Expectations and clinical meaningfulness of randomized controlled trials.

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Depressive symptoms in Chinese-American subjects with cognitive impairment.

OBJECTIVES: To compare the prevalence of depressive symptoms and frequency of antidepressant use between a group of elderly Chinese-American subjects with and without cognitive impairment and a group of matched white subjects. A secondary aim was to examine the clinical and demographic predictors of depressive symptoms across these groups. METHODS: The study was conducted at an academic neurology subspecialty clinic. This was a case-control study with 140 Chinese-American subjects and 140 demographically and cognitively matched white subjects. In each group, there were 48 cognitively normal and 92 cognitively impaired participants (49 with mild cognitive impairment, 43 with Alzheimer disease). The proportion of individuals with significant depressive symptoms, as indicated by a Geriatric Depression Scale score ≥6 of 15, and frequency of antidepressant use were compared across groups by using χ(2) analysis. Factors predicting depressive symptoms, including racial and diagnostic group, age, gender, Mini-Mental State Examination score, level of functional impairment, education level, and medical comorbidities, were assessed by using linear regression analysis. RESULTS: Significant depressive symptoms were more common in cognitively impaired Chinese-American (35%) than cognitively impaired white (15%; χ(2)[1] = 9.4; p = 0.004) subjects. Chinese-American subjects with cognitive impairment were less likely to be receiving treatment for depression (12%) than white subjects with cognitive impairment (37%; χ(2)[1] = 15.6; p = 0.002). Racial and diagnostic group, age, level of functional impairment, Mini-Mental State Examination score, and education level were all statistically significant independent predictors of Geriatric Depression Scale score. CONCLUSIONS: Elderly Chinese-American subjects with cognitive impairment are at increased risk for unrecognized and untreated depressive symptoms compared with elderly white subjects with cognitive impairment. Education level may contribute to this risk or it may be a surrogate marker for other factors contributing to depressive symptoms in this group.

Young-onset dementia.

Young-onset dementia is a neurologic syndrome that affects behavior and cognition of patients younger than 65 years of age. Although frequently misdiagnosed, a systematic approach, reliant upon attainment of a detailed medical history, a collateral history, neuropsychological testing, laboratory studies, and neuroimaging, may facilitate earlier and more accurate diagnosis with subsequent intervention. The differential diagnosis of young-onset dementia is extensive and includes early-onset forms of adult neurodegenerative conditions including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementias, Huntington's disease, and prion disease. Late-onset forms of childhood neurodegenerative conditions may also present as young-onset dementia and include mitochondrial disorders, lysosomal storage disorders, and leukodystrophies. Potentially reversible etiologies including inflammatory disorders, infectious diseases, toxic/metabolic abnormalities, transient epileptic amnesia, obstructive sleep apnea, and normal pressure hydrocephalus also represent important differential diagnostic considerations in young-onset dementia. This review will present etiologies, diagnostic strategies, and options for management of young-onset dementia with comprehensive summary tables for clinical reference.

Frontotemporal dementia in eight Chinese individuals.

Frontotemporal dementia (FTD) has rarely been reported in Chinese populations. There are many potential reasons for this, including possible hesitancy on the part of patients or families to bring FTD-related symptoms to medical attention. Here, we present data on eight Chinese individuals, all of whom met criteria for the behavioral variant of FTD or the semantic variant of primary progressive aphasia. These patients presented for neurological evaluation at a relatively advanced stage. The mean MMSE score at initial presentation was 15. Behavioral symptoms were common and usually elicited during the medical history only after direct questioning. Delay in presentation was attributed to a variety of issues, including family disagreements about whether the symptoms represented a disease and lack of medical insurance. These cases illustrate that the symptoms of FTD in Chinese-Americans are similar to those in Caucasians but various factors, some potentially culturally relevant, may influence the likelihood and timing of clinical presentation for FTD, as well as other dementias. Additional study of FTD in diverse ethnic groups needs to address barriers to clinical presentation, including factors that may be culturally specific.

The Patient Voice: Exploring Treatment Preferences in Participants with Mild Cognitive Concerns to Inform Regulatory Decision Making.

