Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy.

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

A Critical Systematic Review of Current Evidence on the Effects of Physical Exercise on Whole/Regional Grey Matter Brain Volume in Populations at Risk of Neurodegeneration.

BACKGROUND: Despite the intriguing potential of physical exercise being able to preserve or even restore brain volume (grey matter volume in particular)-a tissue essential for both cognitive and physical function-no reviews have so far synthesized the existing knowledge from randomized controlled trials investigating exercise-induced changes of the brain's grey matter volume in populations at risk of neurodegeneration. Our objective was to critically review the existing evidence regarding this topic. METHODS: A systematic search was carried out in MEDLINE and EMBASE databases primo April 2020, to identify randomized controlled trials evaluating the effects of aerobic training, resistance training or concurrent training on brain grey volume changes (by MRI) in adult clinical or healthy elderly populations. RESULTS: A total of 20 articles (from 19 RCTs) evaluating 3-12 months of aerobic, resistance, or concurrent training were identified and included, involving a total of 1662 participants (populations: healthy older adults, older adults with mild cognitive impairment or Alzheimer's disease, adults with schizophrenia or multiple sclerosis or major depression). While few studies indicated a positive effect-although modest-of physical exercise on certain regions of brain grey matter volume, the majority of study findings were neutral (i.e., no effects/small effect sizes) and quite divergent across populations. Meta-analyses showed that different exercise modalities failed to elicit any substantial effects on whole brain grey volume and hippocampus volume, although with rather large confidence interval width (i.e., variability). CONCLUSION: Altogether, the current evidence on the effects of physical exercise on whole/regional grey matter brain volume appear sparse and inconclusive, and does not support that physical exercise is as potent as previously proposed when it comes to affecting brain grey matter volume.

Cerebral metabolic correlates of attention networks in Alzheimer's Disease: A study of the Stroop.

Patients with Alzheimer's Disease (AD) show difficulties with attention. Cognitive neuroscience models posit that attention can be broken down into alerting, orienting, and executive networks. We used the Stroop Color-Word test to interrogate the neural correlates of attention deficits in AD. We hypothesized that the Word, Color, and Color-Word conditions of the Stroop would all tap into the alerting and orienting networks. The Color-Word condition would additionally tap into the executive network. A ratio of Color-Word to Color naming performance would isolate the executive network from the others. To identify the neural underpinnings of attention in AD we correlated performance on the Stroop with brain metabolic activity. Sixty-six patients with probable AD completed [18F] fluorodeoxyglucose PET scanning and neuropsychological testing. Analysis was conducted with SPM12 (p<0.001 uncorrected, extent threshold 50 voxels). Performance on the Word, Color, and Color-Word conditions directly correlated with metabolic rate in right inferior parietal lobules/intraparietal sulci. The Color-Word/Color ratio revealed associations with metabolic rate in right medial prefrontal cortex and insula/operculum. Overall findings were largely consistent with the hypothesized neuroanatomical substrates of the alerting, orienting, and executive networks. As such, attention deficits in AD reflect compromise to multiple large-scale networks.

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging.

OBJECTIVE: To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms. METHODS: Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4ß2* nicotinic cholinergic receptor binding using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used. RESULTS: 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: rs = -0.55, p = 0.008; right: rs = -0.50, p = 0.02; N = 22) and hippocampus (left: rs = -0.65, p = 0.001; right: rs = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: rs = -0.50, p = 0.01; right: rs = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score. CONCLUSION: Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.

18F-Fluorodeoxyglucose Positron Emission Tomography Cortical Metabolic Activity Associated with Distinct Agitation Behaviors in Alzheimer Disease.

OBJECTIVE: This study aimed to investigate the neurobiologic correlates of two distinct clusters of agitation symptoms to identify the unique biologic substrates underlying agitated behaviors. METHODS: Eighty-eight outpatients with mild to moderate Alzheimer disease (AD) were recruited from the VA Greater Los Angeles Healthcare System Geropsychiatry Outpatient Program. A cross-sectional investigation was conducted of the relationship between cerebral glucose metabolism measured via 18F-fluorodeoxyglucose positron emission tomography and agitated symptoms from the Neuropsychiatric Inventory (NPI) in patients with AD. Two empirically derived clusters of agitation symptoms were investigated: an Agitation factor comprising agitation/aggression and irritability/lability items of the NPI, and a Behavioral Dyscontrol factor comprising elation/euphoria, disinhibition, aberrant motor behavior, sleep, and appetite items of the NPI. Mean cerebral metabolism for patients who scored positively on each of the two factors was compared with mean cerebral metabolism for those who did not. RESULTS: Patients with AD who scored positively on the Agitation factor showed reduced glucose metabolism of the right temporal, right frontal, and bilateral cingulate cortex. In contrast, the Behavioral Dyscontrol factor did not show specific neurobiologic correlates. CONCLUSION: Symptoms encompassed within the Agitation factor have distinct neurobiologic underpinnings. The precipitants, course, and outcomes related to these symptoms may be unique from other neuropsychiatric symptoms characteristic of AD. Special attention to treatment of agitated behaviors involving anger, aggressiveness, hostility, and irritability/emotional lability is warranted, because they appear to reflect a clinically relevant symptom cluster with unique underlying neurobiologic correlates.

