Volumetric differences in mapped hippocampal regions correlate with increase of high alpha rhythm in Alzheimer's disease.

Objective. The increase of high alpha relative to low alpha power has been recently demonstrated as a reliable EEG marker of hippocampal atrophy conversion of patients with mild cognitive impairment (MCI) in Alzheimer's disease (AD). In the present study we test the reliability of this EEG index in subjects with AD. Methods. Correlation between EEG markers and volumetric differences in mapped hippocampal regions was estimated in AD patients. Results. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of mapped hippocampal regions in Alzheimer's disease. Conclusions. The findings confirm the possible diagnostic role of EEG markers.

MCI patients' EEGs show group differences between those who progress and those who do not progress to AD.

The theta/gamma and alpha3/alpha2 ratio were investigated as early markers for prognosticating of progression to dementia. 76 subjects with mild cognitive impairment (MCI) underwent EEG recording, MRI scans and neuropsychological (NPS) tests. After 3 years of follow-up, three subgroups were characterized as converters to Alzheimer's disease (AD, N=18), converters to non-AD dementia (N=14) and non-converters (N=44). The theta/gamma and alpha3/alpha2 ratio, performance on cognitive tests and hippocampal volume, as evaluated at the time of initial MCI diagnosis, were studied in the three groups. As expected, MCI to AD converters had the smallest mean hippocampal volume and poorest performance on verbal learning tests, whereas MCI to non-AD converters had poorest cognitive performance in non-verbal learning tests, abstract thinking, and letter fluency. Increased theta/gamma ratio was associated with conversion to both AD and non-AD dementia; increased alpha3/alpha2 ratio was only associated with conversion to AD. Theta/gamma and alpha3/alpha2 ratio could be promising prognostic markers in MCI patients. In particular, the increase of high alpha frequency seems to be associated with conversion in AD. EEG markers allow a mean correct percentage of correct classification up to 88.3%. Future prospective studies are needed to evaluate the sensitivity and specificity of these measures for predicting an AD outcome.

The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment.

To test the validity of the new diagnostic criteria for Alzheimer's disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren's cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz's t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70-0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.

Metabolic compensation and depression in Alzheimer's disease.

BACKGROUND/AIMS: The aim of this study was to map metabolic compensation and depression in Alzheimer's disease (AD) on a voxel-by-voxel basis. METHODS: Twenty-one healthy elderly subjects and 25 AD patients underwent cerebral MR and FDG-PET imaging. All images were processed with SPM2, and whole-brain gray matter (GM) atrophy and hypometabolism maps were computed. Metabolic compensation and depression were assessed using Biological Parametric Mapping software. RESULTS: GM atrophy and hypometabolism mapped to similar regions, with varying degrees of severity. Significant metabolic compensation was found in the amygdala, while exceeding hypometabolism was mainly located in the posterior cingulate cortex. CONCLUSION: Metabolic depression can be due to both distant effects of atrophy and to additional hypometabolism-inducing factors, such as amyloid deposition. Conversely, metabolic compensation could reflect spared synaptic plasticity of the surviving neurons. The investigation of the metabolic compensation mechanism could help in the comprehension of the AD underlying pathology.

EEG markers discriminate among different subgroup of patients with mild cognitive impairment.

Aim of the study is to discriminate among participants with mild cognitive impairment through electroencephalography brain rhythms. A total of 79 participants with MCI were classified into 4 subgroups based on the beginning of memory complaints up to the time of first visit. All participants underwent electroencephalography recording, magnetic resonance imaging, apolipoprotein E characterization, and volumetric morphometry estimation of hippocampal region. Electroencephalography markers show 2 distinct patterns: (1) increase of theta/ delta power ratio and highest value of alpha2 band power in the group with shorter duration of disease, the greater right-left hippocampal volume difference and worst memory performance; (2) the highest value of alpha3 band power and the highest alpha3/alpha2 power ratio in the group with the lesser total hippocampal volume but preserved memory performance. Apolipoprotein E4 is linked to a major risk of early beginning of disease. Electroencephalography markers allow a mean correct percentage of correct classification up to 89%.

Functional compensation in incipient Alzheimer's disease.

