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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.

The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

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.

Background Cognitive screening is important for the oldest-old (age 90 +). This age group is the fastest growing and has the highest risk of dementia. However, norms and score equivalence for screening tests are lacking for this group. Aims To provide norms and score equivalence for commonly used cognitive screening tests for the oldest-old. Methods Data on 157 participants of the Center for Healthy Aging Longevity Study aged 90 + were analyzed. First, we derived norms for (1) subtests and cognitive domains of the in-person Montreal Cognitive Assessment having a maximum score of 30 (MoCA-30) and (2) the total MoCA-22 score, obtained from the in-person MoCA-30 by summing the subtests that do not require visual input to a maximum score of 22. These norms were derived from 124 participants with a Mini-Mental State Examination (MMSE) ≥ 27. Second, we derived score equivalences for MMSE to MoCA-30 and MoCA-22, and MoCA-30 to MoCA-22 using equipercentile equating method with log-linear smoothing, based on all 157 participants. Results MoCA-22 total score norms are: mean = 18.3(standard deviation = 2.2). An MMSE score of 27 is equivalent to a MoCA-30 score of 22 and a MoCA-22 score of 16. Discussion and conclusions Subtest, domain and MoCA-22 norms will aid in evaluation of the oldest-old who cannot complete the MoCA-30 or are tested over the phone. The equivalences of the three cognitive tests (MMSE, MoCA-30, MoCA-22) in the oldest-old will facilitate continuity of cognitive tracking of individuals tested with different tests over time and comparison of the studies that use different cognitive tests.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Aducanumab has been approved by the US Food and Drug Administration for treatment of Alzheimer’s disease (AD). Clinicians require guidance on the appropriate use of this new therapy. An Expert Panel was assembled to construct Appropriate Use Recommendations based on the participant populations, conduct of the pivotal trials of aducanumab, updated Prescribing Information, and expert consensus. Aducanumab is an amyloid-targeting monoclonal antibody delivered by monthly intravenous infusions. The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. The Expert Panel recommends that use of aducanumab be restricted to this population in which efficacy and safety have been studied. Aducanumab is titrated to a dose of 10 mg/kg over a 6-month period. The Expert Panel recommends that the aducanumab be titrated to the highest dose to maximize the opportunity for efficacy. Aducanumab can substantially increase the incidence of amyloid-related imaging abnormalities (ARIA) with brain effusion or hemorrhage. Dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommends MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA. Recommendations are made for measures less cumbersome than those used in trials for the assessment of effectiveness in the practice setting. The Expert Panel emphasized the critical importance of engaging in a process of patient-centered informed decision-making that includes comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits.

Background The need for preventive therapies that interrupt the progression of Alzheimer’s disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meaningfulness of what are likely small initial treatment effects in these earlier stages of the AD patho-clinical disease continuum is a major challenge and warrants further consideration. Body To accommodate a shift towards earlier intervention in AD, we propose meaningful benefits as a new umbrella concept that encapsulates the spectrum of potentially desirable outcomes that may be demonstrated in clinical trials and other studies across the AD continuum, with an emphasis on preclinical AD and early AD (i.e., MCI due to AD and mild AD dementia). The meaningful benefits framework applies to data collection, assessment, and communication across three dimensions: (1) multidimensional clinical outcome assessments (COAs) including not only core disease outcomes related to cognition and function but also patient- and caregiver-reported outcomes, health and economic outcomes, and neuropsychiatric symptoms; (2) complementary analyses that help contextualize and expand the understanding of COA-based assessments, such as number-needed-to-treat or time-to-event analyses; and (3) assessment of both cumulative benefit and predictive benefit, where early changes on cognitive, functional, or biomarker assessments predict longer-term clinical benefit. Conclusion The concept of meaningful benefits emphasizes the importance of multidimensional reporting of clinical trial data while, conceptually, it advances our understanding of treatment effects in preclinical AD and mild cognitive impairment due to AD. We propose that such an approach will help bridge the gap between the emergence of DMTs and their clinical use, particularly now that a DMT is available for patients diagnosed with MCI due to AD and mild AD dementia.

