxiety has not been comprehensively studied in autopsy-confirmed AD cases across subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia stages. We conducted a retrospective longitudinal analysis of 212 participants with autopsy-confirmed AD, followed from 1986-2013 at the NYU Alzheimer's Disease Research Center with staging via the Global Deterioration Scale and NPS assessed via BEHAVE-AD. We found that anxiety varied uniquely with stage and was the most common NPS in SCD and MCI (35-40% prevalence). ApoE4 carriage associated with a higher rate of anxiety only at mild dementia. Anxiety in SCD associated with cerebral amyloid angiopathy and arteriosclerosis on brain autopsy, but there were no such associations with concomitant neuropathology at MCI and mild dementia. Anxiety associated with increased progression rate (∼2.5-fold) from SCD to MCI/dementia stages, but not from MCI to dementia. These results suggest an important relationship between anxiety and AD, especially at the preclinical stage. This warrants further study of anxiety as a possible modifiable factor of disease experience and course.

Psychiatric symptomatology and medications used in their treatment may be modifiable risk factors associated with cognitive function, although findings from population-based studies spanning the full adult age range are lacking. This study aimed to investigate associations between psychiatric symptomatology, psychotropic medication use and cognitive function in a population-based sample of men.

Data for 537 men were drawn from the Geelong Osteoporosis Study. Cognitive function (psychomotor function, attention, working memory and visual learning) was determined using the Cog-State Brief Battery. Current depressive and anxiety symptomatology was determined using the Hospital Anxiety and Depression Scale, and psychotropic medication use was self-reported. Linear regression models were developed to determine associations between psychiatric symptomatology and psychotropic medication use with each cognitive measure.

Depressive symptomatology was associated with lower overall cognitive function (b-0.037 ± 0.010, η2 = 0.025, p < 0.001), psychomotor function (b 0.006 ± 0.002, η2 = 0.028 p < 0.001) and attention (b 0.004 ± 0.001, η2 = 0.021, p < 0.001), whereas psychotropic use was associated with lower overall cognitive function (b - 0.174 ± 0.075, η2 = 0.010, p = 0.021), attention (b 0.017 ± 0.008, η2 = 0.008, p = 0.038 and working memory (b 0.031 ± 0.012, η2 = 0.010, p = 0.010). Anticonvulsant use was associated with lower overall cognitive function (b - 0.723 ± 0.172, η2 = 0.032, p < 0.001), attention (b 0.065 ± 0.018, η2 = 0.029, p < 0.001) and working memory (b 0.088 ± 0.026, η2 = 0.022, p < 0.001). All relationships were found to have a small effect. There were no significant associations between anxiety symptomatology and antidepressant and anxiolytic use with any of the cognitive domains.

Depressive symptomatology and anticonvulsant use were associated with lower cognitive function. Understanding the underlying mechanisms involved in these relationships can advance knowledge on the heterogeneity in cognitive ageing and aid in prevention initiatives.

While some people with mild cognitive impairment (MCI) progress to dementia, many others show no progression. The aim of this study was to identify factors associated with risk of dementia development in this population.

A large naturalistic retrospective cohort study was assembled from mental healthcare records in a south London catchment. Patients were selected at first recorded diagnosis of MCI and subsequent dementia diagnosis was ascertained from case notes or death certificate, excluding those with dementia diagnoses and deaths within 6 months of MCI diagnosis. A range of demographic and clinical characteristics were ascertained around MCI diagnosis and Cox proportional hazards models were used to investigate independent predictors of dementia, focussing on neuropsychiatric symptoms, contextual factors, and antidepressant treatment.

Of 2250 patients with MCI, 236 (10.5%) developed dementia at least 6 months after MCI diagnosis. Aside from older age, lower cognitive function, and activities of daily living impairment, impaired social relationships and recorded loneliness were associated with a higher risk of developing dementia. Patients of Black (compared to White) ethnicity were at a lower risk. For depression and antidepressant receipt, only tricyclic use compared to no antidepressant use was associated with an increased dementia risk.

