Recommendations to address key recruitment challenges of Alzheimer's disease clinical trials.

Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.

Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia.

BACKGROUND: Deficits in instrumental activities of daily living (ADLs) may be more prominent in behavioral variant frontotemporal dementia (bvFTD) than in nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) or semantic variant primary progressive aphasia (svPPA). It is uncertain whether frontotemporal dementia (FTD) subgroups exhibit different patterns and/or predictors of functional impairment. METHODS: We examined data from participants diagnosed with bvFTD (n = 607), svPPA (n = 132), and nfvPPA (n = 155) who were included in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and assessed with the Functional Activities Questionnaire (FAQ). Stepwise multiple linear regression analyses were performed to identify associations between FAQ scores and cognitive/behavioral deficits using the NACC UDS neuropsychological testing battery and the Neuropsychiatric Inventory Questionnaire. RESULTS: FAQ scores were higher in bvFTD than svPPA or nfvPPA. Functional deficits across FTD subtypes differed in severity, but not pattern, and were driven by executive dysfunction and behavioral symptoms. CONCLUSION: Executive dysfunction and behavioral symptoms underlie instrumental ADL deficits in FTD, which are most prominent in bvFTD.

Patient and caregiver reactions to clinical amyloid imaging.

INTRODUCTION: Amyloid imaging is a tool that has recently become available to dementia specialists evaluating patients with possible Alzheimer's disease. Studies have assessed the impact of amyloid imaging on diagnostic and treatment decisions, but patient and family perspectives have received less attention. METHODS: To examine how amyloid imaging affects the diagnostic experience of patients and families, we interviewed members of 26 patient-caregiver dyads with whom a neurologist discussed the option of amyloid positron emission tomography. RESULTS: Most participants who chose to undergo amyloid imaging would choose to do so again. Regardless of the scan outcome, patients and caregivers commonly expressed relief on learning the scan results. Some participants expressed expectations that were beyond scan capabilities. DISCUSSION: Amyloid imaging may provide information that patients and their families find useful. Clinicians must set correct expectations and ensure that families understand the limitations of amyloid imaging.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.

Dementia Prevention and Treatment: A Narrative Review.

Importance: Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance. Observations: Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future. Conclusions and Relevance: Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.

Alerting providers to hospitalized persons with dementia using the electronic health record.

BACKGROUND: While patients with dementia entering the hospital have worse outcomes than those without dementia, early detection of dementia in the inpatient setting is less than 50%. We developed and assessed the positive predictive value (PPV) and feasibility of a novel electronic health record (EHR) banner to identify patients with dementia who present to the inpatient setting using data from the medical record. METHODS: We developed and implemented an EHR algorithm to flag hospitalized patients age ≥65 years with potential cognitive impairment in the Epic EHR system using dementia ICD-10 codes, FDA-approved medications, and the use of the term "dementia" in the emergency department physician note. Medical records were reviewed for all patients who were flagged with an EHR banner from October 2022 to May 2023. RESULTS: A total of 344 individuals were identified who had a banner on their chart of which 280 (81.4%) were either diagnosed with dementia or were on an FDA-approved dementia medication. Forty-three individuals who had confirmed dementia were identified by a medication only (15.4%). Of the patients without confirmed dementia, the majority (N = 33, 9.6%) had a diagnosis of altered mental status, cognitive dysfunction, or mild cognitive impairment. Only 31 individuals (9.0%) had no indication of dementia or cognitive decline in their problem list, past medical history, or medication list. CONCLUSIONS: We found that it was feasible to implement an EHR algorithm for prospective dementia identification with a high PPV. These types of algorithms provide an opportunity to accurately identify hospitalized older individuals for inclusion in quality improvement projects, clinical trials, pay-for-performance programs, and other initiatives.

Pragmatic implementation of comprehensive dementia care management: The Cedars-Sinai C.A.R.E.S. Program preliminary data.

BACKGROUND: The United States faces a growing challenge with over 6.5 million people living with dementia (PLwD). PLwD and their caregivers struggle with cognitive, functional, behavioral, and psychosocial issues. As dementia care shifts to home settings, caregivers receive inadequate support but bear increasing responsibilities, leading to higher healthcare costs. In response, the Centers for Medicare & Medicaid Services (CMS) introduced the Guiding an Improving Dementia Experience (GUIDE) Model. The study explores the real-world implementation of the Cedars-Sinai C.A.R.E.S. Program, a pragmatic dementia care model, detailing its recruitment process and initial outcomes. METHODS: The Cedars-Sinai C.A.R.E.S. Program was integrated into the Epic electronic health record system and focused on proactive patient identification, engagement, interdisciplinary collaboration, care transitions, and ongoing care management. Eligible patients with a dementia diagnosis were identified through electronic health record and invited to join the program. Nurse practitioners with specialized training in dementia care performed comprehensive assessments using the CEDARS-6 tool, leading to personalized care plans developed in consultation with primary care providers. Patients benefited from a multidisciplinary team and support from care navigators. RESULTS: Of the 781 eligible patients identified, 431 were enrolled in the C.A.R.E.S. PROGRAM: Enrollees were racially diverse, with lower caregiver strain and patient behavioral and psychological symptoms of dementia (BPSD) severity compared to other programs dementia care programs. Healthcare utilization, including hospitalizations, emergency department (ED) admissions, and urgent care visits showed a downward trend over time. Completion of advanced directives and Physician Order of Life-Sustaining Treatment (POLST) increased after enrollment. CONCLUSION: The Cedars-Sinai C.A.R.E.S. Program offers a promising approach to dementia care. Its real-world implementation demonstrates the feasibility of enrolling a diverse population and achieving positive outcomes for PLwD and their caregivers, supporting the goals of national dementia care initiatives.