The functional neuroanatomy of verbal memory in Alzheimer's disease: [18F]-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) correlates of recency and recognition memory.

INTRODUCTION: The objective of this study was to distinguish the functional neuroanatomy of verbal learning and recognition in Alzheimer's disease (AD) using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning task. METHOD: In 81 Veterans diagnosed with dementia due to AD, we conducted a cluster-based correlation analysis to assess the relationships between recency and recognition memory scores from the CERAD Word Learning Task and cortical metabolic activity measured using [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). RESULTS: AD patients (Mini-Mental State Examination, MMSE mean = 20.2) performed significantly better on the recall of recency items during learning trials than of primacy and middle items. Recency memory was associated with cerebral metabolism in the left middle and inferior temporal gyri and left fusiform gyrus (p < .05 at the corrected cluster level). In contrast, recognition memory was correlated with metabolic activity in two clusters: (a) a large cluster that included the left hippocampus, parahippocampal gyrus, entorhinal cortex, anterior temporal lobe, and inferior and middle temporal gyri; (b) the bilateral orbitofrontal cortices (OFC). CONCLUSIONS: The present study further informs our understanding of the disparate functional neuroanatomy of recency memory and recognition memory in AD. We anticipated that the recency effect would be relatively preserved and associated with temporoparietal brain regions implicated in short-term verbal memory, while recognition memory would be associated with the medial temporal lobe and possibly the OFC. Consistent with our a priori hypotheses, list learning in our AD sample was characterized by a reduced primacy effect and a relatively spared recency effect; however, recency memory was associated with cerebral metabolism in inferior and lateral temporal regions associated with the semantic memory network, rather than regions associated with short-term verbal memory. The correlates of recognition memory included the medial temporal lobe and OFC, replicating prior studies.

Neurobiology of delusions, memory, and insight in Alzheimer disease.

OBJECTIVE: Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This study's goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. METHODS: In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. (18)F-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. RESULTS: Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. CONCLUSION: Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

Association between cerebral metabolism and Rey-Osterrieth Complex Figure Test performance in Alzheimer's disease.

The copy condition of the Rey-Osterrieth Complex Figure (ROCF) is sensitive to Alzheimer's disease (AD) pathology, but its neural correlates remain unclear. We used fluorodeoxyglucose positron emission tomography (FDG-PET) to elucidate this association in 77 patients with probable AD. We observed a correlation between ROCF and metabolic rate of bilateral temporal-parietal cortex and occipital lobe, and right frontal lobe. Global and local elements of the ROCF correlated with metabolic rate of these same regions. The copy approach correlated with right lateral temporal cortex. The ROCF appears reflective of posterior temporal-parietal cortex functioning, highlighting the role of visuospatial processing in constructional abilities in AD.

Cerebral metabolism, cognition, and functional abilities in Alzheimer disease.

Patients with Alzheimer disease (AD) exhibit profound difficulties in completing instrumental activities of daily living (IADLs), such as managing finances, organizing medications, and food preparation. It is unclear which brain areas underlie IADL deficits in AD. To address this question, we used voxel-based analysis to correlate the performance of IADLs with resting cerebral metabolism as measured during [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in 44 patients with AD. Poorer ability to complete IADLs was associated with hypometabolism in right-sided cortical regions, including the parietal lobe, posterior temporal cortex, dorsolateral prefrontal cortex, and frontal pole. Follow-up path analyses examining anatomically defined regions of interest (ROI) demonstrated that the association between metabolism and IADLs was mediated by global cognition in frontal ROIs, and partially mediated by global cognition in the parietal ROI. Findings suggest that hypometabolism of right sided brain regions involved in executive functioning, visuospatial processing, attention, and working memory underlie functional impairments in patients with AD.

