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.

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.

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 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.

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.

Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample.

OBJECTIVE: This study examined the association between the Apolipoprotein-E epsilon4 allele (APOE epsilon4) and age of disease onset in a bi-ethnic sample of community dwelling Alzheimer's disease (AD) patients. 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=601) and white Hispanic (WH; n = 359) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria. MEASURES: Global cognitive functioning of the subjects was evaluated using the Mini-mental State Exam. The age of onset of AD was calculated from the patient's current age minus the reported duration of disease obtained from a knowledgeable family member. RESULTS: A significant relationship was discovered between APOE epsilon4 and age of onset for WNH, with lower ages of onset among patients carrying the epsilon4/epsilon4 and epsilon3/epsilon4 genotypes in relation to patients with the epsilon3/epsilon3 genotype. The results revealed a more modest effect for APOE genotype in the WH cohort, with a lower age of onset witnessed among epsilon4 positive patients (epsilon2/epsilon4, epsilon3/epsilon4 and epsilon4/epsilon4 genotypes) in comparison to epsilon4 negative patients (epsilon2/epsilon2, epsilon2/epsilon3 and epsilon3/epsilon3 genotypes). CONCLUSION: The association between the epsilon4 allele and earlier age of onset was more pronounced in WNH compared to WH patients, suggesting the impact of APOE polymorphism on clinical phenotype may be different for distinct ethnic groups in the U.S.

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.

Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank.

Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

Apolipoprotein E genotype and cognitive impairment in community-dwelling black older adults.

OBJECTIVE: The relationship between the epsilon 4 allele of the apolipoprotein E gene (APOE-epsilon4) located on chromosome 19 and Alzheimer's disease is well documented among Caucasian populations. However, the findings of research addressing the link between APOE polymorphism and neurocognitive functioning in populations of African origin from around the world have been equivocal. Therefore, the current study explored the relation of APOE-epsilon4 with cognitive impairment in a sample of community-dwelling English-speaking elderly blacks. METHODS: All participants (N = 57) were recruited consecutively from a community memory-screening program at a University affiliated Memory Disorders Clinic and evaluated using standardized assessment procedures. Cognitive impairment was classified according to an age and education adjusted Mini-Mental State Exam score of less than 24 as well as poorer functioning on a measure of delayed verbal memory. RESULTS: Increased risk for global cognitive dysfunction (OR = 9.5, 95 percent CI = 2.3-55.3, p = .004) and poorer verbal recall performance (beta = -.36, p = .006) were linked with the APOE epsilon4 allele after controlling for the potentially confounding effects of age, education, and gender. CONCLUSIONS: This investigation supports the role of APOE polymorphism in determining neurocognitive impairment among black elders residing in the community.

"Life is not worth living": hopelessness in Alzheimer's disease.

This study investigated the prevalence and clinical correlates of hopelessness among 91 patients diagnosed with probable Alzheimer's disease (AD) according to National Institute of Neurological Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Hopeless ideation was measured with Item 3 on the Hamilton Depression Rating Scale (Suicide), which inquires specifically whether the patient thinks "life is not worth living." The results showed that hopelessness was present in 10% (n = 9) of the sample. Patients with these cognitions evidenced greater psychological symptoms of mood disturbance and more insight into their cognitive and functional impairments. Unrelated factors included age, education, Mini-Mental State Examination score, neurovegetative signs of depression, affective expressions of depression, agitation/disinhibition, and psychosis. Although indifference is frequent in AD, these results indicate that thoughts of hopelessness are also a common phenomenon, occurring in approximately 10% of our probable AD cohort. These thoughts appear to be related to the subjective expressions of depression and anxiety rather than the neurovegetative or affective signs and are more prominent among patients with greater deficit awareness.

Apolipoprotein E polymorphism and cognitive impairment in a bi-ethnic community-dwelling elderly sample.

The epsilon 4 (epsilon 4) and epsilon 2 (epsilon 2) alleles of the apolipoprotein gene (APOE) located on chromosome 19 have been associated with increased and decreased risk for Alzheimer disease (AD) in older adults, respectively. However, there is a dearth of studies examining the relation of APOE polymorphism with cognitive functioning among community-dwelling ethnic minority elderly. This study examined the risk for cognitive impairment associated with the APOE epsilon 4 and epsilon 2 alleles in a community-based cohort of non-Hispanic white (NHW; N = 739) and white Hispanics (WH; N=321). All patients were recruited consecutively from a memory-screening program and evaluated using standardized assessment procedures. Cognitive impairment was classified according to an age and education adjusted Folstein Mini-Mental State Exam (MMSAdj) score of less than 24. The results indicated the APOE epsilon 4 allele was associated with increased risk for cognitive dysfunction in NHW and WH after controlling for the effects of age, education, and gender. This risk was generally observed to be dose-dependent, with greater risk among epsilon 4 homozygotes in relation to epsilon 4 heterozygotes. The epsilon 2 allele of APOE did not confer decreased risk for cognitive impairment among NHW and WH. This study supports the relation of APOE polymorphism to cognitive dysfunction among two ethnic populations residing in the community.