Retinal thickness in patients with mild cognitive impairment and Alzheimer's disease

Objectives

Mild cognitive impairment (MCI) may represent a transition to early Alzheimer's disease (AD). The retinal nerve fiber layer (RNFL) is composed of axons originating in retinal ganglion cells that eventually form the optic nerves. Previous studies have shown that degenerative changes occur in optic nerve fibers and manifested as thinning of RNFL in patients with AD. The objective of this study was to assess the relationship between MCI, AD and loss of RNFL.

Patients and methods

In this study, patients fulfilling diagnostic criteria for MCI (n = 24), AD (n = 30) and cognitively normal age-matched controls (n = 24) have undergone neuro-ophthalmologic and optical coherence tomography (OCT) examinations to measure RNFL thickness.

Results

There was a significant decrease in RNFL thickness in both study groups (AD and MCI) compared to the control group, particularly in the inferior quadrants of the optic nerve head, while the superior quadrants were significantly thinner only in AD. Although AD patients may have more severe changes than MCI cases, the differences were statistically nonsignificant. Furthermore among AD patients, there was no relation to the severity of the dementia.

Conclusions

Our data confirm the retinal involvement in AD, as reflected by loss of axons in the optic nerves.     

Kinematic analysis of handwriting movements in patients with Alzheimer's disease,mild cognitive impairment,depression and healthy subjects

A variety of studies have demonstrated that motor disorders, parkinsonism and extrapyramidal motor symptoms (EPMS) are common in patients with Alzheimer's disease (AD). Several studies have reported an association of EPMS with severity, progression and poor prognosis of AD. The majority of these studies used clinical assessments for the rating of EPMS. In this study, kinematic handwriting analysis was used to quantify differences in fine hand motor function in patients with probable AD and mild cognitive impairment (MCI, as an assumed initial stage of AD) compared to depressed patients and healthy controls. Both patients with MCI and patients with probable AD exhibited loss of fine motor performance. Movements of AD patients were significantly less regular than those of healthy controls.     

Alterations of whole-brain cortical area and thickness in mild cognitive impairment and Alzheimer's disease

Gray matter volume and density of several brain regions, determined by magnetic resonance imaging (MRI), are decreased in Alzheimer's disease (AD). Animal studies have indicated that changes in cortical area size is relevant to thinking and behavior, but alterations of cortical area and thickness in the brains of individuals with AD or its likely precursor, mild cognitive impairment (MCI), have not been reported. In this study, 25 MCI subjects, 30 AD subjects, and 30 age-matched normal controls were recruited for brain MRI scans and Functional Activities Questionnaire (FAQ) assessments. Based on the model using FreeSurfer software, two brain lobes were divided into various regions according to the Desikan-Killiany atlas and the cortical area and thickness of every region was compared and analyzed. We found a significant increase in cortical area of several regions in the frontal and temporal cortices, which correlated negatively with MMSE scores, and a significant decrease in cortical area of several regions in the parietal cortex and the cingulate gyrus in AD subjects. Increased cortical area was also seen in some regions of the frontal and temporal cortices in MCI subjects, whereas the cortical thickness of the same regions was decreased. Our observations suggest characteristic differences of the cortical area and thickness in MCI, AD, and normal control subjects, and these changes may help diagnose both MCI and AD.     

Cortical thickness in frontotemporal dementia, mild cognitive impairment, and Alzheimer's disease

Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.     

Caregiver perception of apathy in persons with mild cognitive impairment or Alzheimer's disease: a longitudinal study

Objective: Discrepancy between self- and caregiver apathy ratings was examined longitudinally for persons with mild cognitive impairment or Alzheimer's disease. Particular focus was on the distinction between the positive and negative caregiver bias and its predictive value for a clinical diagnosis of apathy.

Method: Apathy rating discrepancy was based on the apathy evaluation scale. Dyads were categorized depending on whether the caregiver reported fewer deficits (positive caregiver bias) or more deficits (negative caregiver bias) than the cognitively impaired person did.

Results: Caregiver ratings and rating discrepancy showed a significant increase from baseline to follow-up. By contrast, self- and clinician ratings showed no change across the two time points. Ratings with a negative caregiver bias remained stable, while those with a positive caregiver bias showed a significant increase in the caregiver ratings but also a significant decrease in the self-ratings. A negative caregiver bias at baseline was significantly related to greater likelihood of having clinical apathy at follow-up, adjusted for an array of control variables.