Effect of memantine treatment on regional cortical metabolism in Alzheimer's disease.

OBJECTIVES: Cortical systems involved in the response to medication treatment for Alzheimer's disease (AD) are poorly understood. Preclinical studies have demonstrated the effect of memantine on neuroreceptors and cell physiology, although the impact of treatment on cortical activity in vivo is not known. DESIGN: F-fluorodeoxyglucose positron emission tomography (PET) imaging and clinical assessment before and after open-label memantine treatment. PARTICIPANTS/SETTING: Seventeen outpatients with probable AD on stable cholinesterase inhibitor medication. INTERVENTION: Memantine up to 10 mg twice daily for 10 weeks. MEASUREMENTS: Voxel-based analyses of change in cortical metabolic activity; Mattis Dementia Rating Scale (DRS), and Neurobehavioral Rating Scale (NRS). RESULTS: : Mean age was 81 years; mean Mini-Mental State Examination score was 19.4. Compared with baseline, metabolic activity was significantly higher after 10 weeks memantine treatment in two cortical regions bilaterally: the inferior temporal gyrus (BA 20) and the angular gyrus/supramarginal gyrus (BA 39, 40). There was no significant relationship between change in DRS score and change in cortical metabolism, although change in NRS score was associated with the extent of metabolic change in the right parietal and temporal cortex. CONCLUSION: Metabolic activity in bilateral inferior parietal and temporal cortex increases during 10 weeks of memantine treatment in patients with AD. PET imaging can reveal functional effects of medications on neural activity and may help to define critical mechanisms involved in drug treatment.

Executive deficits and regional brain metabolism in Alzheimer's disease.

OBJECTIVE: Executive deficits are common in patients with Alzheimer's disease (AD), contribute prominently to clinical disability, and may be associated with frontal lobe pathology. This study examined regional brain hypometabolism associated with executive dysfunction in patients with AD. METHODS: Forty-one patients with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging at rest. Neuropsychological measures of executive control included the Conceptualization (Conc) and Initiation/Perseveration (I/P) subscales of the Mattis Dementia Rating Scale (DRS), the Wechsler Adult Intelligence Scale (WAIS) Similarities subtest, the Tower test, and the Ruff Figural Fluency test (Ruff). Voxel-based analyses were conducted using statistical parametric mapping (SPM2) to measure the correlation between regional cerebral metabolism and executive measures. Correlations independent of global cognitive impairment were identified by including Mini-Mental State Examination (MMSE) score as a covariate in the model. RESULTS: Executive deficits, as measured by poor performances on the DRS I/P and Conc subscales, were associated with hypometabolism in the bilateral mid-dorsolateral frontal region. Activity in posterior cortical regions also contributed uniquely to some aspects of executive functioning, as lower resting metabolism in parietal or temporal cortex was correlated with poor performance on four of the five executive measures. After controlling for global cognitive score, there were significant extra-frontal correlations with hypometabolism in insula, occipital lobe, and temporal cortex. CONCLUSIONS: Some but not all executive deficits in AD are associated with neural activity in the dorsolateral frontal cortex. Activities in distributed neural systems that include parietal and temporal cortex also contribute to some executive abilities. The pathophysiology of executive dysfunction is complex and includes abnormalities not limited to a single region.

The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer's disease.

OBJECTIVE: This study examined the association between a history of heavy alcohol use and smoking, presence of the apolipoprotein-E epsilon 4 allele (APOE epsilon4), and age of disease onset in a community dwelling sample of 685 Alzheimer's disease (AD) patients spanning three ethnic groups. DESIGN: Cross-sectional study of AD patients evaluated at a University-affiliated outpatient memory disorders clinic. SUBJECTS: A clinic-based cohort of white non-Hispanic (WNH; n = 397), white Hispanic (WH; n = 264), and African-American (AA; n = 24) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria. MEASUREMENTS: The age of onset of AD was obtained from a knowledgeable family member. All patients were assessed for APOE genotype. History of alcohol and tobacco consumption prior to the onset of dementia was obtained via an interview with the patient and the primary caregiver. A history of heavy drinking was defined as >2 drinks per day and a history of heavy smoking was defined as > or =1 pack per day. RESULTS: Presence of an APOE epsilon4 allele, a history of heavy drinking, or a history of heavy smoking were each associated with an earlier onset of AD by 2-3 years. Patients with all three risk factors were likely to be diagnosed with AD nearly 10 years earlier than those with none of the risk factors. CONCLUSION: The results suggest that APOE epsilon4 and heavy drinking and heavy smoking lower the age of onset for AD in an additive fashion.

