INTRODUCTION: Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS. AREAS COVERED: This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD. EXPERT OPINION: Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.
BACKGROUND: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. OBJECTIVE: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. METHOD: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: Higher plasma NfL was correlated with worse MoCA scores at baseline (ß = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). CONCLUSION: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.
OBJECTIVE: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. METHOD: Older adults (age 50 + ) with objective health measures (n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. RESULTS: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta -0.060, P = 0.038) as did cerebrovascular disease (beta -0.197, P < 0.001), HbA1C (beta -0.059, P < 0.001), visual impairment (beta -0.070, P = 0.007), hearing impairment (beta -0.098, P < 0.001) and physical inactivity (beta -0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease (z = -3.525, P < 0.001), HbA1C (z = -4.976, P < 0.001) and physical inactivity (z = -3.998, P < 0.001) partially mediated the association between depression and cognitive decline. CONCLUSIONS: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care.
Importance: Neuropsychiatric syndromes (NPSs) are common in neurodegenerative disorders (NDDs); compromise the quality of life of patients and their care partners; and are associated with faster disease progression, earlier need for nursing home care, and poorer quality of life. Advances in translational pharmacology, clinical trial design and conduct, and understanding of the pathobiology of NDDs are bringing new therapies to clinical care. Observations: Consensus definitions have evolved for psychosis, agitation, apathy, depression, and disinhibition in NDDs. Psychosocial interventions may reduce mild behavioral symptoms in patients with NDD, and pharmacotherapy is available for NPSs in NDDs. Brexpiprazole is approved for treatment of agitation associated with Alzheimer disease dementia, and pimavanserin is approved for treatment of delusions and hallucinations associated with psychosis of Parkinson disease. Trials are being conducted across several of the NDDs, and a variety of mechanisms of action are being assessed for their effect on NPSs. Conclusions and Relevance: Detection and characterization of NPSs in patients with NDDs is the foundation for excellent care. New definitions for NPSs in NDDs may inform choices regarding clinical trial populations and translate into clinical practice. Psychosocial and pharmacologic therapies may reduce behavioral symptoms and improve quality of life for patients and caregivers. Approved agents may establish regulatory precedents, demonstrate successful trial strategies, and provide the foundation for further advances in treatment development.
BACKGROUND: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. OBJECTIVES: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. DESIGN, SETTING AND PARTICIPANTS: We conducted a cohort analysis of participants in the COMPASS-ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. MEASUREMENTS: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. RESULTS: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312) = -2.4, p = 0.02 and t(328) = -3.8, p = 0.001, respectively) and visuospatial reasoning (t(301) = -2.3, p = 0.02 and t(321) = -2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex-stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166) = 2.4, p = 0.01) and verbal learning (t(167) = -4.3, p = 0.001) compared to the female neither group. CONCLUSIONS: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes.
Alzheimer Disease , Apathy , Frontotemporal Dementia , Neurodegenerative Diseases , Female , Male , Humans , Depression
INTRODUCTION: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes. METHODS: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-. RESULTS: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-. DISCUSSION: HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles. HIGHLIGHTS: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology.
Alzheimer Disease , Atherosclerosis , Cerebral Amyloid Angiopathy , Diabetes Mellitus , Hypertension , Humans , Alzheimer Disease/epidemiology , Alzheimer Disease/pathology , Hypertension/complications , Hypertension/epidemiology , Diabetes Mellitus/epidemiology
Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen's d of the difference in global cognition between the high and low TGC groups to Cohen's d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen's d values using the whole sample. As hypothesized, Cohen's d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen's d's of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.
Cognitive Dysfunction , Depressive Disorder, Major , Humans , Aged , Depressive Disorder, Major/diagnosis , Cognition , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/psychology , Neuropsychological Tests
BACKGROUND: Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer's disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD. METHODS: The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models. RESULTS: The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period. CONCLUSIONS: The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.
Alzheimer Disease , Cognitive Dysfunction , Dementia , Humans , Aged , Activities of Daily Living , Disease Progression , Alzheimer Disease/drug therapy , Dementia/diagnosis , Cognitive Dysfunction/psychology , Mental Status and Dementia Tests , Probability
OBJECTIVES: To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures. DESIGN: Secondary cross-sectional analysis using latent profile analysis. SETTING: Multisite clinical trial in Toronto, Canada. PARTICIPANTS: One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118). MEASUREMENTS: Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function. RESULTS: We identified three latent profiles: Profile 1 (poor cognition; n = 75, 42.1%), Profile 2 (intermediate cognition; n = 75, 42.1%), and Profile 3 (normal cognition; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal. CONCLUSION: Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups.
INTRODUCTION: We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS: We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global. RESULTS: Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). DISCUSSION: CDR-global staged AD by capturing differences in relevant outcomes along AD progression. Highlights: There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.
