Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up

OBJECTIVE: This study evaluated the predictive utility of olfactory identification deficits in patients with mild cognitive impairment for follow-up diagnosis of probable Alzheimer's disease. METHOD: Ninety outpatients with mild cognitive impairment were examined at 6-month intervals. Matched healthy comparison subjects (N=45) were examined annually. The University of Pennsylvania Smell Identification Test was given at baseline. RESULTS: Olfaction scores were lower in patients with mild cognitive impairment than in healthy comparison subjects. Seventy-seven patients were followed up; 19 were diagnosed with Alzheimer's disease by 2 years. Patients with low olfaction scores (< or =34 of 40), and patients with low olfaction scores who reported no subjective problems smelling, were more likely to develop Alzheimer's disease than other patients. In a Cox proportional hazards model adjusted for age, sex, modified Mini-Mental State score, and education, low olfaction scores did not predict time until development of Alzheimer's disease, but low olfaction scores accompanied by lack of awareness of olfactory deficits predicted time to development of Alzheimer's disease. This effect remained when attention or memory measures replaced modified Mini-Mental State score in the model. In patients with high Mini-Mental State scores (> or =27 of 30), low olfaction with lack of awareness remained a significant predictor of Alzheimer's disease. Olfaction scores of 30-35 showed moderate to strong sensitivity and specificity for diagnosis of Alzheimer's disease at follow-up. CONCLUSIONS: In patients with mild cognitive impairment, olfactory identification deficits, particularly with lack of awareness of olfactory deficits, may have clinical utility as an early diagnostic marker for Alzheimer's disease.     

Alzheimer's disease and mild cognitive impairment

As our society ages, age-related diseases assume increasing prominence as both personal and public health concerns. Disorders of cognition are particularly important in both regards, and Alzheimer's disease is by far the most common cause of dementia of aging. In 2000, the prevalence of Alzheimer's disease in the United States was estimated to be 4.5 million individuals, and this number has been projected to increase to 14 million by 2050. Although not an inevitable consequence of aging, these numbers speak to the dramatic scope of its impact. This article focuses on Alzheimer's disease and the milder degrees of cognitive impairment that may precede the clinical diagnosis of probable Alzheimer's disease, such as mild cognitive impairment.     

Amnestic mild cognitive impairment in Parkinson's disease: A brain perfusion SPECT study

The purpose of this study was to investigate cortical dysfunction in Parkinson's disease (PD) patients with amnestic deficit (PD‐MCI). Perfusion single photon emission computed tomography was performed in 15 PD‐MCI patients and compared (statistical parametric mapping [SPM2]) with three groups, i.e., healthy subjects (CTR), cognitively intact PD patients (PD), and common amnestic MCI patients (aMCI). Age, depression, and UPDRS‐III scores were considered as confounding variables. PD‐MCI group (P < 0.05, false discovery rate–corrected for multiple comparisons) showed relative hypoperfusion in bilateral posterior parietal lobe and in right occipital lobe in comparison to CTR. As compared to aMCI, MCI‐PD demonstrated hypoperfusion in bilateral posterior parietal and occipital areas, mainly right cuneus and angular gyrus, and left precuneus and middle occipital gyrus. With a less conservative threshold (uncorrected P < 0.01), MCI‐PD showed hypoperfusion in a left parietal region, mainly including precuneus and inferior parietal lobule, and in a right temporal‐parietal‐occipital region, including middle occipital and superior temporal gyri, and cuneus‐precuneus, as compared to PD. aMCI versus PD‐MCI showed hypoperfusion in bilateral medial temporal lobe, anterior cingulate, and left orbitofrontal cortex. PD‐MCI patients with amnestic deficit showed cortical dysfunction in bilateral posterior parietal and occipital lobes, a pattern that can be especially recognized versus both controls and common aMCI patients, and to a lesser extent versus cognitively intact PD. The relevance of this pattern in predicting dementia should be evaluated in longitudinal studies. © 2008 Movement Disorder Society     

Gender-specificities in Alzheimer's disease and mild cognitive impairment

Background Amnestic Mild Cognitive Impairment (MCI) is a condition with an increased risk for developing Alzheimer's disease (AD). Presently, gender differences are neglected in the assessment of MCI and AD. Methods We examined verbal and visuospatial episodic memory in 143 subjects diagnosed as healthy controls (HC; N = 48, Mini-Mental State Examination (MMSE) 29.2 ± 1.0 (mean ± standard deviation)), MCI (N = 43,MMSE 28.5 ± 1.4), and AD (N = 49, MMSE 25.1 ± 2.2). Findings Female HC and MCI subjects performed better on verbal episodic memory tasks than males. In contrast, visuospatial episodic memory was better in male than female AD patients. Conclusions We interpret the results in light of a genderspecific cognitive reserve and conclude that the gender-specificity of neuropsychological performance needs to be accounted for in clinical diagnosis of Alzheimer’s disease.     

Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment

Objective Aim of this study was to find cerebral perfusion correlates of conversion to dementia in patients with amnestic MCI. Methods 17 healthy subjects (age = 69 ± 3, 9 females), and 23 amnestic MCI patients (age = 70 ± 6, 10 females) underwent brain MR scan and ^99mTc ECD SPECT. Conversion to AD was ascertained on average 19 ± 10 months after baseline: 9 had converted (age = 69 ± 3, 4 females), and 14 had not (age = 71 ± 8, 6 females). We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing amnestic MCI patients converted to AD and non-converted to dementia vs controls. We assessed the effect of gray matter atrophy on the above results with SPM2 using an optimized Voxel-Based Morphometry (VBM) protocol.We compared significant hypoperfusion with significant atrophy on a voxel-byvoxel basis. Results In comparison with normal controls, amnestic MCI patients who converted to AD showed hypoperfusion in the right parahippocampal gyrus and left inferior temporal and fusiform gyri,whereas those who did not convert showed hypoperfusion in the retrosplenial cortex, precuneus and occipital gyri, mainly on the left side.We found no overlap between significant atrophy and significant hypoperfusion regions. Conclusions Parahippocampal and inferior temporal hypoperfusion in amnestic MCI patients appears as a correlate of conversion to AD; hypoperfusion in the retrosplenial cortex is involved in memory impairment but does not seem the key prognostic indicator of conversion to dementia.     

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.     

Semantic interference deficits and the detection of mild Alzheimer's disease and mild cognitive impairment without dementia.

Impairment in delayed recall has traditionally been considered a hallmark feature of Alzheimer's disease (AD). However, vulnerability to semantic interference may reflect early manifestations of the disorder. In this study, 26 mildly demented AD patients (mild AD), 53 patients with mild cognitive impairment without dementia (MCI), and 53 normal community-dwelling elders were first presented 10 common objects that were recalled over 3 learning trials. Subjects were then presented 10 new semantically related objects followed by recall for the original targets. After controlling for the degree of overall memory impairment, mild AD patients demonstrated greater proactive but equivalent retroactive interference relative to MCI patients. Normal elderly subjects exhibited the least amount of proactive and retroactive interference effects. Recall for targets susceptible to proactive interference correctly classified 81.3% of MCI patients and 81.3% of normal elderly subjects, outperforming measures of delayed recall and rate of forgetting. Adding recognition memory scores to the model enhanced both sensitivity (84.6%) and specificity (88.5%). A combination of proactive and retroactive interference measures yielded sensitivity of 84.6% and specificity of 96.2% in differentiating mild AD patients from normal older adults. Susceptibility to proactive semantic interference may be an early cognitive feature of MCI and AD patients presenting for clinical evaluation.     

Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (-14% and -12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism.     

Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches.     

EEG synchronization in mild cognitive impairment and Alzheimer's disease

OBJECTIVES: To compute the synchronization likelihood of multichannel electroencephalogram (EEG) data in Alzheimer (AD) patients, subjects with mild cognitive impairment (MCI) and subjects with subjective memory complaints (SC). MATERIAL AND METHODS: EEGs (200 Hz sample frequency; 21 channels; average reference) were recorded in 10 AD patients (two males; age 76.2; SD 9.36; range 59-86), 17 subjects with MCI (eight males; age 77.41; SD 6.25; range 62-88) and 20 subjects with SCI (11 males; age 68.9; SD 12.96; range: 51-89). The synchronization likelihood, a novel type of coherence measure, was computed, comparing each channel with all other channels, for the 2-6, 6-10, 10-14, 14-18, 18-22 and 22-50 Hz band. RESULTS: The synchronization likelihood was significantly decreased in the 14-18 and 18-22 Hz band in AD patients compared with both MCI subjects and healthy controls. Lower beta band synchronization correlated with lower Mini-Mental state examination (MMSE) scores. CONCLUSION: Loss of beta band synchronization occurs early in mildly affected AD patients and correlates with cognitive impairment.     

Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment

The neural basis of the amnesia characterizing early Alzheimer's disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.     

Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease

Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer's disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E epsilon4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.     