No evidence was found for co-morbid affective disorders or different antidepressant classes as risk factors for dementia development following MCI diagnosis, but loneliness and social impairment were independent predictors and would be worth evaluating as targets for interventions to delay progression.

Neuropsychiatric symptoms (NPS) have been associated with a risk of accelerated cognitive decline or conversion to dementia of the Alzheimer's Disease (AD) type. Moreover, the NPS were also associated with higher AD biomarkers (brain tau and amyloid burden) even in non-demented patients. But the effect of the relationship between NPS and biomarkers on cognitive decline has not yet been studied. This work aims to assess the relationship between longitudinal cognitive changes and NPS, specifically depression and anxiety, in association with AD biomarkers in healthy middle-aged to older participants. The cohort consisted of 101 healthy participants aged 50-70 years, 66 of whom had neuropsychological assessments of memory, executive functions, and global cognition at a 2-year follow-up. At baseline, NPS were assessed using the Beck Depression and Anxiety Inventories while brain tau and amyloid loads were measured using positron emission topography. For tau burden, THK5351 uptake is used as a proxy of tau and neuroinflammation. Participants, declining or remaining stable at follow-up, were categorized into groups for each cognitive domain. Group classification was investigated using binary logistic regressions based on combined AD biomarkers and the two NPS. The results showed that an association between anxiety and prefrontal amyloid burden significantly classified episodic memory decline, while the classification of global cognitive decline involved temporal and occipital amyloid burden but not NPS. Moreover, depression together with prefrontal and hippocampal tau burden were associated with a decline in memory. The classification of participants based on executive decline was related to depression and mainly prefrontal tau burden. These findings suggest that the combination of NPS and brain biomarkers of AD predicts the occurrence of cognitive decline in aging.

The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD).

Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included.

The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy.

Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic.

We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter.

Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 μM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic.

Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

Both the loss of awareness for cognitive decline (a. k.a anosognosia) and neuropsychiatric symptoms (NPS) are common in patients with Alzheimer's disease (AD) dementia, even in prodromal stages, and may exacerbate functional impairment and negatively impact caregiver burden. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross-sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI).

We included 237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with a baseline clinical diagnosis of MCI. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study-partners at baseline and annually over a mean of 4.29 years [standard deviation (SD) = 2.72]. Anosognosia was defined as the study-partner having an ECog score ≥2.5/4 and the participant having an ECog score < 2.5/4 on their baseline measure and their last observation without more than two consecutive deviating observations during the follow-up period. The 12-item study-partner-rated Neuropsychiatric Inventory determined the presence or absence of specific NPS. Survival analyses were performed to analyze the frequency and temporal onset of NPS over time in individuals with and without anosognosia.

Thirty-eight out of 237 participants displayed anosognosia. Groups had similar lengths of follow-up at baseline (p > 0.9), though participants with anosognosia had lower MMSE scores (p = 0.049) and a higher proportion of amyloid-positivity using PET (p < 0.001. At baseline, the frequencies of agitation (p = 0.029) and disinhibition (p < 0.001) were higher in the anosognosia group compared to the non-anosognosia group. Survival analyses showed earlier onset of seven of the 12 NPS in the anosognosia group (p's < 0.001).

Loss of awareness for cognitive decline is associated with greater frequency and earlier onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process for anosognosia and NPS, a finding that needs to be addressed in future studies.

The most prevalent type of dementia, Alzheimer's disease (AD), is a compelling illustration of the link between cognitive deficits and neurophysiological anomalies. We investigated the possible protective effect of intranasal insulin intake with exercise on amyloid-β (Aβ)-induced neuronal damage. The level of hippocampal brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were analyzed to understand the involvement of BDNF-TrkB pathway in this modulation. In this study, we induced AD-like pathology by amyloid-β (Aβ) administration. Then, we examined the impact of a 4-week pretreatment of moderate treadmill exercise and intranasal intake of insulin on working and spatial memory in male Wistar rats. We also analyzed the mechanisms of improved memory and anxiety through changes in the protein level of BDNF and TrkB. Results showed that animals received Aβ had impaired working memory, increased anxiety which were accompanied by lower protein levels of BDNF and TrkB in the hippocampus. The exercise training and intranasal insulin improved working memory deficits, decreased anxiety, and increased BDNF, and TrkB levels in the hippocampus of animals received Aβ. Our finding of improved memory performance after intranasal intake of insulin and exercise may be of significance for the treatment of memory impairments and anxiety-like behavior in AD.

