The role of sex differences in depression in pathologically defined Alzheimer's disease.

Introduction: Sex differences in Alzheimer's disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life. Methods: We compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication. Results: In the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men - control men: 24%) than in women (AD women - control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately. Discussion: Control women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Diagnosing and Treating Alzheimer Disease During the Early Stage.

Recent advances in technology can lead to earlier detection of Alzheimer disease (AD) in patients and therefore opportunities for early diagnosis and treatment. In addition, novel agents can slow disease progression and improve symptoms. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Early detection and intervention are crucial to slow symptom progression, and these advances provide a window of opportunity to diagnose the disease early and even prevent it from becoming symptomatic. Clinicians need education on early recognition of AD and on sharing the diagnosis of AD with patients and families as well as guidance for providing patients and families with information on next steps and facilitating early treatment initiation for AD. Partnering with clinicians in the primary care setting and providing them with the necessary tools can change the trajectory of the disease for patients and caregivers.

Timely Diagnosis of Alzheimer Disease.

Diagnosing early-stage Alzheimer disease can lead to prompt initiation of treatment and slow down symptom progression. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Tests for biomarkers, new symptomatic treatments and disease-modifying agents, and the addition of the preclinical stage to the diagnostic criteria for AD can aid in earlier disease recognition and developing treatment plans. Communicating diagnosis and information on next steps with patients and caregivers can lead to patient and caregiver involvement in decision-making and planning as well as participation in clinical trials and maximizing benefits and lifestyle interventions.

Facilitating Treatment Initiation in Early-Stage Alzheimer Disease.

Once a diagnosis of Alzheimer disease is established, a wide variety of therapy options are available to treat different stages of the disease. Patients have the opportunity to delay onset of the disease or delay its progression if diagnosed early enough through new FDA-approved disease-modifying treatments. For mild to moderate stages, new symptomatic treatments can slow the progression of the disease and improve symptoms. A multi-component approach is recommended in order to tailor treatments to each patient's needs.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Design and Development of a Community-Based, Interdisciplinary, Collaborative Dementia Care Program.

OBJECTIVE: To describe the design, development, and baseline characteristics of enrollees of a home-based, interdisciplinary, dyadic, pilot dementia care program. DESIGN: Single-arm, dementia care intervention in partnership with primary care providers delivered by Health Coaches to persons with dementia and caregiver "dyads" and supervised by an interdisciplinary team. SETTING: Home- and virtual-based dyad support. PARTICIPANTS: Persons with mild cognitive impairment or dementia diagnosis and/or who were prescribed antidementia medications; had an identified caregiver willing to participate; were under the care of a partner primary care provider; and had health insurance through the affiliated accountable care organization (Banner Health Network). INTERVENTION: Provision of personalized dementia education and support in the home or virtually by Health Coaches supported by an interdisciplinary team. MEASUREMENTS: Cognition, function, mood, and behavior of persons with dementia; caregiver stress and program satisfaction; primary care provider satisfaction. RESULTS: Served dyads from three primary care clinics with a total of 87 dyads enrolled between December 2018 and June 2020. CONCLUSION: A pilot Dementia Care Partners demonstrated feasibility and suggested acceptability, and high satisfaction among primary care providers and caregivers.

Advances in Diagnosis of Alzheimer Disease and Emerging Treatment Targets.

Until recently, the diagnosis of Alzheimer disease (AD) could not be truly made until an autopsy was done. Patients' diagnosis relied on clinicians' skills to recognize signs and symptoms of AD, and the diagnosis was often incorrect. The rate of misdiagnosis was higher in earlier disease stages when symptoms are milder. Researchers have made great strides over the past 2 decades in identifying diagnostic biomarkers and treatment targets. Can AD now be diagnosed before patients show symptoms? What do potential treatments look like? This CME presentation highlights exciting developments.

The relationship between cerebral and retinal microbleeds in cerebral amyloid angiopathy (CAA): A pilot study.

BACKGROUND: The standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients. METHODS: We used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients. RESULTS: We found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements. CONCLUSION: Retinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA.

Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease.

The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal ß-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aß-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

BACKGROUND: Abnormal beta-amyloid (Aß) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. RESULTS: Significant differences in both cognitive performance and in Aß neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.

Current and Emerging Solutions to Challenges in the Management of Alzheimer's Disease.

​​​​Effective multifactorial management of Alzheimer's disease (AD) requires a triadic alliance of the clinician, the patient, and the patient's family and/or care partner(s). During the evaluation process and when the diagnosis of AD is delivered, these parties must work together to set goals and develop care plans. Care plans should be designed to help the patient maintain safety and autonomy as long as he or she can and, once autonomy is no longer possible, to allow the patient and care partner(s) to experience as much comfort and the best possible quality of life for as long as possible. In this Academic Highlights, faculty members from neurology, psychiatry, neuropsychology, and primary care share their recommendations, supported by current evidence and guidelines, for handling the complexities of providing care for patients with AD.