Conclusion: Positive and negative caregiver bias should be distinguished, as they seem to reflect distinct dyadic processes and are relevant for clinical outcome. Furthermore, negative rating discrepancies can be considered a risk factor for developing apathy.     

Motor function in subjects with mild cognitive impairment and early Alzheimer's disease

Basic mobility, balance, gait and dual-task performance were characterised in 140 consecutive subjects referred to a multidisciplinary university hospital in a geriatric setting for cognitive symptoms and possible dementia. After completion of an extensive diagnostic evaluation, subjects were classified into four diagnostic categories: no cognitive impairment, mild cognitive impairment, Alzheimer's disease (AD) and other dementia. Mean age was 57 +/- 9.2, 60 +/- 7.3, 68 +/- 9.9 and 64 +/- 10.5, respectively. Data on motor function, medication use and presence of white matter changes were evaluated and compared between the diagnostic groups. Motor function seems to be affected in very mild AD but not in mild cognitive impairment, as assessed with performance-based tests. AD subjects were slowed and had difficulties in dual-task performance requiring concurrently performing a cognitive task while walking.     

Comprehension of lexical ambiguity in healthy aging, mild cognitive impairment, and mild Alzheimer's disease

Two experiments examined processing of lexical ambiguity in healthy older control (HC), mild cognitive impairment (MCI) and Alzheimer's disease (AD) participants. In Experiment 1, groups of HC, MCI and AD participants took part in an ERP study in which they read lexically ambiguous items presented in a subordinate context and primed by the same item presented in a dominant context. Ambiguous items were homonyms (e.g., bank), metaphorical polysemes (e.g., star), or metonyms (e.g., rabbit). All participants exhibited smaller N400s for items preceded by a related prime. In addition, HC participants exhibited a smaller N400 for metonyms than for metaphorical polysemes or homonyms; this effect was diminished in MCI and AD participants. In Experiment 2, HC and MCI participants completed a primed lexical decision task where targets related to the subordinate meaning/sense of ambiguous items were preceded by primes biasing the dominant meaning/sense (e.g., financial-bank-river). In contrast to the results of Experiment 1, both HC and MCI participants showed priming for metonymic items, but not homonyms or metaphorical polysemes. These results suggest that basic knowledge of multiple senses of metonyms is preserved in MCI, but the processing advantage conveyed by this semantic richness is diminished in MCI and AD.     

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.     

Sulcal span in Azheimer's disease, amnestic mild cognitive impairment, and healthy controls

Differences of cortical morphology between healthy controls (HC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD) have been repeatedly investigated using voxel-based morphometry (VBM). However, the results obtained using mainly VBM remain difficult to interpret as they can be explained by various mechanisms. The aim of the present study was to evaluate the differences of cortical morphology between HC, MCI, and AD patients using a new post-processing method based on reconstruction and identification of cortical sulci. Thirty HC, 33 MCI, and 30 AD patients were randomly selected from the ADNI database. For each subject, cortical sulci were reconstructed and automatically identified using Brainvisa software. Depth and fold opening of nine large sulci were compared between HC, MCI, and AD patients. Fold opening of parietaloccipital fissure and intraparietal sulcus on both sides strongly differed between the 3 groups, with gradual increase from HC to MCI of about 1 mm and from MCI to AD of about 2 mm (right intraparietal: p = 0.005; left intraparietal: p = 0.004; right parietaloccipital: p = 0.003; left parietaloccipital: p = 0.0009). Results were left unchanged after adjustment for age, gender, and level of education. These variables were also strongly linked to neuropsychological scores, independent of age, gender, and level of education. In the present study, we found important regional differences of cortical morphology with gradual deterioration from HC to MCI to AD. The most important differences were found in parietaloccipital fissure and intraparietal sulcus. Further studies are needed to understand the involved underlying mechanisms.     

Aging, mild cognitive impairment, and Alzheimer's disease

Research in the field of aging and dementia is moving forward at a rapid pace, in both basic biology of dementing disorders and clinical investigations. These two approaches to research on aging and dementia need to advance in parallel, such that when work on the pathophysiology of these disorders is translated into therapeutic practice, the appropriately characterized clinical cohorts will be available for therapeutic trials of these treatment strategies.     