Apathy is a common motivational deficit in neurodegenerative diseases, but lacks a culturally sensitive tool accounting for ethnic Chinese culture's impact on motivation initiation. This study developed and validated the Geriatric Apathy Scale (GAS), comprehensively incorporating cultural nuances, setting diagnostic cutoffs, and examining apathy's multi-dimensional aspects in a neurodegenerative cohort.

The 16-item GAS was developed by considering ethnic Chinese cultural characteristics and conducting a literature review. The study involved 296 participants, comprising 113 with Parkinson's disease (PD), 66 with Alzheimer's disease (AD), and 117 healthy controls (HC). All participants completed the GAS, Apathy Evaluation Scale (AES), Geriatric Depression Scale (GDS-15), Mini-Mental State Examination, and Activities of Daily Living (ADLs).

The GAS showed good internal consistency (r = 0.862) and test-retest reliability (r = 0.767). It correlated moderately with the AES (r = 0.639, p < .001), weakly with GDS-15 (r = 0.166, p < .01), and negatively with ADLs (r = -1.19, p < .05). Clinical diagnosis cutoff scores were identified at 15.5 for PD (sensitivity: 0.789; specificity: 0.693) and 12.5 for AD (sensitivity: 0.821; specificity: 0.632). Noteworthy disparities were observed in the Cognition and Social Motivation dimension, with elevated severity in both PD and AD compared to HC (p < .01). Interestingly, within-group comparisons revealed greater apathy severity in the Cognition and Social Motivation dimension for PD (p < .001) and AD (p = .001) versus Emotional Response and Expression and Spontaneous Behavioral Activation.

The GAS, a psychometrically validated scale, assesses apathy in neurodegenerative populations, accounting for ethnic Chinese culture's influence. It establishes clinical cutoff points and explores the multi-dimensional nature of apathy.

The association between depression and dementia, particularly Alzheimer's disease (AD) and cerebrovascular disease (CVD), remains an active area of research. This study aimed to investigate the relationship between a history of depression and biomarkers of AD and CVD in patients with dementia in a clinical setting. A total of 126 patients from the University Health Network (UHN) Memory Clinic with comprehensive clinical evaluations, including neuropsychological testing and medical examinations, were included. Lumbar puncture was performed to collect cerebrospinal fluid (CSF) for biomarker analysis, and brain magnetic resonance imaging (MRI) scans were obtained to assess white matter hyperintensity (WMH) burden. The presence of depression was determined through medical records. The study findings did not reveal significant differences between participants with and without a history of depression in terms of AD biomarkers, WMH burden, neurofilament light chain levels, cognitive scores, age of symptom onset, disease duration, or vascular risk scores. Logistic regression analysis did not indicate a meaningful predictive value of these variables for depression status. This clinical study contributes to our understanding regarding the association between depression and AD/CVD biomarkers in patients with cognitive impairment. Further research is needed to elucidate the complex relationship between depression and dementia and to explore the potential mechanisms linking depression, AD, and CVD.

Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin-1 (PSEN1) E280A mutation for autosomal dominant AD.

A total of 27 PSEN1 mutation carriers and 26 non-carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15-item Geriatric Depression Scale.

Carriers and non-carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non-carriers.

Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention.

We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non-carriers. Carriers and non-carriers did not differ in severity of depressive symptoms. In carriers, hippocampal volume was inversely associated with depressive symptoms. Depressive symptoms may be a useful target in AD prevention.

Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity.

We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations.

MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared.

MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.

Patients with mild cognitive impairment (MCI) often have depressive symptoms. The purpose of this study was to investigate the effects of depressive symptoms on lipid metabolism and future cognitive function in patients with MCI.

