Cognitive profiles of mild cognitive impairment with and without vascular disease

This study examined whether the cognitive profile of subjects with mild cognitive impairment (MCI) with vascular disease differs from that of MCI subjects with no vascular disease. Consecutive MCI subjects with vascular disease (n=60) and matched MCI subjects with no vascular disease (n=60) were included in the study and were compared with healthy control subjects (n=60). The neuropsychological assessment comprised tests of speed and attention, episodic memory, visuospatial function, language, and executive function. Control subjects performed significantly better than did both MCI groups on the neuropsychological battery. MCI subjects with no vascular disease performed better overall than did MCI subjects with vascular disease, most clearly on tests of speed and attention, visuospatial function, and executive function. MCI subjects with and without vascular disease exhibited differences, both in terms of overall performance and of cognitive profiles. These differences can be largely explained by deficits in speed and attention and in executive function of the MCI subjects with vascular disease.     

Prediction of Alzheimer's disease in mild cognitive impairment: a prospective study in Taiwan

The relationship between apolipoprotein E (ApoE) and clinical manifestations of mild cognitive impairment (MCI) has not been investigated in non-Caucasian populations. This prospective study was conducted in an ethnic Chinese population to evaluate the correlations of ApoE genotype, cognitive performance, medial temporal structure volumes, and clinical outcome in amnestic MCI. Twenty normal elders, 58 MCI, and 20 mild Alzheimer's disease (AD) patients received neuropsychological, MRI, and ApoE genotype assessments at baseline. Patients with MCI had intermediate cognitive performance and hippocampal volumes between those in normal and AD groups. In each diagnostic group, 4 carriers (E4+) consistently had smaller hippocampal volume than non-carriers (E4−) did. Nineteen MCI subjects (32.7%) converted to AD during the 3-year study period. Compared with MCI non-converters and E4− MCI converters, E4+ MCI converters had the smallest hippocampal volume. However, 4 was not a predictor for AD. Both cognitive performance and hippocampal volume were predictive for progression to AD. However, stepwise Cox regression model integrating both neuropsychological and radiological variables showed that global cognitive performance was the only significant predictor for AD. A poor global cognitive score may be more crucial than a small hippocampal volume in the prediction of AD.     

Sensitivity and specificity of neuropsychological tests for mild cognitive impairment,vascular cognitive impairment and Alzheimer's disease

BACKGROUND: Early diagnosis of dementia is important for those who might benefit from treatment. We designed a brief comprehensive neuropsychological test battery to help differentiate control subjects from patients with mild cognitive impairment (MCI) and dementia. METHOD: The battery included tests of memory, attention, executive function, speed, perception and visuospatial skills. It was administered to subjects from the OPTIMA cohort: 51 controls, 29 with MCI, 60 with 'possible' or 'probable' Alzheimer's disease (AD) (NINCDS/ADRDA) and 12 with cerebrovascular disease (CVD). Mann-Whitney U tests were used to compare performance of controls with other diagnostic groups. The sensitivity and specificity of the tests were determined using Receiver Operating Characteristic curve analyses. The effects of age, gender and years of education on test performance were determined with Spearman's rank correlations. RESULTS: The AD group performed worse than controls on all tests except an attention task. The Hopkins Verbal Learning Test and The Placing Test for episodic memory showed significant discriminative capacity between controls and other groups. Attention and processing speed tests discriminated CVD from controls. Category fluency, episodic memory tests and the CLOX test for executive function distinguished MCI from AD. Spearman's correlations showed negative associations between age and processing speed. Years of education affected performance on all tests, except The Placing Test. CONCLUSIONS: Certain neuropsychological tests have been shown to be sensitive and specific in the differential diagnosis of various types of dementia and may prove to be useful for detection of MCI.     

Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment

We determined whether oxidative stress is an early event in the pathogenesis of sporadic Alzheimer disease (AD), and correlated oxidative stress with neuropsychological functions and neurofibrillary pathology in AD and mild cognitive impairment (MCI). Oxidative stress was measured as the percentage of astrocytes expressing heme oxygenase-1 (HO-1) in post mortem temporal cortex and hippocampus after dual HO-1/glial fibrillary acidic protein (GFAP) immunohistochemistry. Glial HO-1 expression in the MCI temporal cortex and hippocampus was significantly greater than in the non-demented group and did not differ from AD values. Astroglial HO-1 expression in the temporal cortex was associated with decreased scores for global cognition, episodic memory, semantic memory and working memory. Hippocampal astroglial HO-1 expression was associated with lower scores for global cognition, semantic memory and perceptual speed. Glial HO-1 immunoreactivity in the temporal cortex, but not hippocampus, correlated with the burden of neurofibrillary pathology. Cortical and hippocampal oxidative stress is a very early event in the pathogenesis of sporadic AD and correlates with the development of specific cognitive deficits in this condition.     

Medial temporal lobe neuromagnetic hypoactivation and risk for developing cognitive decline in elderly population: a 2-year follow-up study

Cognition declines as a function of age. However, some elders could develop more severe status such as mild cognitive impairment (MCI). The aim of this study was the early detection of neurophysiological patterns of brain activity that may predict the possibility of certain subjects to develop MCI. Brain magnetic activity was recorded from 15 healthy subjects during a memory task by means of magnetoencephalography. None of the participants could be considered as MCI at the time of the first clinical evaluation. After 2-year follow-up, five subjects developed MCI and 10 maintained their cognitive status across time. The subjects who developed cognitive decline showed a lower number of activity sources in the left medial temporal lobe between 400 and 800 ms after stimulus onset, as compared to the non-cognitive decline group. These findings may help with the early identification of elderly subjects at high risk of cognitive decline, allowing the possibility of neuropsychological or pharmaceutical treatment that delay or prevent the progression of the cognitive impairment.     

Effect of mild cognitive impairment on the patterns of neural activity in early Parkinson's disease

We have previously observed decreased activation of corticostriatal loops involved in planning (cognitive loop) and execution (motor loop) of a set shift in patients with early Parkinson's disease (PD) compared with control subjects. Here, we aimed to assess whether cognitive impairment in PD could drive these differences. Nondemented patients underwent a comprehensive neuropsychological evaluation and participated in our Wisconsin Card Sorting task functional magnetic resonance imaging protocol. Patients were separated into 2 groups according to the presence of mild cognitive impairment (MCI). Patients with MCI displayed reduced activity in the cognitive corticostriatal loop, which includes the caudate nucleus and prefrontal cortex while planning a set shift, whereas non-MCI patients exhibited activation patterns similar to those of healthy participants from our previous studies. Furthermore, reduced activation was observed in the premotor cortex of the MCI patients. Finally, hippocampal activity, correlated with individual memory scores, suggesting a compensatory mechanism in patients with preserved memory. These results suggest that the presence of MCI in PD affects activity in the prefrontal cortex and caudate nucleus as well as motor-related regions.     

Changes in cognition

The clinical hallmark of Alzheimer's disease (AD) is a gradual decline in cognitive function. For the majority of patients the initial symptom is an impairment in episodic memory, i.e., the ability to learn and retain new information. This is followed by impairments in other cognitive domains (e.g., executive function, language, spatial ability). This impairment in episodic memory is evident among individuals with mild cognitive impairment (MCI) and can be used to predict likelihood of progression to dementia, particularly in association with AD biomarkers. Additionally, cognitively normal individuals who are likely to progress to mild impairment tend to perform more poorly on tests of episodic memory than do those who remain stable. This cognitive presentation is consistent with the pathology of AD, showing neuronal loss in medial temporal lobe structures essential for normal memory. Similarly, there are correlations between magnetic resonance imaging (MRI) measures of medial temporal lobe structures and memory performance among individuals with mild cognitive impairment. There are recent reports that amyloid accumulation may also be associated with memory performance in cognitively normal individuals.     

Self- and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints.