The role of cognitive impairment and caregiver support in diabetes management of older outpatients.

OBJECTIVES: To examine the role of cognitive impairment and caregiver support in diabetes care adherence and glycemic control. METHODS: Fifty-one veteran male outpatients (27 with caregivers) aged 60 years and older with type 2 diabetes were evaluated for cognitive impairment with the Cognitive Abilities Screening Instrument. Patients or caregivers completed diabetes self-care and depression scales. Medical morbidity information and HbA1c plasma levels at baseline and 1 year later were obtained from electronic medical records. RESULTS: Greater cognitive impairment (F = 5.1, p < .05), and presence of a caregiver (F = 5.3, p < .05), were independently associated with worse diabetes care adherence (adjusting for age, education, medical comorbidity, and depression). In addition, Mean HbA1c levels were worse in the cognitively impaired group with caregivers relative to the three other groups (F = 4.10, p < .05, eta2 = .09). One year later, mean HbA1c levels rose from 7.7 to 8.2% in the cognitively impaired group with caregivers. CONCLUSION: Cognitive impairment is associated with worse diabetes care management. Surprisingly, the presence of a caregiver is not protective. Further research is necessary to examine the healthcare needs of cognitively impaired, diabetic patients and their caregivers.

The neural correlates of naming and fluency deficits in Alzheimer's disease: an FDG-PET study.

OBJECTIVE: To examine the neural processes associated with language deficits in Alzheimer's disease (AD), and in particular to elucidate the correlates of confrontation naming and word retrieval impairments. METHODS: Sixty patients with probable AD were included. Confrontation naming was assessed using the number of words spontaneously named correctly on the Boston Naming Test. We recorded the number of additional words stated following phonemic cuing. We also assessed phonemic (FAS) and semantic (supermarket items) fluency. We then correlated performance on each measure with resting cortical metabolic activity using FDG-PET images. RESULTS: We found that poorer ability to spontaneously name an object was associated with hypometabolism of bilateral inferior temporal lobes. In contrast, when a phonemic cue was provided, successful naming under this condition was associated with higher metabolic activity in bilateral inferior frontal gyrus (IFG), right superior frontal gyrus (SFG), left temporal, and occipital regions. Consistent with these findings, we found that poorer semantic fluency was associated with hypometabolism in regions including both IFG and temporal regions, and poorer phonemic fluency was associated with hypometabolism in only left IFG. Across analyses, measures that required cued retrieval were associated with metabolism in the left IFG, whereas measures taxing semantic knowledge were associated with metabolic rate of left temporal cortex. CONCLUSIONS: Naming deficits in AD reflect compromise to temporal regions involved in the semantic knowledge network, and frontal regions involved in the controlled retrieval of information from that network.

Patterns of depression in Spanish- and English-speaking patients with Alzheimer's disease.

The purpose of this study was to evaluate whether distinct subtypes of depression could be identified in patients with Alzheimer's disease and, if so, to evaluate the patients in these subgroups. Ratings on the Cornell Scale for Depression in Dementia (CSDD) of 306 patients with Alzheimer's disease, 129 of whom were Spanish- and 177 English-speaking, were subjected to latent class analysis. Four subgroups were identified based on CSDD symptoms. These included an asymptomatic group, groups with mild and more severe typical depression, and a group characterized by prominent anxiety and irritability in addition to sadness. Group differences on demographic, cognitive, clinical, and functional status measures were explored via chi-square tests and analyses of variance. Results show that for some patients with Alzheimer's disease, patterns of symptoms of depression are similar to those in younger adult populations. A distinct subtype may exist, however, with prominent anxiety and irritability.

Positron emission tomography metabolic correlates of apathy in Alzheimer disease.

BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.

Anxiety and regional cortical glucose metabolism in patients with Alzheimer's disease.

In this study, the authors investigated the relationship between anxiety and regional cortical metabolism in Alzheimer's disease. Using the Neuropsychiatric Inventory (NPI), the authors evaluated anxiety in 41 patients with Alzheimer's disease. Regional cortical glucose metabolism was measured using [(18)F] fluorodeoxyglucose positron emission tomography in the resting state. Relationships were assessed using voxel-based (SPM2) and anatomic region-based analyses. Higher NPI anxiety score (frequency x severity) was associated with lower metabolism in bilateral entorhinal cortex, anterior parahippocampal gyrus, and left superior temporal gyrus and insula. Functional activity changes in distinct regions of the cortex contribute to the expression of anxiety in Alzheimer's disease.