A total of 1014 patients with MCI were included. Their demographic data, clinical data, and lipid parameters were collected. Meanwhile, they also completed a series of scale assessments, including Geriatric depression scale (GDS), Ability of Daily Living (ADL), Montreal cognitive assessment (MoCA) and Block Design Test (BDT). Then these patients were also followed for five years.

Patients with depressive symptoms had lower serum apolipoprotein B (ApoB) levels, lower BDT scores and higher ADL scale scores. Correlation analysis showed that GDS was significantly associated with BDT and ADL. Moreover, logistic regression analysis found that ApoB was associated with depressive symptoms. Cox regression analysis showed that only baseline MoCA scores could predict the risk of future MCI transition to dementia.

Our results suggest low serum ApoB levels may be associated with depressive symptoms in patients with MCI. However, depressive mood or lipids alone may not predict the risk of MCI transition to dementia.

Neuropsychiatric symptoms (NPS) are a common aspect of Alzheimer's disease (AD). Multiple studies have investigated its brain correlates, but it still remains unclear how they relate with brain atrophy in mild cognitive impairment (MCI).

Our objective was to investigate brain volume in MCI patients as a function of NPS.

We measured grey matter volume, neuropsychological status and NPS (Neuropsychiatric Inventory, NPI), in a sample of 81 MCI patients (43 females). Participants were divided in groups depending on presence (NPS+) or absence (NPS-) of NPS and on type of NPS.

We found lower volume of left temporal pole in patients with depression compared to NPS- (p = 0.012), and in patients with agitation compared to NPS- in the right middle occipital gyrus (p = 0.003). We also found a significant correlation between volume of left temporal pole and MMSE (r (78)  = 0.232, p = 0.019). Finally, NPS+ presented lower cross-sectional cognitive level than NPS- (t (79)  = 1.79, p = 0.038), and faster cognitive decline (t (48)  = -1.74, p = 0.044).

Our results support the colocalization of structural damage as a possible mechanism underlying the relationship between MCI and depression and provide novel evidence regarding agitation. Moreover, our longitudinal evidence highlights the relevance of an adequate identification of NPS in MCI patients to identify those at risk of faster cognitive decline.

The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain.

We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies.

Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration.

We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-β (Aβ) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aβ deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aβ, the mediation percentage varied from 6.05% to 17.51% (p < 0.05).

NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aβ.

Neuropsychiatric symptoms (NPSs) are common in neurodegenerative diseases; however, little is known about the prevalence of NPSs in Hispanic populations.

Using data from community-dwelling participants age 65 years and older enrolled in the 10/66 study (N = 11,768), we aimed to estimate the prevalence of NPSs in Hispanic populations with dementia, parkinsonism, and parkinsonism-dementia (PDD) relative to healthy aging. The Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPSs.

NPSs were highly prevalent in Hispanic populations with neurodegenerative disease; approximately 34.3%, 56.1%, and 61.2% of the participants with parkinsonism, dementia, and PDD exhibited three or more NPSs, respectively. NPSs were the major contributor to caregiver burden.

Clinicians involved in the care of elderly populations should proactively screen for NPSs, especially in patients with parkinsonism, dementia, and PPD, and develop intervention plans to support families and caregivers. Highlights Neuropsychiatric symptoms (NPSs) are highly prevalent in Hispanic populations with neurodegenerative diseases. In healthy Hispanic populations, NPSs are predominantly mild and not clinically significant. The most common NPSs include depression, sleep disorders, irritability, and agitation. NPSs explain a substantial proportion of the variance in global caregiver burden.

The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI.

Neuropsychiatric symptoms are common in subjects with MCI and associated with higher risk of progression to AD. The cognitive and neuroanatomical correlates of neuropsychiatric symptoms in MCI have not been fully elucidated. In this study, we sought to evaluate the association between neuropsychiatric symptoms, cognitive function, regional tau deposition, and brain volumes in MCI subjects.