Interhemispheric differences in knowledge of animals among patients with semantic dementia.

OBJECTIVE: To investigate interhemispheric differences on naming and fluency tasks for living versus nonliving things among patients with semantic dementia (SD). BACKGROUND: In SD, left-temporal involvement impairs language and word comprehension, and right-temporal involvement impairs facial recognition. There may be other interhemispheric differences, particularly in the animate-inanimate dichotomy. METHOD: On the basis of magnetic resonance imaging (MRI) ratings of anterior temporal atrophy, 36 patients who met criteria for SD were divided into 21 with left-predominant and 11 with right-predominant involvement (4 others were too symmetric for analysis). The left and right-predominant groups were compared on naming, fluency, and facial recognition tests. RESULTS: Consistent with greater language impairment, the left-predominant patients had worse naming, especially inanimate and letter fluency, than the right-predominant patients. In contrast, difference in scores suggested selective impairment of animal naming, animal name fluency, and semantic knowledge for animate items among the right-predominant patients. Proportionally more right than left-predominant patients misnamed animal items and faces. CONCLUSIONS: These findings support interhemispheric differences in animal knowledge. Whereas left-predominant SD equally affects animate and inanimate words from language involvement, right-predominant SD, with greater sparing of language, continues to impair other semantic aspects of animals. The right anterior temporal region seems to make a unique contribution to knowledge of living things.

"Fantastic thinking" in pathologically proven Pick disease.

BACKGROUND: Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear. OBJECTIVE: To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies. METHODS: We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD. RESULTS: Early in her course, she reported interactions with different actors, having torrid affairs with them, and other related fantasies. When confronted with her false beliefs, she admitted that these relationships were imaginary. Autopsy revealed Pick disease with tau-immunoreactive Pick bodies in the frontal and temporal cortices, and in the hippocampi. CONCLUSIONS: Fantastic thinking, or vividly experienced imagination, may be a manifestation of bvFTD that is distinct from delusions and confabulations and could be the source of previously reported delusions and confabulations in bvFTD.

African Americans are less likely to enroll in preclinical Alzheimer's disease clinical trials.

INTRODUCTION: Alzheimer's disease (AD) incidence is disproportionately high in African Americans, yet, recruitment of this community to AD clinical trials is challenging. METHODS: We compared 47 African Americans and 78 whites in their willingness to enroll in a hypothetical preclinical AD trial and examined barriers and facilitators in their decision making. RESULTS: African American race (OR = 0.45; 95% CI, 0.22-0.93) and score on the research attitude questionnaire (OR = 1.12; 95% CI, 1.04-1.22) were independently associated with willingness to participate. African Americans rated study risks, the requirement of a study partner, study procedures, the ratio of drug to placebo, and study location as more important factors in the decision whether to enroll than did whites. DISCUSSION: These results suggest that researchers will encounter challenges in recruiting African Americans to preclinical AD trials. Future research will be necessary to understand the optimal means to improve recruitment of underrepresented populations.

Communicating mild cognitive impairment diagnoses with and without amyloid imaging.

BACKGROUND: Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. METHODS: We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. RESULTS: Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. CONCLUSIONS: In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care.

INTRODUCTION: The utility of the Appropriate Use Criteria (AUC) for amyloid imaging is not established. METHODS: Fifty-three cognitively impaired patients with clinical F18-florbetapir imaging were classified as early and late onset, as well as AUC-consistent or AUC-inconsistent. Chi-square statistics and t test were used to compare demographic characteristics and clinical outcomes as appropriate. RESULTS: Early-onset patients were more likely to be amyloid positive. Change in diagnosis was more frequent in late-onset cases. Change in therapy was more common in early-onset cases. AUC-consistent and AUC-inconsistent cases had comparable rates of amyloid positivity. We saw no difference in the rate of treatment changes in the AUC-consistent group as opposed to the AUC-inconsistent group. DISCUSSION: The primary role of amyloid imaging in the early-onset group was to confirm the clinically suspected etiology, and in the late-onset group in detecting amyloid-negative cases. The rate of therapeutic changes was significantly greater in the early-onset cases.

Observation of social behavior in frontotemporal dementia.