Resting state cortical rhythms in mild cognitive impairment and Alzheimer's disease: electroencephalographic evidence

Physiological brain aging is characterized by a combination of synaptic pruning, loss of cortico-cortical connections and neuronal apoptosis that provoke age-dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. Unfortunately, in pathological situations, aging triggers neurodegenerative processes that impact on cognition, like Alzheimer's disease (AD). Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including digital electroencephalography (EEG) allow non-invasive analysis of cortico-cortical connectivity and neuronal synchronization of firing, and coherence of brain rhythmic oscillations at various frequencies. The present review of field EEG literature suggests that discrimination between physiological and pathological brain aging clearly emerges at the group level, with some promising result on the informative value of EEG markers at the individual level. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost, widely available on the territory and non-invasive screening of at-risk populations.     

Subjective memory complaints in Chinese subjects with mild cognitive impairment and early Alzheimer's disease

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia. However, there is inconsistent opinion as to the validity of subjective memory complaints as a criterion for diagnosis. OBJECTIVE: This study aimed to examine the potential significance of applying a short memory questionnaire in the assessment of Chinese subjects with MCI and early dementia. METHODS: Three hundred and six ambulatory Chinese subjects were recruited. Each participant completed a short memory questionnaire. They were also assessed with the Chinese versions of the mini-mental state examination (CMMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), category verbal fluency test (CVFT) and span tests. Severity of cognitive impairment was evaluated using the Clinical Dementia Rating (CDR); subjects with CDR 0.5 were further classified into MCI not demented (MCIND) and MCI possible incipient dementia (MCIID) depending on the subscale scores of CDR. RESULTS: An increasing frequency of memory complaints with increasing CDR was observed (Kruskal Wallis test, chi square = 21.29, df 3, p < 0.001). With a cutoff of 3 or more memory complaints, the memory questionnaire demonstrated a sensitivity of 65.3% and 70.4% in identifying subjects with incipient and early dementia respectively. Significant associations between memory complaints and most cognitive test performance were found (Spearman's correlations, p < 0.01). Logistic regression analysis revealed that educational level, the memory questionnaire, ADAS-Cog total and delayed recall scores were significant predictors of MCIID status. CONCLUSIONS: The findings suggested that a short memory questionnaire is useful in the screening of MCI, particularly in subjects who already present with subtle functioning disturbances. Subjective memory complaints were significant correlated with objective performance of memory functions, reflecting the usefulness of memory complaints in the assessment of MCI.     

Olfaction and apathy in Alzheimer's disease,mild cognitive impairment,and healthy older adults

Objectives: Apathy is a prevalent neuropsychiatric manifestation in individuals with Alzheimer's disease (AD) that is associated with decreased social functioning and increased caregiver burden. Olfactory deficits are also commonly observed in AD, and prior work has indicated a link between increased apathy and olfactory dysfunction in individuals with Parkinson's disease. Here, we examined odor identification performance in patients with probable AD (n = 172), individuals with mild cognitive impairment (MCI; n = 112), and neurologically and psychiatrically healthy older adults (n = 132) and its relation to apathy, depression, and overall psychopathology. Method: Participants were administered the Sniffin’ Sticks odor identification test and measures assessing severity of apathy, depression, and overall neuropsychiatric symptomatology. Results: Consistent with previous research, AD and MCI patients were significantly worse at identifying odors than healthy older adults. Additionally, a sex by diagnosis interaction was observed. AD patients had significantly higher levels of apathy relative to MCI and control participants. Of note, across the entire sample odor identification deficits were correlated with level of apathy at the level of p < 0.01, but not with depression or neuropsychiatric symptom severity, when controlling for Mini-Mental State Examination (MMSE) score. Conclusion: Collectively, these data suggest that olfactory disturbance and apathy in AD may result from the progression of disease pathology in shared neural substrates.     

Prediction of Alzheimer's disease and mild cognitive impairment using cortical morphological patterns

This article describes a novel approach to extract cortical morphological abnormality patterns from structural magnetic resonance imaging (MRI) data to improve the prediction accuracy of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Conventional approaches extract cortical morphological information, such as regional mean cortical thickness and regional cortical volumes, independently at different regions of interest (ROIs) without considering the relationship between these regions. Our approach involves constructing a similarity map where every element in the map represents the correlation of regional mean cortical thickness between a pair of ROIs. We will demonstrate in this article that this correlative morphological information gives significant improvement in classification performance when compared with ROI‐based morphological information. Classification performance is further improved by integrating the correlative information with ROI‐based information via multi‐kernel support vector machines. This integrated framework achieves an accuracy of 92.35% for AD classification with an area of 0.9744 under the receiver operating characteristic (ROC) curve, and an accuracy of 83.75% for MCI classification with an area of 0.9233. In differentiating MCI subjects who converted to AD within 36 months from non‐converters, an accuracy of 75.05% with an area of 0.8426 under ROC curve was achieved, indicating excellent diagnostic power and generalizability. The current work provides an alternative approach to extraction of high‐order cortical information from structural MRI data for prediction of neurodegenerative diseases such as AD. Hum Brain Mapp 34:3411–3425, 2013. © 2012 Wiley Periodicals, Inc.     

Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study

BACKGROUND: Disease-modifying treatment strategies for Alzheimer's disease have led to an urgent need for biomarkers to identify the disease at a very early stage. Here, we assess the association between CSF biomarkers and incipient Alzheimer's in patients with mild cognitive impairment (MCI). METHODS: From a series of 180 consecutive patients with MCI, we assessed 137 who underwent successful lumbar puncture at baseline. Patients at risk of developing dementia were followed clinically for 4-6 years. Additionally, 39 healthy individuals, cognitively stable over 3 years, served as controls. We analysed CSF concentrations of beta amyloid(1-42) (Abeta42), total tau (T-tau), and phosphorylated tau (P-tau181) using Luminex xMAP technology. FINDINGS: During follow-up, 57 (42%) patients with MCI developed Alzheimer's disease, 21 (15%) developed other forms of dementia, and 56 (41%) remained cognitively stable for 5.2 years (range 4.0-6.8). A combination of CSF T-tau and Abeta42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD in patients with MCI. The relative risk of progression to Alzheimer's disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Abeta42 at baseline (hazard ratio 17.7, p<0.0001). The association between pathological CSF and progression to Alzheimer's disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. The combination of T-tau and Abeta42/P-tau181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19.8). INTERPRETATION: Concentrations of T-tau, P-tau181, and Abeta42 in CSF are strongly associated with future development of Alzheimer's disease in patients with MCI.     

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.     

阿尔茨海默病和轻度认知障碍患者视网膜纤维层和黄斑异常的研究

目的本研究通过光学相干断层显像仪(OCT)观察阿尔茨海默病(AD)患者及轻度认知障碍(MCI)患者视网膜纤维层(RNFL)厚度和黄斑厚度及容积与正常对照组是否存在异常。方法阿尔茨海默病患者25人,轻度认知障碍患者26人,正常对照组20人。通过OCT对入组者RNFL及黄斑进行观察,以P<0.05作为差异有统计学意义。结果 AD组的RNFL厚度较对照组减小,除鼻侧象限、12:00、2:00、3:00、4:00以外均达到统计学意义。AD组RNFL厚度较MCI组变薄,平均厚度、下象限、5:00、6:00、10:00和11:00的差异有统计学意义(P<0.05)。与对照组相比时,MCI患者的RNFL厚度在上象限、颞侧象限及8:00、10:00、11:00明显变薄且有统计学意义。AD组黄斑容积较对照组明显减小,且P<0.05。结论 AD和MCI患者出现视神经视网膜退行性变,表现为视网膜纤维层厚度平均值及不同位点选择性的变薄和黄斑容积的改变。     

Free copper and resting temporal EEG rhythms correlate across healthy, mild cognitive impairment, and Alzheimer's disease subjects.

OBJECTIVE: The present study tested the hypothesis that the serum copper abnormalities were correlated with alterations of resting electroencephalographic (EEG) rhythms across the continuum of healthy elderly (Hold), mild cognitive impairment (MCI), and AD subjects. METHODS: Resting eyes-closed EEG rhythms delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz), estimated by LORETA, were recorded in 17 Hold, 19 MCI, 27 AD- (MMSE< or =20), and 27 AD+ (MMSE20) individuals and correlated with copper biological variables. RESULTS: Across the continuum of Hold, MCI and AD subjects, alpha sources in parietal, occipital, and temporal areas were decreased, while the magnitude of the delta and theta EEG sources in parietal, occipital, and temporal areas was increased. The fraction of serum copper unbound to ceruloplasmin positively correlated with temporal and frontal delta sources, regardless of the effects of age, gender, and education. CONCLUSIONS: These results sustain the hypothesis of a toxic component of serum copper that is correlated with functional loss of AD, as revealed by EEG indexes. SIGNIFICANCE: The present study represents the first demonstration that the fraction of serum copper unbound to ceruloplasmin is correlated with cortical delta rhythms across Hold, MCI, and AD subjects, thus unveiling possible relationships among the biological parameter, advanced neurodegenerative processes, and synchronization mechanisms regulating the relative amplitude of selective EEG rhythms.