A total of 233 MCI and 305 healthy comparisons were selected from the ADNI-3 cohort. All the subjects underwent a comprehensive neuropsychological assessment, volumetric MR brain scan, and Flortaucipir PET for in vivo assessment of regional tau deposition. Prevalence of neuropsychiatric symptoms was evaluated by means of the NPI questionnaire. Multivariate analyses of variance were used to detect differences in cognitive and imaging markers in MCI subjects with and without neuropsychiatric symptoms.

61.4% MCI subjects showed at least one neuropsychiatric symptom, with the most prevalent ones being depression (26.1%), irritability (23.6%), and sleep disturbances (23.6%). There was a significant effect of neuropsychiatric symptoms on cognitive tests of frontal and executive functions. MCI subjects with neuropsychiatric symptoms showed reduced brain volumes in the orbitofrontal and posterior cingulate cortices, while no effects were detected on regional tau deposition. Posterior cingulate cortex volume was the only predictor of global neuropsychiatric burden in this MCI population.

Neuropsychiatric symptoms occur early in the AD trajectory and are mainly related to defects of control executive abilities and to the reduction of gray matter volume in the orbitofrontal and posterior cingulate cortices. A better understanding of the cognitive and neuroanatomical mechanisms of neuropsychiatric symptoms in MCI could help develop more targeted and efficacious treatment alternatives.

We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults.

We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q).

Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior.

CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

In addition to memory deficits, patients with Alzheimer's disease (AD) experience neuropsychiatric disturbances. Recent studies have suggested the association of obsessive-compulsive disorder with the early stages of AD. However, there is a lack of understanding of the neurobiological underpinnings of compulsive-like behaviors at the neuronal circuit level and their relationship with AD.

We have addressed this issue in an amyloid-β 1-42-induced mouse model of AD by studying compulsive-like behaviors. Next, we compared the hippocampal and medial prefrontal cortex (mPFC) local field potential pattern and coherence between these regions of control and AD mice. We also assessed the expression pattern of acetylcholine and glutamatergic signaling in these regions, using quantitative polymerase chain reaction.

Our findings show that AD mice exhibit compulsive-like behaviors, as evidenced by enhanced marble burying, nest building, and burrowing. Furthermore, AD mice exhibited hippocampo-cortical circuit dysfunction demonstrated by decreased power of rhythmic oscillations at the theta (4-12 Hz) and gamma (25-50 Hz) frequencies in the hippocampus and mPFC, two functionally interconnected brain regions involved both in AD and compulsive behaviors. Importantly, coherence between the hippocampus and mPFC in the theta band of AD animals was significantly reduced. Furthermore, we found reduced cholinergic and glutamatergic neurotransmission in the hippocampus and mPFC of AD mice.

We conclude that the hippocampo-cortical functional alterations may play a significant role in mediating the compulsive-like behaviors observed in AD mice. These findings may help in understanding the underlying circuit mechanisms of obsessive-compulsive disorder-like phenotypes associated with AD.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular β-amyloid (Aβ) plaques and neuronal damage. Although AD is typically considered a cognitive neurodegenerative disorder, almost all people diagnosed with AD develop neuropsychiatric complications at some stage in their life span. The present study investigated the effect of chronic Nattokinase (NK) administration on β-Amyloid peptide (Aβ1-42) induced neuropsychiatric conditions (depression-like behaviour, anxiety, and memory impairment) in mice. Aβ1-42 peptide injected mice demonstrated depression, anxiety, and impairment of cognitive abilities evaluated as increased immobility time in forced swim test (FST), decreased open arm time/entries in elevated plus maze (EPM) and reference and working memory error in radial arm maze (RAM) respectively with elevation in Interleukin-6 (IL-6), Tumour necrosis factor-α (TNF-α), reduction in Interleukin-10 (IL-10) and Brain-derived neurotrophic factor (BDNF) immunocontent within the hippocampus. Chronic administration of NK (50-100 mg/kg, i.p.) from day 8-27, prevented depression-like behaviour, anxiety, and memory impairment and normalized the neurochemical alteration within the hippocampus of mice injected with Aβ1-42 peptide. The effect of NK on psychiatric complications, learning, and memory was comparable to peripheral donepezil treatment. This study suggests that NK improves learning, memory impairment, and neuropsychiatric complications possibly through the downregulation of neuroinflammatory pathways and restoring BDNF signalling in AD.