OBJECTIVE: We aimed to assess the feasibility of developing a discrete-choice experiment survey to elicit preferences for a treatment to delay cognitive decline among people with a clinical syndrome consistent with early Alzheimer's disease, including the development of self-reported screening criteria to recruit the sample. METHODS: Using input from qualitative interviews, we developed a discrete-choice experiment survey containing a multifaceted beneficial treatment attribute related to slowing cognitive decline for respondents with self-reported cognitive concerns. In two rounds of in-person pretest interviews, we tested and revised the survey text and discrete-choice experiment questions, including examples, language, and levels associated with the Alzheimer's Disease Assessment Scale-Cognitive Subscale, along with a set of de novo self-reported questions for identifying respondents who had neither too mild nor too advanced cognitive decline. Self-reported memory and thinking problems were compared with symptoms from studies of patients with early Alzheimer's disease (e.g., mild cognitive impairment, mild Alzheimer's disease) to determine whether those studies' recruited patients were similar to our anticipated target population. Round 1 pretest interviews resulted in significant simplifications in the survey instrument, revisions to the inclusion and exclusion criteria, and revisions to the screening process. In round 2 of the pretest interviews, the ability of participants to provide consistent responses to the self-reported screening questions was further assessed. In addition, to evaluate participants' ability to understand and independently complete the discrete-choice experiment survey, two interviewers independently evaluated each participant's ability to make trade-offs in the discrete-choice experiment questions and to understand the content of the survey. RESULTS: Round 1 (15 pretest interviews) identified challenges with the survey instrument related to the complexity of the choice questions. The screening process did not screen out seven respondents with more advanced cognitive decline, as determined qualitatively by the interviewers and by these participants' inability to complete the survey. The survey instrument and screening criteria were revised, and an initial online screener was added to the screening process before round 2 pretests. In round 2 pretests, 12 participants reported cognitive problems similar to the target population for the survey but were judged able to understand and independently complete the discrete-choice experiment survey. CONCLUSIONS: We developed self-reported screening criteria that identified a sample of individuals with memory and thinking concerns who were similar to individuals with clinical symptoms of early Alzheimer's disease and who were able to independently complete a simplified discrete-choice experiment survey. Quantitative patient preference studies provide important information on patients' willingness to trade off treatment benefits/risks. Adapting the technique for patients with cognitive decline requires careful testing and adjustments to survey instruments. This work suggests it is the severity of cognitive impairment, rather than its presence, that determines the ability to complete a simplified discrete-choice experiment survey.

Implementing innovative models of dementia care: The Healthy Aging Brain Center.

BACKGROUND: Recent randomized controlled trials have demonstrated the effectiveness of the collaborative dementia care model targeting both the patients suffering from dementia and their informal caregivers. OBJECTIVE: To implement a sustainable collaborative dementia care program in a public health care system in Indianapolis. METHODS: We used the framework of Complex Adaptive System and the tool of the Reflective Adaptive Process to translate the results of the dementia care trial into the Healthy Aging Brain Center (HABC). RESULTS: Within its first year of operation, the HABC delivered 528 visits to serve 208 patients and 176 informal caregivers. The mean age of HABC patients was 73.8 (standard deviation, SD 9.5), 40% were African-Americans, 42% had less than high school education, 14% had normal cognitive status, 39% received a diagnosis of mild cognitive impairment, and 46% were diagnosed with dementia. Within 12 months of the initial HABC visit, 28% of patients had at least one visit to an emergency room (ER) and 14% were hospitalized with a mean length of stay of five days. The rate of a one-week ER revisit was 14% and the 30-day rehospitalization rate was 11%. Only 5% of HABC patients received an order for neuroleptics and only 16% had simultaneous orders for both definite anticholinergic and anti-dementia drugs. CONCLUSION: The tools of 'implementation science' can be utilized to translate a health care delivery model developed in the research laboratory to a practical, operational, health care delivery program.

Evaluation of Patients with Insufficient Efficacy and/or Tolerability to Triptans for the Acute Treatment of Migraine: A Systematic Literature Review.