Amnestic mild cognitive impairment (MCI) is characterized by impaired episodic memory, although subtle executive problems have been noted on neuropsychological tests. Recent research also has described a group of healthy, non-depressed older adults with significant cognitive complaints (CC) but normal performance on neuropsychological testing. These individuals show structural and functional brain changes intermediate between those seen in MCI and healthy older adults without such complaints (HC). We evaluated executive functions in MCI and CC using the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A), a newly developed self- and informant report questionnaire in 29 patients with amnestic MCI, 28 CCs, and 30 demographically matched HCs. MCI and CC participants reported significant difficulties with selective aspects of executive functioning relative to HCs despite clinically normal performance on neuropsychological tests of this cognitive domain. Scores were generally in the pattern of MCI>CC>HC, and findings were most pronounced for working memory. Additionally, MCI and CC participants were more likely than their informants to report clinically meaningful executive problems, though informants identified a similar pattern of difficulty overall. Results failed to reveal strong relations between the BRIEF-A and standardized neuropsychological tests of executive function. Overall findings indicate that the BRIEF-A is sensitive to subtle executive changes in MCI and CC and suggest the need for research to determine if executive complaints are predictive of clinical course.     

Cholinergic system function and cognition in mild cognitive impairment

Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N-[(11)C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function.     

Variability in memory performance in aged healthy individuals: an fMRI study

Episodic memory performance varies in older subjects but underlying biological correlates remain as yet ambiguous. We investigated episodic memory in healthy older individuals (n=24; mean age: 64.4+/-6.7 years) without subjective memory complaints or objective cognitive impairment. Episodic memory was assessed with repetitive learning and recall of abstract geometric patterns during fMRI. Group analysis of brain activity during initial learning and maximum recall revealed hippocampal activation. Correlation analysis of brain activation and task performance demonstrated significant hippocampal activity during initial learning and maximum recall in a success-dependent manner. Neither age nor gray matter densities correlated with hippocampal activation. Functional imaging of episodic memory thus permits to detect objectively variability in hippocampal recruitment in healthy aged individuals without subjective memory complaints. Correlation analysis of brain activation and performance during an episodic memory task may be used to determine and follow-up hippocampal malfunction in a very sensitive manner.     

Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study

Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer's disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with ¹⁸Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.     

Reduced plasticity and mild cognitive impairment-like deficits after entorhinal lesions in hAPP/APOE4 mice

Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-ε3 (APOE3), the apolipoprotein E-ε4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.     

Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.     

Cognitive intervention for persons with mild cognitive impairment: A meta-analysis

Cognitive training for persons with mild cognitive impairment (MCI) has become a hot topic. However to date it remains controversial whether persons with MCI can really benefit from cognitive intervention. We aim to further investigate this by using meta-analysis of seventeen clinical studies of cognitive intervention for MCI. The results demonstrate that after training, patients with MCI improve significantly both in overall cognition and overall self-ratings. Specifically, persons with MCI obtain moderate benefits in language, self-rated anxiety and functional ability, and receive mild benefits in episodic memory, semantic memory, executive functioning/working memory, visuo-spatial ability, attention/processing speed, MMSE, self-rated memory problem, quality of life, activities of daily life and self-rated depression. The results also suggest that persons with MCI benefit from the cognitive intervention in the follow-up data. The present meta-analysis demonstrates that cognitive intervention can be a potential efficient method to enhance cognitive and functional abilities in persons with MCI, although the improvements may be domain-specific.     

Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats

Reduced levels of hippocampal acetylcholine are a common finding in patients diagnosed with Alzheimer’s disease, but it remains unclear what role this depletion plays in the development of dementia. It is possible that the reduced levels of acetylcholine increases the vulnerability of hippocampal neurons to future insults which could lead to neuronal death and cognitive impairment. One insult that is commonly observed in the demented elderly and often co-exists with Alzheimer’s disease is stroke. In the current experiment, we used the immunotoxin 192 IgG-Saporin to specifically lesion the cholinergic neurons of the medial septum that project to the hippocampus. We then explored the effects of small, localised strokes in the hippocampus on spatial learning and memory. The combination of cholinergic depletion and stroke resulted in significant impairment on the spatial water maze compared to the performance of rats receiving either factor alone. Quantification of hippocampal damage revealed no difference in the overall lesion size of stroke-only or combined (cholinergic depletion and stroke) rats, suggesting that a more subtle mechanism is responsible for the observed impairment. We propose that healthy hippocampal neurons may normally be able to withstand, and compensate for a small ischemic insult. However, in the absence of cholinergic projections from the medial septum, these compensatory processes in the hippocampus may be compromised resulting in the spatial learning impairment reported here. This suggests an association between the cholinergic depletion observed during aging and the potential for functional recovery following stroke.     