Apathy is a prevalent mood disturbance that occurs in a wide range of populations, including those with normal cognitive aging, mental disorders, neurodegenerative disorders and traumatic brain injuries. Recently, neuroimaging technologies have been employed to elucidate the neural substrates underlying brain disorders accompanying apathy. However, the consistent neural correlates of apathy across normal aging and brain disorders are still unclear.

This paper first provides a brief review of the neural mechanism of apathy in healthy elderly individuals, those with mental disorders, neurodegenerative disorders, and traumatic brain injuries. Further, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, the structural and functional neuroimaging meta-analysis using activation likelihood estimation method is performed on the apathy group with brain disorders and the healthy elderly, aiming at exploring the neural correlates of apathy.

The structural neuroimaging meta-analysis showed that gray matter atrophy is associated with apathy in the bilateral precentral gyrus (BA 13/6), bilateral insula (BA 47), bilateral medial frontal gyrus (BA 11), bilateral inferior frontal gyrus, left caudate (putamen) and right anterior cingulate, while the functional neuroimaging meta-analysis suggested that the functional connectivity in putamen and lateral globus pallidus is correlated with apathy.

Through the neuroimaging meta-analysis, this study has identified the potential neural locations of apathy in terms of brain structure and function, which may offer valuable pathophysiological insights for developing more effective therapeutic interventions for affected patients.

To examine whether associations between individual neuropsychiatric symptoms (NPS) and incident Alzheimer's dementia (AD) differ in men versus women.

Data were acquired from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Two sets of older (≥ 60 years) participants were formed: one of cognitively unimpaired (CU) individuals, and one of participants with mild cognitive impairment (MCI). NPS were assessed using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models examined associations between individual NPS and AD incidence separately for each participant set. These models featured individual NPS, sex, NPS by sex interactions as well as a number of covariates.

The analysis involved 9,854 CU individuals followed for 5.5 ± 3.8 years and 6,369 participants with MCI followed for 3.8 ± 3.0 years. NPS were comparably associated with future AD in men and women with MCI. Regarding CU participants, the following significant sex by NPS interactions were noted: female sex moderated the risk conferred by moderate/severe apathy (HR = 7.36, 3.25-16.64) by 74%, mitigated the risk conferred by moderate/severe depression (HR = 3.61, 2.08-6.28) by 52%, and augmented the risks conferred by mild depression (HR = 1.00, 0.60-1.68) and agitation (HR = 0.81, 0.40-1.64) by 83% and 243%, respectively.

Apathy, depression and agitation were differentially associated with incident AD in CU men and women. No individual NPS was associated with different risks of future AD in men versus women with MCI.

To compare the utility of the Mild Behavioral Impairment-Checklist (MBI-C) and Neuropsychiatric Inventory Questionnaire (NPI-Q) to capture NPS in subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia.

In this cross-sectional memory clinic study, linear regression models compared MBI-C (n = 474) and NPI-Q (n = 1040) scores in relation to Montreal Cognitive Assessment (MoCA) score.

MBI prevalence was 37% in subjective cognitive decline, 54% in mild cognitive impairment, and 62% in dementia. Worse diagnostic status was associated with higher MBI-C and NPI-Q score (P < .001), lower MoCA (P < .001), and greater age (P < .001). Higher MBI-C (β -.09; 95% CI -.13, -.05) and NPI-Q (β -.17; 95% CI -.23, -.10) scores were associated with lower MoCA scores, with psychosis most strongly associated (β -1.11; 95% CI -1.56, -.65 vs β -1.14; 95% CI -1.55, -.73).

The MBI-C captures global and domain-specific NPS across cognitive stages. Both the MBI-C and NPI-Q have utility in characterizing NPS.