OBJECTIVES: To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA). DESIGN: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion. SETTING: IPA Agitation Workgroup. PARTICIPANTS: IPA panel of international experts on agitation. INTERVENTION: Integration of available information into a comprehensive algorithm. MEASUREMENTS: None. RESULTS: The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented. CONCLUSIONS: The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.
Geriatric Psychiatry , Neurocognitive Disorders , Humans , Consensus , Psychomotor Agitation/etiology , Psychomotor Agitation/prevention & control , Emergency Service, Hospital
BACKGROUND: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove "provisional" from the definition. METHODS: This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. RESULTS: We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. CONCLUSION: The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.
Cognition Disorders , Cognitive Dysfunction , Humans , Consensus , Geriatric Psychiatry , Psychomotor Agitation/diagnosis , Cognitive Dysfunction/diagnosis
BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.
Dementia , Diabetes Mellitus, Type 2 , Metformin , Humans , Aged , Metformin/therapeutic use , Hypoglycemic Agents/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Retrospective Studies , Sulfonylurea Compounds/therapeutic use , Dementia/epidemiology , Dementia/prevention & control
Impaired angiogenesis is associated with cognitive decline in older adults. While exercise has been broadly associated with increased angiogenesis, the relevant mechanisms in older adults are not clear. Here, we present a systematic review and meta-analysis on the relationship between exercise and specific blood angiogenesis markers in older adults to better understand the relevant mechanisms. MEDLINE, Embase, and Cochrane CENTRAL were searched for original reports of angiogenesis markers' concentrations in blood before and after exercise in older adults (≥50 years). Heterogeneity was investigated using sub-group analyses and meta-regressions. Of the 44 articles included in the review, 38 were included in the meta-analyses for five markers: vascular endothelial growth factor (VEGF), e-selectin (CD62E), endostatin, fibroblast growth factor 2, and matrix metallopeptidase-9. VEGF levels were higher (SMD[95%CI]= 0.18[0.03, 0.34], and CD62E levels were lower (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04) after exercise. No other markers were altered. Although more studies are needed, changes in angiogenesis markers may help explain the beneficial effects of exercise on angiogenesis in older adults.
Cognitive Dysfunction , Vascular Endothelial Growth Factor A , Humans , Aged , Angiogenesis , Exercise
BACKGROUND: Many individuals with Alzheimer's disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments. OBJECTIVE: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD. METHODS: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD. RESULTS: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost. CONCLUSIONS: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions.
Alzheimer Disease , Humans , Alzheimer Disease/epidemiology , Alzheimer Disease/therapy , Anxiety/psychology , Caregivers/psychology , Emotions , Quality of Life/psychology
Background: People with Alzheimer's disease (AD) have difficulties in performing activities of daily living (ADLs) as the disease progresses, commonly experience neuropsychiatric symptoms (NPS), and often have comorbidities such as cardiovascular disease. These factors all contribute to a requirement for care and considerable healthcare costs in AD. The Clinical Dementia Rating (CDR) scale is a widely used measure of dementia staging, but the correlations between scores on this scale and patient-/care partner-relevant outcomes have not been characterized fully. We conducted a systematic literature review to address this evidence gap. Methods: Embase, MEDLINE, and the Cochrane Library were searched September 13, 2022, to identify published studies (no restriction by date or country) in populations with mild cognitive impairment due to AD or AD dementia. Studies of interest reported data on the relationships between CDR Global or CDR-Sum of Boxes (CDR-SB) scores and outcomes including NPS, comorbidities, ADLs, nursing home placement, healthcare costs, and resource use. Results: Overall, 58 studies met the inclusion criteria (42 focusing on comorbidities, 14 on ADLs or dependence, five on nursing home placement, and six on economic outcomes). CDR/CDR-SB scores were correlated with the frequency of multiple NPS and with total scores on the Neuropsychiatric Inventory. For cardiovascular comorbidities, no single risk factor was consistently linked to AD progression. Increasing CDR/CDR-SB scores were correlated with decline in multiple different measures of ADLs and were also associated with nursing home placement and increasing costs of care. Conclusion: NPS, ADLs, and costs of care are clearly linked to AD progression, as measured using CDR Global or CDR-SB scores, from the earliest stages of disease. This indicates that scores derived from the CDR are a meaningful way to describe the severity and burden of AD for patients and care partners across disease stages.
INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.