Role of androgens in mild cognitive impairment and possible interventions during andropause

Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like PET scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.     

Amnestic mild cognitive impairment: difference of memory profile in subjects who converted or did not convert to Alzheimer's disease

Episodic long-term, short-term, and implicit memory were investigated in 79 elderly subjects who fulfilled criteria for the amnestic form of mild cognitive impairment (a-MCI; i.e., by having an idiopathic amnestic disorder with absence of impairment in cognitive areas other than memory and without confounding medical or psychiatric conditions) and who developed Alzheimer's disease (AD) after 2 years as well as in 111 subjects affected by a-MCI who did not develop dementia. Results document a memory profile in a-MCI subjects characterized by preserved short-term and implicit memory and extensive impairment of episodic long-term memory. In virtually all episodic memory indexes examined (learning, forgetting, recognition abilities), a-MCI subjects who converted to AD were more severely impaired than were subjects who did not become demented. This memory profile, which closely resembles that exhibited by amnestic patients with bilateral mesial-temporal lobe lesions, confirms a precocious phase in preclinical AD characterized by selective involvement of mesial-temporal areas and worsening of the memory impairment as atrophic changes progress in hippocampal structures. In this context of pervasive episodic memory impairment, tests assessing the free recall of verbal material following a delay interval demonstrated the greater sensitivity to memory deficits of a-MCI subjects who developed AD.     

Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests

BACKGROUND: Early detection of cognitive decline in the elderly is important because this may precede progression to Alzheimer's disease. The aim of this study was to see whether sensitive neuropsychological tests could identify pre-clinical cognitive deficits and to characterize the cognitive profile of a subgroup with poor memory. METHODS: A neuropsychological test battery was administered to a community-dwelling sample of 155 elderly volunteers who were screened with CAMCOG at enrolment (mean age 74.7 years). The battery included tests of episodic memory. semantic and working memory, language and processing speed. RESULTS: Episodic memory test z scores below 1 S.D. from the cohort mean identified 25 subjects with non-robust' memory performance. This group was compared to the remaining 'robust memory' group with a General Linear Model controlling for age, IQ, education and gender. Test performance was significantly different in all tests for episodic and semantic memory, but not in tests for working memory, processing speed and language. CANTAB paired associates learning and spatial recognition tests identified the highest percentages of those in the 'non-robust memory group. Processing speed partialled out the age effect on memory performance for the whole cohort, but the 'non-robust memory' group's performance was not associated with age or processing speed. CONCLUSIONS: Sensitive neuropsychological tests can detect performance below the norm in elderly people whose performance on MMSE and CAMCOG tests is well within the normal range. Age-related decline in memory performance in a cohort of the elderly may be largely due to inclusion within the cohort of individuals with undetected pre-clinical Alzheimer's disease or isolated memory impairment.     

Role of androgens in mild cognitive impairment and possible interventions during andropause

Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like positron emission tomography (PET) scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.     

Cholinergic modulation of a specific memory function of prefrontal cortex

Deficits in prefrontal cholinergic function are implicated in cognitive impairment in many neuropsychiatric diseases, but acetylcholine's specific role remains elusive. Rhesus monkeys with selective lesions of cholinergic input to prefrontal cortex (PFC) were unimpaired in tests of decision making and episodic memory that require intact PFC, but were severely impaired on a spatial working memory task. These observations are consistent with a specific role for prefrontal acetylcholine in working memory.