BACKGROUND: The most characteristic manifestations of behavioral variant frontotemporal dementia (bvFTD) are abnormalities in social behavior. However, distinguishing bvFTD based on social behavior can be difficult in structured clinical settings. METHODS: Using a Social Observation Inventory, 10 patients with bvFTD and 10 patients with Alzheimer's disease (AD) were compared to their caregiver interlocutors on 1-hour mealtime, in-home videotaped segments. RESULTS: Compared to caregivers and patients with AD, patients with bvFTD were significantly disturbed in social behavior. In contrast, patients with AD were indistinguishable from their caregivers. The lack of "you" comments and decreased tact and manners distinguished 92.6% of the patients with bvFTD from patients with AD and caregivers. The Social Observation Inventory scores correlated with scores on frontal-executive tests and socioemotional scales. CONCLUSIONS: The systematic observation of social behavior during routine activities may be one of the best ways to distinguish patients with bvFTD from normal individuals and from patients with other dementias.

Extrapyramidal signs in the primary progressive aphasias.

BACKGROUND: Extrapyramidal signs (EPS) may vary across 3 major subtypes of primary progressive aphasia (PPA): progressive nonfluent aphasia (PNFA), semantic dementia (SD), and progressive logopenic aphasia (PLA). METHODS: We reviewed initial neurological examinations from a clinical PPA cohort (PNFA = 49, SD = 26, PLA = 28) to determine the prevalence of specific categories of EPS. RESULTS: The presence of any EPS was more common in PNFA (38.8%) and PLA (35.7%) than in SD (3.8%). The PNFA group exhibited the highest prevalence of bradykinesia (PNFA: 22.4%, SD: 3.8%, PLA: 0.0%) and rigidity (PNFA: 30.6%, SD: 0.0%, PLA: 10.7%). Calculated positive likelihood ratios indicated bradykinesia (12.1) or rigidity (5.5) was more strongly associated with PNFA than other PPAs. CONCLUSION: These findings suggest that on initial presentation, specific EPS may help distinguish PPA subtypes when linguistic and/or neuroimaging profiles are indistinct. Moreover, EPS could represent a marker of underlying tauopathy, linking clinical presentation to neuropathology in PPA.

False reports from patients with frontotemporal dementia: delusions or confabulations?

Patients with behavioral variant frontotemporal dementia (bvFTD) can make false statements consistent with delusions or confabulations. It is unclear whether bvFTD is primarily associated with either delusions or with confabulations and whether they can be explained by the pathophysiology of this disease. In order to clarify this, we retrospectively surveyed the records of 48 patients with bvFTD for the presence of any false reports and identified four patients. Their false reports included continued interaction with a favorite but dead relation, fictitious marriages with movie stars, and two who claimed that their partner was having an affair. When confronted with the falsity of their statements, the patients conveyed a lack of certainty regarding their external or internal source but persisted in the constancy of their reports. On functional neuroimaging, the patients had predominant frontal involvement. This report found that patients with bvFTD can have both fantastic, wish fulfilling confabulations and typical content-specific delusions. We propose that both phenomena result from known disturbances of ventromedial prefrontal cortex in bvFTD, including deficits in source monitoring and in activating an automatic "doubt tag" for false reports.

Creutzfeldt-Jakob disease presenting with alien limb sign.

Creutzfeldt-Jakob disease is a fatal spongiform encephalopathy, which typically presents with a rapidly progressing dementia and additional neurological findings that can be quite variable and diverse. Here we report the unusual case of a patient who presented with left alien limb sign without overt cognitive impairment and was ultimately diagnosed with pathologically confirmed Creutzfeldt-Jakob disease.

Object activation from features in the semantic system.

The human brain is thought to elicit an object representation via co-activation of neural regions that encode various object features. The cortical regions and mechanisms involved in this process have never been elucidated for the semantic system. We used functional magnetic resonance imaging (fMRI) to evaluate regions activated during a task designed to elicit object activation within the semantic system (e.g., presenting the words "desert" and "humps" with the task to determine if they combine to form an object, in this case a "camel"). There were signal changes in the thalamus for word pairs that activated an object, but not for pairs that (a) failed to activate an object, (b) were simply semantically associated, or (c) were members of the same category. These results suggest that the thalamus has a critical role in coordinating the cortical activity required for activating an object concept in the semantic system.

Object activation in semantic memory from visual multimodal feature input.

The human brain's representation of objects has been proposed to exist as a network of coactivated neural regions present in multiple cognitive systems. However, it is not known if there is a region specific to the process of activating an integrated object representation in semantic memory from multimodal feature stimuli (e.g., picture-word). A previous study using word-word feature pairs as stimulus input showed that the left thalamus is integrally involved in object activation (Kraut, Kremen, Segal, et al., this issue). In the present study, participants were presented picture-word pairs that are features of objects, with the task being to decide if together they "activated" an object not explicitly presented (e.g., picture of a candle and the word "icing" activate the internal representation of a "cake"). For picture-word pairs that combine to elicit an object, signal change was detected in the ventral temporo-occipital regions, pre-SMA, left primary somatomotor cortex, both caudate nuclei, and the dorsal thalami bilaterally. These findings suggest that the left thalamus is engaged for either picture or word stimuli, but the right thalamus appears to be involved when picture stimuli are also presented with words in semantic object activation tasks. The somatomotor signal changes are likely secondary to activation of the semantic object representations from multimodal visual stimuli.