Frontal lobe hypometabolism and impaired insight in Alzheimer disease.

OBJECTIVE: The authors examined the relationship between impaired insight regarding cognitive and functional deficits and frontal cortex hypometabolism in 41 patients with Alzheimer disease (AD). METHODS: Regional cerebral glucose metabolism was determined with (18F)fluorodeoxyglucose and positron emission tomography. Level of insight was measured with the clinician-rated Neurobehavioral Rating Scale, and severity of global cognitive impairment was determined with the Mini-Mental State Exam. RESULTS: Inaccurate insight was correlated with glucose metabolic rate in the right lateral frontal cortex (Brodmann areas 6 and 45, and the lateral aspect of Brodmann areas 8 and 9) after controlling for global cognitive dysfunction. CONCLUSIONS: The findings from this study help to further elucidate the neurobiological mechanisms underlying impaired insight in AD, indicating a link between this important clinical phenomenon and dysmetabolism in a focal region of the right prefrontal cortex.

The effect of a memory screening program on the early diagnosis of Alzheimer disease.

CONTEXT: Alzheimer Disease (AD) is often diagnosed at a moderately advanced stage, even though its early detection has become increasingly important, because of the continuing development of treatments that may improve its outcome. OBJECTIVE: To determine if a free memory screening program is associated with an earlier diagnosis of AD, compared with traditional referral methods, such as by physicians and family members. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study of 1489 consecutive patients with AD who presented to an outpatient memory disorders clinic between 1993 and 2002. Subjects were classified according to referral source (memory screening, physician, family/friend, other), and self-reported ethnicity (white non-Hispanic, white Hispanic). The associations between referral source and the presenting cognitive and behavioral status of subjects were evaluated using analysis of variance and logistic regression analyses, after controlling for potentially confounding factors. MAIN OUTCOME MEASURES: Score on the Folstein Mini-Mental State Examination (MMSE), duration of cognitive symptoms, and presence of psychosis, defined as delusions and/or hallucinations. RESULTS: After controlling for ethnicity, gender, and the year of diagnosis, subjects with AD, who were referred by the memory screening program, scored significantly higher at presentation on the MMSE (20.8 +/- 5.7), than those referred by physicians (18.8 +/- 6.6), family/friends (16.8 +/- 6.6), or other referral sources (15.3 +/- 7.1). Subjects with AD, referred by the memory screening program, also had a lower reported duration of illness at presentation, and a decreased frequency of psychosis compared with those referred by family/friend and other methods. Other factors related to a diagnosis of AD at a later stage included female gender, Hispanic ethnicity, and a diagnosis early in the 1993 to 2002 time period. CONCLUSIONS: The memory screening program referred patients with AD to a memory clinic at an earlier phase of illness compared with traditional methods such as physician referral.

No association between subjective memory complaints and apolipoprotein E genotype in cognitively intact elderly.

OBJECTIVE: This cross-sectional study examined the relationship between subjective memory complaints and the apolipoprotein epsilon 4 allele (epsilon4), a genetic risk factor for Alzheimer's disease (AD), among cognitively normal subjects identified from a community memory screening. DESIGN: The sample comprised 232 consecutive white non-Hispanic older adults who presented to a free community-based memory-screening program at a University affiliated memory disorders center. Participants were classified as cognitively normal based on scores on the age and educated adjusted Folstein Mini-Mental Status Exam (MMSAdj) and a brief Delayed Verbal Recall Test (DRT). Subjects were assessed for APOE genotype, subjective memory complaints (Memory Questionnaire, MQ), depressive symptoms (Hamilton Depression Rating Scale, HDRS), and history of four major medical conditions that have been associated with memory loss (stroke/transient ischemic attack [TIA], atherosclerotic heart disease, hypertension, and diabetes). A hierarchical regression analysis was performed to examine the association between APOE genotype and memory complaints after controlling for a host of potential confounding factors. RESULTS: The APOE epsilon4 allele frequency for cognitively normal subjects was 0.13. Subjective memory complaints were predicted by depressive symptoms and a history of stroke/TIA. They were not associated with APOE genotype, MMSAdj score, DRT score, age, education, gender, and reported history of atherosclerotic heart disease, hypertension, or diabetes. CONCLUSION: The results did not suggest an association between subjective memory complaints and the APOE epsilon4 allele in this sample of cognitively intact subjects. This indicates that memory complaints may confer risk for future dementia through pathways independent of APOE genotype. The results also show that older adults with memory complaints are at increased risk for underlying depression.