Mild cognitive impairment (MCI) is a well-established prodromal stage of dementia (e.g., Alzheimer's disease) that is often accompanied by early signs of neurodegeneration. To facilitate a better characterization of the underlying pathophysiology, we assessed the available literature to evaluate potential fluid biomarkers in MCI. Peer-reviewed articles that measured cerebrospinal fluid (CSF) and/or peripheral biomarkers of neuronal injury (total-tau [T-tau], neurofilament light chain [NfL], heart-type fatty acid binding protein [HFABP], neuron-specific enolase, ubiquitin C-terminal hydrolase L1) and/or astroglial pathology (glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B) in MCI and healthy controls were assessed. Group differences were summarized by standardized mean differences (SMDs) and 95% confidence intervals calculated using a random-effects model. Heterogeneity was quantified using I2. A total of 107 studies were included in the meta-analysis and 10 studies were qualitatively reviewed. In CSF, concentrations of NfL (SMD = 0.69 [0.56, 0.83]), GFAP (SMD = 0.41 [0.07, 0.75]), and HFABP (SMD = 0.57 [0.26, 0.89]) were elevated in MCI. In blood, increased concentrations of T-tau (SMD = 0.19 [0.09, 0.29]), NfL (SMD = 0.41 [0.32, 0.49]), and GFAP (SMD = 0.39 [0.23, 0.55]) were found in MCI. Heterogeneity that was identified in all comparisons was explored using meta-regression and subgroup analysis. Elevated NfL and GFAP can be detected in both CSF and peripheral blood. Monitoring these biomarkers in clinical settings may provide important insight into underlying neurodegenerative processes in MCI.
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnosis , Cognitive Dysfunction/diagnosis , tau Proteins , Biomarkers , Neurons , Astrocytes , Amyloid beta-Peptides
BACKGROUND: Alzheimer's dementia (AD) is associated with electroencephalography (EEG) abnormalities including in the power ratio of beta to theta frequencies. EEG studies in mild cognitive impairment (MCI) have been less consistent in identifying such abnormalities. One potential reason is not excluding the EEG aperiodic components, which are less associated with cognition than the periodic components. Here, we investigate whether aperiodic and periodic EEG components are disrupted differently in AD or MCI vs. healthy control (HC) individuals and whether a periodic based beta/theta ratio differentiates better MCI from AD and HC groups than a ratio based on the full spectrum. METHODS: Data were collected from 44 HC (mean age (SD) = 69.1 (5.3)), 114 MCI (mean age (SD) = 72.2 (7.5)), and 41 AD (mean age (SD) = 75.7 (6.5)) participants. Aperiodic and periodic components and full spectrum EEG were compared among the three groups. Receiver operating characteristic curves obtained via logistic regression classifications were used to distinguish the groups. Last, we explored the relationships between cognitive performance and the beta/theta ratios based on the full or periodic spectrum. RESULTS: Aperiodic EEG components did not differ among the three groups. In contrast, AD participants showed an increase in full spectrum and periodic relative powers for delta, theta, and gamma and a decrease for beta when compared to HC or MCI participants. As predicted, MCI group differed from HC participants on the periodic based beta/theta ratio (Bonferroni corrected p-value = 0.036) measured over the occipital region. Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI participants, and outperformed classifiers based on beta/theta power ratio in full spectrum EEG. Beta/theta ratios were comparable in their association with cognition. CONCLUSIONS: In contrast to a full spectrum EEG analysis, a periodic-based analysis shows that MCI individuals are different on beta/theta ratio when compared to healthy individuals. Focusing on periodic components in EEG studies with or without other biological markers of neurodegenerative diseases could result in more reliable findings to separate MCI from healthy aging, which would be valuable for designing preventative interventions.
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/complications , Electroencephalography , Cognitive Dysfunction/psychology , Cognition , Biomarkers
BACKGROUND: Bipolar disorder (BD) and cannabis use are each associated with neurocognitive deficits in adolescents. However, little is known regarding the association of neurocognition with cannabis use among adolescents with BD. Therefore, we examined this topic in a sample of adolescents with BD and healthy control (HC) adolescents. METHODS: Participants included 121 adolescents (n = 32 with BD and lifetime cannabis use (BDCB+), n = 31 with BD and no lifetime cannabis use (BDCB-), n = 58 HC with no lifetime cannabis use), aged 14-20 years. Five neurocognitive subtests of the computerized CANTAB battery were assessed. Groups were compared using an analysis of covariance (ANCOVA) covarying for age, sex, and intelligence quotient. RESULTS: The three groups differed significantly on tests of visuospatial working memory (F = 4.41, p = 0.014, ηp2=0.07) and sustained attention (F = 5.15, p = 0.007, ηp2=0.08). Post hoc analyses revealed working memory scores were significantly worse in BDCB+ versus HC (p = 0.04, d = 0.59), and sustained attention was significantly worse in BDCB- versus HC (p = 0.006, d = 0.70). CONCLUSION: These preliminary findings suggest that cannabis use among adolescents with BD is associated with working memory deficits. Future studies in larger samples are warranted to evaluate causation versus predisposition to cannabis use, and to evaluate duration, quantity, and potency of cannabis on neurocognition among adolescents with BD.
Bipolar Disorder , Cannabis , Humans , Adolescent , Bipolar Disorder/complications , Bipolar Disorder/psychology , Cannabis/adverse effects , Memory, Short-Term , Memory Disorders , Attention , Neuropsychological Tests