ObjectiveTo update data for diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard.MethodsData from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) were used to determine the predictive value of a clinical PD diagnosis. Two clinical diagnostic confidence levels were used, possible PD (PossPD, never treated or not responsive) and probable PD (ProbPD, 2/3 cardinal clinical signs and responsive to dopaminergic medications). Neuropathologic diagnosis was the gold standard.ResultsBased on the first visit to AZSAND, 15/54 (27.8%) PossPD participants and 138/163 (84.7%) ProbPD participants had confirmed PD. PD was confirmed in 24/34 (70.6%) ProbPD with ConclusionsThis updated study confirmed lower clinical diagnostic accuracy for elderly, untreated or poorly responsive PossPD participants and for ProbPD with Classification of EvidenceThis study provides Class II evidence that a clinical diagnosis of ProbPD at the first visit identifies participants who will have pathologically confirmed PD with a sensitivity of 82.6% and a specificity of 86.0%.

OBJECTIVE: The Uniform Data Set 3.0 neuropsychological battery (UDS3NB) is well developed for research with Alzheimer’s disease and related dementias, and may serve as a common set of measures of cognitive decline across neurodegenerative diseases. However, the battery has not been formally assessed in persons with Parkinson’s disease (PD). The current research provides initial information on the convergent and ecological validity of the UDS3NB in individuals with PD. METHODS: Participants included 75 individuals diagnosed with PD from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical dementia ratings, administered independently from the cognitive measures, identified individuals as having normal cognition (n=38), Mild Cognitive Impairment (MCI; n=25) and dementia (n=12). UDS3NB measures were compared between these groups, and correlations between UDS3NB measures, gold standard neuropsychological measures, and informant rated activities of daily living ability (ADL) were evaluated. RESULTS: At the group-level, UDS3NB scores followed the expected pattern with higher scores in participants with PD but no cognitive diagnosis and lower in those with dementia; scores in the MCI group were between these extremes. Convergent validity was suggested by moderate correlations between UDS specific measures (i.e. Craft story) and measures such as the RAVLT. Ecological validity was suggested by statistically significant correlations between UDS3NB performance and caregiver ratings of ADLs, with speed and executive functioning measures (Trailmaking A; r=−.51, p

While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

The foundation of current Alzheimer's disease (AD) treatment involves pharmacological and nonpharmacological management and care planning predicated on patient-centered psychoeducation, shared goal-setting, and decision-making forged by a strong triadic relationship between clinician and the patient-caregiver dyad. Food and Drug Administration (FDA) approved AD medications, cholinesterase-inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) antagonist memantine, when utilized as part of a comprehensive care plan, while generally considered symptomatic medications, can provide modest “disease course-modifying” effects by enhancing cognition, and reducing loss of independence. When combined, pharmacologic and nonpharmacologic treatments can meaningfully mitigate symptoms and reduce clinical progression and care burden. AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements. First line treatment for neuropsychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions. Intensive research efforts are underway to develop more accurate and practical AD diagnostic biomarkers and clinical tools and better therapeutics. Ongoing research studies for primary and secondary prevention of AD and clinical trials evaluating symptomatic and disease-modifying treatments in symptomatic AD are directed at diverse therapeutic targets including neurochemicals, amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions.

Introduction Heterogeneity of outcomes in Alzheimer's disease (AD) clinical trials necessitates large sample sizes and contributes to study failures. This analysis determined whether mild-to-moderate AD populations could be enriched for cognitive decline based on apolipoprotein (APOE) ε4 genotype, family history of AD, and amyloid abnormalities. Methods Modeling estimated the number of randomized patients needed to detect a 2-point treatment difference on the AD Assessment Scale–Cognitive subscale using placebo data from three randomized, double-blind trials (ClinicalTrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654). Results An 80% power to detect a 2-point treatment effect required the randomization of 148 amyloid-positive patients; 178 ε4 homozygous or amyloid-positive patients; and 231 ε4 homozygous, family history-positive, or amyloid-positive patients, compared with 1619 unenriched patients (per arm). Discussion Enrichment in mild-to-moderate AD clinical trials can be achieved using combinations of biomarkers/risk factors to increase the likelihood of observing potential treatment effects., Highlights • APOE ɛ4, family history, and amyloid status can enrich mild-to-moderate AD samples. • Enrichment increases the likelihood of detecting a treatment effect on cognition. • Enrichment may reduce sample sizes in clinical trials of symptomatic drugs in AD.

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 β-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.

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimer’s disease dementia, 127 with idiopathic Parkinson’s disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.

Introduction Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD). Methods To develop a neuropsychological composite (FLAME – Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework. Results The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials. Discussion FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD. Conclusion FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.

​​​​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.

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.

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.

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.