Odorant-induced brain activation as a function of normal aging and Alzheimer's disease: A preliminary study.

Olfactory dysfunction consistently occurs in patients with Alzheimer's disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The purpose of the current preliminary fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients. We also explored the interplay between age and disease-related psychophysical olfactory declines and odorant-induced brain activation. Results indicated AD patients had decreased odor detection task-related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Moderated-mediation analyses on neuro-psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease-related threshold changes on olfactory detection. Therefore, even in the face of higher (worse) olfactory thresholds, older adults and AD patients compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory detection task may eventually be useful in improving early discovery of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD.

Olfaction Modulates Inter-Subject Correlation of Neural Responses.

Odors can be powerful stimulants. It is well-established that odors provide strong cues for recall of locations, people and events. The effects of specific scents on other cognitive functions are less well-established. We hypothesized that scents with different odor qualities will have a different effect on attention. To assess attention, we used Inter-Subject Correlation of the EEG because this metric is strongly modulated by attentional engagement with natural audiovisual stimuli. We predicted that scents known to be "energizing" would increase Inter-Subject Correlation during watching of videos as compared to "calming" scents. In a first experiment, we confirmed this for eucalyptol and linalool while participants watched animated autobiographical narratives. The result was replicated in a second experiment, but did not generalize to limonene, also considered an "energizing" odorant. In a third, double-blind experiment, we tested a battery of scents including single molecules, as well as mixtures, as participants watched various short video clips. We found a varying effect of odor on Inter-Subject Correlation across the various scents. This study provides a basis for reliably and reproducibly assessing effects of odors on brain activity. Future research is needed to further explore the effect of scent-based up-modulation in engagement on learning and memory performance. Educators, product developers and fragrance brands might also benefit from such objective neurophysiological measures.

Olfactory identification deficits and MCI in a multi-ethnic elderly community sample.

Odor identification deficits occur in Alzheimer's disease (AD) and mild cognitive impairment (MCI), and predict clinical conversion from MCI to AD. In an epidemiologic study conducted in a multi-ethnic community elderly sample (average 80 years old), the University of Pennsylvania Smell Identification Test (UPSIT, range 0-40) was administered to 1092 non-demented subjects. Women (mean 26.6, S.D. 6.6) scored higher than men (mean 24.4, S.D. 7.4, p<.02), and ethnic differences were not significant after controlling for age and education. UPSIT scores correlated inversely with age (r=-0.24, p<.0001) and positively with Selective Reminding Test immediate recall (r=0.33), delayed recall (r=0.28), category fluency (r=0.28) and the 15-item Boston Naming Test (r=0.23), all ps<.0001. In a sub-sample in which MRI was done, UPSIT scores showed a significant correlation with hippocampal volume (n=571, r=0.16, p<.001) but not entorhinal cortex volume nor total number of white matter hyperintensities. In ANOVA, UPSIT scores differed (p<.0001) as a function of MCI classification: no MCI (mean 26.6, S.D. 6.8), non-amnestic MCI (mean 24.4, S.D. 7.2), and amnestic MCI (mean 23.5, S.D. 6.7). The difference between amnestic MCI and no MCI remained significant after controlling for relevant covariates. These findings indicate that the predictive utility of olfactory identification deficits for decline from no MCI to MCI and AD needs to be assessed in longitudinal studies of elderly community samples.

The impact of anxiety on conversion from mild cognitive impairment to Alzheimer's disease.

OBJECTIVE: To compare state and trait anxiety in mild cognitive impairment (MCI) patients and matched control subjects, and to assess the impact of these variables in predicting conversion to Alzheimer's disease. METHODS: One hundred and forty-eight patients with MCI, broadly defined, were assessed and followed systematically. Baseline predictors for follow-up conversion to AD (entire sample: 39/148 converted to Alzheimer's disease (AD)) included the Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: At baseline evaluation, MCI patients had higher levels of state and trait anxiety than controls, with no differences between future AD converters (n = 39) and non-converters. In age-stratified Cox proportional hazards model analyses, STAI State was not a significant predictor of conversion to AD (STAI State < or =30 vs. > 30 risk ratio, 1.68; 95% CI, 0.75, 3.77; p = 0.21), but higher Trait scores indicated a lower risk of conversion when STAI State, education, the Folstein Mini-Mental State Examination and HAM-D (depression score) were also included in the model (STAI Trait < or =30 vs. > 30 risk ratio, 0.36; 95% CI, 0.16, 0.82; p = 0.015). CONCLUSIONS: In contrast to two other recent studies that showed anxiety predicted cognitive decline or conversion to AD, in this clinic-based sample, state anxiety was not a significant predictor. However, higher Trait anxiety predicted a lower risk of future conversion to AD. Further research with systematic long-term follow-up in larger samples is needed to clarify the role of state and trait anxiety in predicting MCI conversion to AD.

Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease.

BACKGROUND: The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer's Disease (AD) remains uncertain. METHODS: Included in the study were 148 outpatients with MCI, broadly defined, followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, and magnetic resonance imaging (MRI) hippocampal and entorhinal cortex volumes. RESULTS: In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: Pfeffer Functional Activities Questionnaire (FAQ; informant report of functioning), University of Pennsylvania Smell Identification Test (UPSIT; olfactory identification), Selective Reminding Test (SRT) immediate recall (verbal memory), MRI hippocampal volume, and MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and Mini-Mental State Examination (MMSE) showed 39.4% sensitivity; combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (.948) than age plus MMSE (.821; p = .0009) and remained high in subsamples with MMSE > or = 27/30 and amnestic MCI. CONCLUSIONS: The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining the clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD.

Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study.

OBJECTIVE: To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment. METHODS: Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points. RESULTS: At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains. CONCLUSION: These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial.

Mild Parkinsonian signs are associated with lower olfactory test scores in the community-dwelling elderly.

Mild Parkinsonian signs (MPS, impaired gait, rigidity, bradykinesia, rest tremor) are commonly found during the clinical examination of older people and may be a precursor to Parkinson's disease (PD) or Alzheimer's disease (AD). Marked deficits in olfaction occur in PD and AD. The objective of this study was to determine whether University of Pennsylvania Smell Test (UPSIT) scores were lower in nondemented community-dwelling elderly with versus without MPS. Nondemented persons age >or=65 years without PD in Washington Heights-Inwood, NY were evaluated with an abbreviated motor Unified PD Rating Scale and a 40-item UPSIT. Lower UPSIT and higher transformed UPSIT score (square root [UPSIT - 41]) indicated greater olfactory dysfunction. One-hundred-seventy-seven (16.4%) of 1,078 participants had MPS. Mean UPSIT scores (MPS vs. without MPS) were 24.3 +/- 7.1 versus 26.4 +/- 6.8, P < 0.001. In a logistic regression analysis adjusting for age and education, transformed UPSIT score was associated with MPS (OR 1.25, 95% CI 1.04-1.52, P = 0.02). In an adjusted logistic regression analysis, participants with higher transformed UPSIT scores (based on a median split) were 1.55 times more likely to have MPS than were those with lower scores (P = 0.01). Within transformed UPSIT score quartiles, the odds of having MPS were 1.0 (reference), 1.35, 2.02, and 2.20 (P < 0.05). The association with transformed UPSIT scores was similar across MPS subtypes (axial dysfunction, rigidity, tremor).MPS were associated with a mild reduction in olfactory function. These observations further support the view of MPS as a marker of emerging degenerative brain pathologies.

Validation and optimization of statistical approaches for modeling odorant-induced fMRI signal changes in olfactory-related brain areas.

Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A second approach modeled an early transient response by simply shortening the odorant 'ON' period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the 'optimal' model fit to the data was achieved by shortening the odorant 'ON' period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.

Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment.

CONTEXT: The likelihood of conversion to Alzheimer disease (AD) in mild cognitive impairment (MCI) and the "optimal" early markers of conversion need to be established. OBJECTIVES: To evaluate conversion rates to AD in subtypes of MCI and to identify neuropsychological measures most predictive of the time to conversion. DESIGN: Patients were followed up semiannually and controls annually. Subtypes of MCI were determined by using demographically adjusted regression norms on neuropsychological tests. Survival analysis was used to identify the most predictive neuropsychological measures. SETTING: Memory disorders clinic. PARTICIPANTS: One hundred forty-eight patients reporting memory problems and 63 group-matched controls. MAIN OUTCOME MEASURE: A consensus diagnosis of probable AD. RESULTS: At baseline, 108 patients met criteria for amnestic MCI: 87 had memory plus other cognitive domain deficits and 21 had pure memory deficits. The mean duration of follow-up for the 148 patients was 46.6 +/- 24.6 months. In 3 years, 32 (50.0%) of 64 amnestic-"plus" and 2 (10.0%) of 20 "pure" amnestic patients converted to AD (P = .001). In 148 patients, of 5 a priori predictors, the percent savings from immediate to delayed recall on the Selective Reminding Test and the Wechsler Adult Intelligence Scale-Revised Digit Symbol Test were the strongest predictors of time to conversion. From the entire neuropsychological test battery, a stepwise selection procedure retained 2 measures in the final model: total immediate recall on the Selective Reminding Test (odds ratio per 1-point decrease, 1.10; 95% confidence interval, 1.05-1.14; P < .0001) and Digit Symbol Test coding (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .01). The combined predictive accuracy of these 2 measures for conversion by 3 years was 86%. CONCLUSIONS: Mild cognitively impaired patients with memory plus other cognitive domain deficits, rather than those with pure amnestic MCI, constituted the high-risk group. Deficits in verbal memory and psychomotor speed/executive function abilities strongly predicted conversion to AD.

Olfactory dysfunction as a predictor of neurodegenerative disease.

Olfactory dysfunction is present in patients diagnosed with Alzheimer's disease or idiopathic Parkinson's disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer's disease or Parkinson's disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.

PET network abnormalities and cognitive decline in patients with mild cognitive impairment.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01-0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considered.

A 10-item smell identification scale related to risk for Alzheimer's disease.

University of Pennsylvania Smell Identification Test data from control subjects (n = 63), patients with mild cognitive impairment (n = 147), and patients with Alzheimer's disease (n = 100) were analyzed to derive an optimal subset of items related to risk for Alzheimer's disease (ie, healthy through mild cognitive impairment to early and moderate disease stages). The derived 10-item scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects, and it strongly predicted conversion to Alzheimer's disease on follow-up evaluation in patients with mild cognitive impairment. Independent replication is needed to validate these findings.

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment.

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.

Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele).

OBJECTIVE: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. METHODS: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. RESULTS: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. CONCLUSION: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.