New developments in mild cognitive impairment and Alzheimer's disease

PURPOSE OF REVIEW: In this paper, we review current concepts of Alzheimer's disease, recent progress in diagnosis and treatment and important developments in our understanding of its pathogenesis with a focus on beta-amyloid both as culprit and therapeutic target. RECENT FINDINGS: The amyloid cascade hypothesis of Alzheimer's disease pathogenesis continues to predominate with evidence suggesting that small oligomeric forms of Abeta-42 rather than fibrils or senile plaques are the key pathological substrates. The concept of mild cognitive impairment continues to be refined to define better those patients who will progress to Alzheimer's disease. Structural and functional imaging techniques and cerebrospinal fluid biomarkers are gaining acceptance as diagnostic markers of Alzheimer's disease, with a potentially exciting advance being the ability to image amyloid in vivo using novel positron emission tomography ligands. Whilst available treatments afford only symptomatic benefits, disease-modifying treatments may be within reach. Despite the halting of the first amyloid beta-vaccination trial due to adverse effects, amyloid immunotherapy continues to show promise, with new approaches already entering clinical trials. Other therapeutic strategies under investigation include inhibition of beta -and gamma-secretase, key enzymes implicated in Alzheimer's disease pathogenesis. SUMMARY: Current research demonstrates the potential for diagnostic strategies and disease modifying treatments to follow from an ever more detailed understanding of the molecular mechanisms underlying the pathogenesis of Alzheimer's disease.     

Neuropathology of mild cognitive impairment Alzheimer's disease]

The pathological study of mild cognitive impairment (MCI) was very few. Consecutive 1,628 autopsy cases from the Brain Bank for Aging Research (BBAR) with the mean age of 80.7 years were employed for this study. All the cases were studied with the BBAR protocol (www.mci.gr.jp/BrainBank/) and clasasified into Braak's seven neuforibrillary tangle (NFT) stages (0-VII) and four senile plaque (SP) stages (0-C). CDR from the most recent 545 cases were independently evaluated by three neurologists in two different occasions. Among the 1,628 cases, 10.1% fulfilled morphological requirement of Alzheimer disease, consisting of NFT stage equal to or more than IV and SP stage equal to or more than C. Postmortem assessment of CDR was possible for 486 cases amoug 545 cases with frozem half brain and 57 cases were classified into CDR 0.5. CDR 0.5 group was clinicopathologically classified into 33 cases with degenerative changes, nine cases with vascular changes and four cases with combined degenerative and vascular changes. Only 6 among the 57 cases presented pure AD pathology. These data indicate that the pathological background of MCI is not always Alzheimer disease and combined pathology with AD as well as non-AD pathology should be carefully ruled out. For this purpose, ADNI (Alzheimer Disease Neuroimage Initiative) approach could be useful to identify MCI stage of AD.     

Biological markers of Alzheimer's disease and mild cognitive impairment

The diagnosis of Alzheimer's disease (AD) is mainly performed by excluding other disorders with similar clinical features. In addition, an analysis of symptoms and signs, blood studies and brain imaging are major ingredients of the clinical diagnostic work-up. However, the diagnosis based on these instruments is unsatisfactory, indicating the need of a highly sensitive and reliable approaches, selective for AD and based on biological markers. Ideally, such markers should reflect the pathophysiological mechanisms of AD, which according to the current hypotheses, derive from the actions of two major protein aggregates, the extracellular beta-amyloid (Abeta) plaques and the neurofibrillary tangles. Since AD is a multifactorial disease, other factors that cause neuronal insult and that contribute to neuronal degeneration in AD include free radical and oxidative stress promoting molecules, proinflammatory cytokines and neurotoxic agents. In this context, the search for anomalous levels or changes in the molecular patterns of Abeta(1-42) or Abeta(1-40), hyperphosphorylated tau isoforms, oxidation products in the cell or cytokines such as interleukin-1 or 6 facilitates the selection of biomarkers in AD. There is clear evidence that the cerebrospinal fluid (CSF) levels of beta(1-42) are significantly reduced in AD patients as compared with senile controls, while increased levels of tau have been revealed. The CSF levels of these proteins reflect their metabolism in the central nervous system. Approaches using ELISA and immunochemical methods for the quantification of these markers in CSF have been preferentially used. Diagnosis criteria and number of patients exhibits variations in the different reports, while clinico-pathological studies are scarce. An increasing number of studies suggest that supplementary use of these CSF markers preferably in combination, adds to the accuracy of an AD diagnosis.     

Hippocampal formation alterations differently contribute to autobiographic memory deficits in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi‐structured interview (E‐AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2‐3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.     

Hormonal treatment, mild cognitive impairment and Alzheimer's disease

A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.