The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment

Subjects in the preclinical stages of Alzheimer's disease (AD) typically record neuropsychological performance between that of healthy older individuals and demented patients. More specifically, deficits on measures of verbal episodic memory are commonly reported in these patients, while other cognitive functions (e.g. language, praxis and executive function) seem to be spared. A similar neuropsychological profile is observed in elderly subjects with mild cognitive impairment (MCI), a disorder that is attracting increasing research interest. Evidence from lesion and functional imaging studies, as well as volumetric imaging in probable AD and MCI patients, suggests that the cognitive deficits observed in these disorders may be related to medial temporal lobe dysfunction. An issue currently under investigation is whether MCI represents the preclinical stages of AD or a distinct and static cognitive aetiology. In an attempt to address this issue, present investigations are adopting a convergent approach to the detection of preclinical AD, where multiple risk factors are considered when making a diagnosis.     

Mild cognitive impairment: a cross-national comparison

OBJECTIVE: The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). METHODS: Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. RESULTS: When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. CONCLUSIONS: Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.     

Hippocampal morphology and autobiographic memory in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.     

Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors

BACKGROUND: Individuals who have Mild Cognitive Impairment (MCI) may be in a transitional stage between aging and Alzheimer's disease (AD). The high rate of conversion from MCI to AD makes early treatment an important clinical issue. Recent evidence suggests that cognitive training intervention may reduce the rate of progression to AD. OBJECTIVES: To evaluate the efficacy of a NeuroPsychological Training (TNP) in patients with MCI who are treated with cholinesterase inhibitors (ChEIs), compared with patients MCI treated only with ChEIs and patients not treated, in a longitudinal, one year follow-up study. METHODS: One year longitudinal and retrospective comparison study of neuropsychological performances in 59 subjects affected by Mild Cognitive Impairment (MCI) according to Petersen's criteria. Fifteen subjects were randomised to receive TNP plus cholinesterase inhibitors; 22 subjects cholinesterase inhibitors alone and 22 subjects no treatment. All the subjects referring memory complaints, corroborated by an informant, underwent a multidimensional assessment concerning neuropsychological, behavioural and functional characteristics, at baseline and after one year follow-up. RESULTS: Subjects without treatment maintained their cognitive, functional and behavioural status after one year; patients treated only with ChEIs improved in depressive symptoms whereas subjects treated with TNP and ChEIs showed significant improvements in different cognitive areas, such as memory, abstract reasoning and in behavioural disturbances, particularly depressive symptoms. CONCLUSIONS: A long-term TNP in ChEIs-treated MCI subjects induces additional cognitive and mood benefits.     

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid‐rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI‐MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior–posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression. J. Comp. Neurol. 521:4300–4317, 2013. © 2013 Wiley Periodicals, Inc.     

Strukturelle zerebrale Veränderungen bei Probanden mit leichter kognitiver Beeinträchtigung Eine MR-volumetrische Studie

The aim of the present study was to investigate the morphological changes in subjects with mild cognitive impairment (MCI) revealed by quantitative magnetic resonance imaging (MRI). Twenty-one subjects with cognitive impairment and 22 healthy controls were compared with 12 patients suffering from mild Alzheimer's disease (AD). The volumes of the following brain structures were assessed: total intracranial compartment, cerebrospinal fluid compartment, whole brain, and medial temporal substructures (hippocampus and parahippocampal gyrus). Subjects with mild cognitive impairment showed a significantly reduced volume of the right parahippocampal gyrus over healthy controls. Volumes of the other regions and structures did not differ between the MCI group and controls. The volumetric and neuropsychological findings of the present study support the hypothesis that mild cognitive impairment - at least in some of the affected individuals - can be seen as a preclinical stage of AD and that atrophy of the parahippocampal gyrus might be useful as an early marker of AD.     

Neuropsychological markers of progression from mild cognitive impairment to Alzheimer's disease

To find early clinical markers that may predict a likely progression to Alzheimer's disease (AD), the authors performed neuropsychological tests on 82 mild cognitive impairment (MCI) subjects. After 3 years, 38 patients developed AD while 44 retained the diagnosis of MCI. The cognitive differences between the groups were studied. Patients who developed AD showed significantly lower values than did MCI subjects in some neuropsychological scores (P = .02-.001), with sensitivities and specificities higher than 84% and 64%, respectively, for detecting early-onset AD, with a 7.9-fold increased risk of converting to AD (P < .001). Regarding the logistic regression model, the CAMCOG Memory and Perception cognitive screening items were the optimum independent tools to classify the patients who will progress to AD, showing a relative risk of progression of 10.5 (P = .002), 5.5 (P = .008), and 3.9 times (P = .05), respectively, with a sensibility of of 92.1% and a specificity 72.7%.     

The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: a volumetric MRI study

The fornix and mammillary bodies are important limbic structures that have not been systematically investigated in the earliest stages of preclinical dementia. The present study examined volumetric changes in the fornix and mammillary bodies and improved previously established tracing guidelines to increase reliability and provide more comprehensive measurements. Volumetric measurements were made in euthymic older adults, including 16 patients with mild Alzheimer's disease (AD), 20 patients with amnestic mild cognitive impairment (MCI), 20 individuals with cognitive complaints (CC) but normal neuropsychological test performance, and 20 demographically matched healthy controls (HC). Structural magnetic resonance imaging included a T1-weighted 1.5-mm coronal volume, acquired on a GE 1.5T LX scanner. After adjustment for total intracranial volume (ICV), significant volume reductions were observed in the fornix and mammillary bodies in patients with AD as compared with HC, CC, and MCI participants. No volume differences were seen between the HC, CC, and MCI groups. Study findings are consistent with previous research showing volume decreases of the fornix and mammillary bodies in AD, and provide new data on the relative preservation of these structures in preclinical disease stages. Results suggest that atrophy of the fornix and mammillary bodies becomes apparent at the point of conversion from MCI to AD. Longitudinal assessments are needed to delineate the time course and extent of the observed volumetric changes.     

A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer's disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer's disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man's diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.     

A decade of pre-diagnostic assessment in a case of familial Alzheimer’s disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer’s disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer’s disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man’s diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.