A Multidisciplinary Approach for Addressing Challenges in Alzheimer's Disease.

In this webcast, experts from the Banner health care system discuss the evaluation of cognitive concerns and cognitive impairment, and the diagnosis and management of Alzheimer's disease (AD). Topics of the brief video clips include methods for developing therapeutic rapport with patients and their families, identifying and assessing the patient's and/or the care partner's concern, detecting cognitive impairment, characterizing the patient's cognitive-behavioral syndrome, and investigating and determining the etiology of the cognitive impairment or dementia syndrome. The experts also address strategies for delivering a diagnosis to patients and their care partners, planning treatment regimens, and offering education and support. Task-sharing and collaboration must occur between specialists and primary care clinicians to address the growing number of individuals with AD and related dementias.

Diagnosing and Treating Depression in Patients with Alzheimer's Disease.

Although cognitive and functional impairment are the hallmark features of Alzheimer's disease (AD), neuropsychiatric symptoms associated with AD account for increased rates of disability and profoundly impact the quality of life of both patients and their caregivers. This narrative review of current evidence provides practical guidance in diagnosing and managing depression in patients with AD using pharmacological and nonpharmacological interventions. After apathy, depression is the second most common neuropsychiatric symptom in AD. Diagnosing late-life depression (LLD), particularly in those affected by AD, is complicated because older patients may not meet the criteria for a major depressive disorder. Clinically, late-life depression and dementia can be indistinguishable. Although these two entities are now thought to be related, the pathologic mechanisms remain unclear. Evidence suggests that LLD may be a prodromal symptom of neurodegenerative disease. The various geropsychiatric measures currently used to diagnose, rate the severity of, and monitor the progress of treatment for depression are imperfect. Neuroimaging represents a promising avenue toward understanding the complex pathophysiologic relationships between dementia and LLD, and will support the pursuit of biomarker-driven diagnosis and treatment. Nonpharmacologic interventions to relieve depression in persons with cognitive impairment and dementia include emotion-oriented therapies, behavioral and cognitive-behavioral modification programs, and structured activity programs. Sensory-stimulation therapies and multisensory approaches show some promise for successfully treating depression in patients with dementia, but further rigorous research is needed to establish their validity. Clinical consensus and research appear to support selective serotonin reuptake inhibitors as a first choice for the pharmacological treatment of depression in patients with dementia. However, initial support for these therapies remains variable, and further investigation is needed. Extra care is required in prescribing to this population because of the generally high level of medical and psychiatric comorbidity and the potential difficulty in assessing the cognitively impaired patient's response.

Cognitive Assessment of Alzheimer's Disease and Dementias in Clinical Practice: Pragmatics of Brief Instruments and Neuropsychological Evaluation.

Detection of cognitive impairment and dementia (CID) through the use of brief cognitive assessment tools (BCATs) is the first step to establishing an accurate diagnosis and care plan for individuals seen in primary practices. While the cognitive-behavioral syndrome and underlying etiology may not be readily apparent through brief assessment, clinicians can refer patients for a more comprehensive neuropsychological evaluation. A timely diagnosis maximizes the potential for patients to be involved in decision-making and planning for their future, and allows for expedited intervention and harm reduction. This activity provides a practical review of validated and standardized BCATs that can aid in the detection of CID; reviews cognitive and neuropsychological domains and their clinical relevance; and delineates circumstances for referral to neuropsychology and the utility of neuropsychological evaluation to practicing clinicians.

Disclosure of Alzheimer's Disease and Dementia: Patient- and Care Partner-Centric Decision-Making and Communication.

Disclosing the diagnosis of cognitive impairment or dementia due to Alzheimer's disease (AD) and Related Dementias (ADRD) can be one of the most challenging aspects of dementia care for clinicians. However difficult the diagnosis is to give or receive, evidence and evidence-based consensus support that disclosing a timely AD/ADRD diagnosis, accompanied by psychoeducation and care planning, is beneficial to patient-care partner dyads. Diagnosis, provided as early as possible, increases the likelihood for patients to be involved in decision-making and planning for their future and allows care options to be implemented sooner to provide greater clinical and quality-of-life benefits, reduce potential for harm, and mitigate symptoms and decline. Using patient-centered communication and following a structured process, clinicians can provide a successful disclosure of diagnosis as a component of the necessary foundation to implement impactful management and care planning for patients and caregivers going through a life-changing process.