INTRODUCTION: Use of triptans for acute treatment of migraine is associated with insufficient efficacy and/or tolerability in approximately 30-40% of people. We conducted a systematic literature review (SLR) to synthesize definitions, terminology, subsequent treatment outcomes, and characteristics associated with this subpopulation. METHODS: A comprehensive SLR was conducted to identify studies, published from Jan 1995 to May 2019, which focused on insufficient efficacy and/or tolerability to triptans. RESULTS: Thirty-five publications were identified, of which 22 described randomized controlled trials and open-label studies, and 13 described observational studies. Across studies, multiple objectives and a high amount of variability in methodologies and outcomes were noted. The most commonly applied measures of efficacy were headache pain freedom and pain relief at 2 h. Ten studies assessed efficacy of switching or optimizing treatment in patients with historical insufficient efficacy or tolerability to previous triptan treatment and demonstrated varying levels of success. Factors associated with increased risk of triptan insufficient efficacy included severe baseline headache severity, photophobia, phonophobia, nausea, and depression. CONCLUSIONS: Irrespective of the methodology or definition used to identify people with insufficient efficacy and/or tolerability to triptans, study results support the assertion that a high unmet need remains for effective acute treatment of migraine.

Temporal and Geographic Variation in the Incidence of Alzheimer's Disease Diagnosis in the US between 2007 and 2014.

OBJECTIVES: Our aim was to describe the incidence of Alzheimer's disease (AD) in the United States, overall and by geographic region. DESIGN: We conducted retrospective analyses of administrative claims data for a 5% random sample of US Medicare beneficiaries aged 65 years or older. AD incidence, defined as a diagnosis for AD (International Classification of Disease, Ninth Revision, Clinical Modification code 331.0×) in a given year, with no AD diagnosis in the beneficiary's entire medical history, was estimated for each calendar year between 2007 and 2014. Beneficiaries were required to be enrolled in Medicare for the calendar year of evaluation as well as the preceding 12 months. In addition, a cross-sectional assessment of geographic variation in AD incidence was conducted for 2014. For each population area (specifically, core-based statistical area, as defined by the US Census Bureau), AD incidence was estimated overall, as well as adjusted for differences in underlying patient demographics and metrics of access to care and quality of care. Changes in AD incidence from 2007 were also estimated. SETTING: US fee-for-service Medicare. PARTICIPANTS: US Medicare beneficiaries aged 65 years or older with no history of AD. RESULTS: Overall, the diagnosed incidence of AD decreased over time, from 1.53% in 2007 to 1.09% in 2014; trends were similar for most population areas. In 2014, the rates of AD incidence ranged from 0% to more than 3% across population areas, with the highest observed incidence rates in areas of the Midwest and the South. Statistical models explain little of the geographic variation, although following adjustment, the incidence rates increased the most (in relative terms) in rural areas of western states. CONCLUSION: Our findings are consistent with previously reported estimates of incidence of AD in the United States and its recent declining trend. Additionally, the study highlights the considerable geographic variation in the incidence of AD in the United States and suggests that further research is needed to better understand the determinants of this geographic variation. J Am Geriatr Soc 68:346-353, 2020.

Improvement in Function after Lasmiditan Treatment: Post Hoc Analysis of Data from Phase 3 Studies.

INTRODUCTION: Migraine is associated with substantial functional impairment and affects many aspects of daily life. METHODS: Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase 3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations. RESULTS: For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (p < 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN. CONCLUSION: All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.

Importance: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/ß-secretase), was developed to modify the clinical course of AD by slowing disease progression. Objective: To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. Design, Setting, and Participants: AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. Interventions: Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. Main Outcomes and Measures: The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. Results: Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. Conclusions and Relevance: Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. Trial Registration: ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573.

Unravelling Boléro: progressive aphasia, transmodal creativity and the right posterior neocortex.

Most neurological lesion studies emphasize performance deficits that result from focal brain injury. Here, we describe striking gains of function in a patient with primary progressive aphasia, a degenerative disease of the human language network. During the decade before her language deficits arose, Anne Adams (AA), a lifelong scientist, developed an intense drive to produce visual art. Paintings from AA's artistic peak revealed her capacity to create expressive transmodal art, such as renderings of music in paint, which may have reflected an increased subjective relatedness among internal perceptual and conceptual images. AA became fascinated with Maurice Ravel, the French composer who also suffered from a progressive aphasia, and painted his best-known work, 'Boléro', by translating its musical elements into visual form. Later paintings, achieved when AA was nearly mute, moved towards increasing photographic realism, perhaps because visual representations came to dominate AA's mental landscape during this phase of her illness. Neuroimaging analyses revealed that, despite severe degeneration of left inferior frontal-insular, temporal and striatal regions, AA showed increased grey matter volume and hyperperfusion in right posterior neocortical areas implicated in heteromodal and polysensory integration. The findings suggest that structural and functional enhancements in non-dominant posterior neocortex may give rise to specific forms of visual creativity that can be liberated by dominant inferior frontal cortex injury.

Pleasurable emotional response to music: a case of neurodegenerative generalized auditory agnosia.

Recent functional neuroimaging studies implicate the network of mesolimbic structures known to be active in reward processing as the neural substrate of pleasure associated with listening to music. Psychoacoustic and lesion studies suggest that there is a widely distributed cortical network involved in processing discreet musical variables. Here we present the case of a young man with auditory agnosia as the consequence of cortical neurodegeneration who continues to experience pleasure when exposed to music. In a series of musical tasks, the subject was unable to accurately identify any of the perceptual components of music beyond simple pitch discrimination, including musical variables known to impact the perception of affect. The subject subsequently misidentified the musical character of personally familiar tunes presented experimentally, but continued to report that the activity of 'listening' to specific musical genres was an emotionally rewarding experience. The implications of this case for the evolving understanding of music perception, music misperception, music memory, and music-associated emotion are discussed.

Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials.

INTRODUCTION: This study estimated the minimal clinically important difference (MCID) for Mini Mental State Examination, Clinical Dementia Rating Scale sum of boxes, and Functional Activities Questionnaire across the Alzheimer's disease (AD) spectrum. METHODS: Retrospective analysis of the National Alzheimer's Coordinating Center Uniform Data Set (9/2005-9/2016) and MCID for clinical outcomes were estimated using anchor-based (clinician's assessment of meaningful decline) and distribution-based (1/2 baseline standard deviation) approaches, stratified by severity of cognitive impairment. RESULTS: On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline. The MCID values generally increased by disease severity; the effect size and standardized response mean for those with meaningful decline were consistently in the acceptable ranges for MCID. DISCUSSION: These findings can inform design and interpretation of future clinical trials.

On the path to 2025: understanding the Alzheimer's disease continuum.

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

Cerebellar ataxia and central nervous system whipple disease.

BACKGROUND: Whipple disease (WD) is an infectious disease, which may affect the central nervous system. Central nervous system symptoms are eventually present in as many as 43% of the cases. To our knowledge, cerebellar ataxia in WD has never been formally studied in any large series. OBJECTIVE: To determine the prevalence of cerebellar ataxia in central nervous system WD. RESULTS: Between January 1974 and December 2003, we identified 11 patients who met criteria for definite central nervous system WD, the second largest series to date. Surprisingly, while oculomasticatory myorrhythmia was recorded in only 1 patient (9%), cerebellar ataxia had been documented in 5 cases (45%). CONCLUSION: Our data suggest that cerebellar ataxia should be considered a more common feature of central nervous system WD.

Memory dysfunction.

PURPOSE OF REVIEW: This article highlights the dissociable human memory systems of episodic, semantic, and procedural memory in the context of neurologic illnesses known to adversely affect specific neuroanatomic structures relevant to each memory system. RECENT FINDINGS: Advances in functional neuroimaging and refinement of neuropsychological and bedside assessment tools continue to support a model of multiple memory systems that are distinct yet complementary and to support the potential for one system to be engaged as a compensatory strategy when a counterpart system fails. SUMMARY: Episodic memory, the ability to recall personal episodes, is the subtype of memory most often perceived as dysfunctional by patients and informants. Medial temporal lobe structures, especially the hippocampal formation and associated cortical and subcortical structures, are most often associated with episodic memory loss. Episodic memory dysfunction may present acutely, as in concussion; transiently, as in transient global amnesia (TGA); subacutely, as in thiamine deficiency; or chronically, as in Alzheimer disease. Semantic memory refers to acquired knowledge about the world. Anterior and inferior temporal lobe structures are most often associated with semantic memory loss. The semantic variant of primary progressive aphasia (svPPA) is the paradigmatic disorder resulting in predominant semantic memory dysfunction. Working memory, associated with frontal lobe function, is the active maintenance of information in the mind that can be potentially manipulated to complete goal-directed tasks. Procedural memory, the ability to learn skills that become automatic, involves the basal ganglia, cerebellum, and supplementary motor cortex. Parkinson disease and related disorders result in procedural memory deficits. Most memory concerns warrant bedside cognitive or neuropsychological evaluation and neuroimaging to assess for specific neuropathologies and guide treatment.

Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults.

Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.