Aim of this study was to investigate the functional compensation mechanism in incipient Alzheimer's disease (AD). Seventeen elderly healthy subjects and nine amnestic MCI patients with incipient AD underwent brain MR scan and 99mTc ECD SPECT. We processed all images with SPM2, we created t maps, showing the wholebrain GM atrophy and functional changes, and we properly masked them with each other in order to assess relatively preserved perfusion or depression. Incipient AD showed GM atrophy in the medial temporal and temporoparietal lobes, in the insula and in the retrosplenial cortex, and GM hypoperfusion in the medial temporal and temporoparietal lobes. Relatively preserved perfusion, we could hypothesize to be compensatory in the setting of neuronal loss, was found in the posterior cingulate, in the head of the hippocampus, in the amigdala, and in the insula bilaterally, while functional depression occurred in bilateral parahippocampal gyri. In AD, a perfusional compensatory mechanism takes place in the neocortex, while perfusional depression occurs in the medial temporal lobe. These results help understand the reactive phenomena induced by the brain to try and counteract the pathological changes of AD.

Increase of theta/gamma ratio is associated with memory impairment.

OBJECTIVE: In this study the theta/gamma ratio was investigated as early marker of cognitive decline. METHODS: Forty-nine subjects with mild cognitive impairment (MCI) underwent EEG recording and MRI scan. The theta/gamma ratio of the relative power at the peak frequency was computed. Based on the tertiles values of the ratio, three groups with increasing values of theta/gamma ratio were obtained. The groups were characterized by the performance on cognitive tests. Changes in functional brain connectivity, as expressed by interhemisperic and intrahemispheric EEG linear coherence in the groups were also evaluated. RESULTS: Increase in theta/gamma ratio was associated with impairment in memory tests. This relationship was confirmed by correlation and multiple regression analysis. An independent association was found between theta/gamma ratio and alpha3/alpha2 power ratio. Coherence analysis showed modifications of interhemispheric functional coupling on temporal regions on slow frequencies. CONCLUSIONS: Theta/gamma ratio of relative power at peak frequency is significantly associated to memory decline. It could be a useful tool in detecting MCI subjects which are at major risk to develop Alzheimer's disease (AD) or other dementias. SIGNIFICANCE: A global modulation of brain rhythms could be driven by the pathological alterations of theta/gamma ratio.

MRI-based automated computer classification of probable AD versus normal controls.

Automated computer classification (ACC) techniques are needed to facilitate physician's diagnosis of complex diseases in individual patients. We provide an example of ACC using computational techniques within the context of cross-sectional analysis of magnetic resonance images (MRI) in neurodegenerative diseases, namely Alzheimer's dementia (AD). In this paper, the accuracy of our ACC methodology is assessed when presented with real life, imperfect data, i.e., cohorts of MRI with varying acquisition parameters and imaging quality. The comparative methodology uses the Jacobian determinants derived from dense deformation fields and scaled grey-level intensity from a selected volume of interest centered on the medial temporal lobe. The ACC performance is assessed in a series of leave-one-out experiments aimed at separating 75 probable AD and 75 age-matched normal controls. The resulting accuracy is 92% using a support vector machine classifier based on least squares optimization. Finally, it is shown in the Appendix that determinants and scaled grey-level intensity are appreciably more robust to varying parameters in validation studies using simulated data, when compared to raw intensities or grey/white matter volumes. The ability of cross-sectional MRI at detecting probable AD with high accuracy could have profound implications in the management of suspected AD candidates.

Serum leptin levels are higher in females affected by frontotemporal lobar degeneration than Alzheimer's disease.

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.

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 (99m)Tc 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.

Hippocampal atrophy and EEG markers in subjects with mild cognitive impairment.

OBJECTIVE: The present study evaluates the potential relationship between hippocampal atrophy and EEG brain rhythmicity, as assessed by relative band power and alpha frequency indices in a cohort of subjects with mild cognitive impairment (MCI). METHODS: Eighty-eight subjects falling within the definition of MCI patients were enrolled. All subjects underwent EEG recording and magnetic resonance imaging (MRI). Volumetric morphometry estimates of the hippocampal region were computed. Individual EEG frequencies were indexed by the theta/alpha transition frequency (TF) and the individual alpha frequency (IAF). The relative power was separately computed for delta, theta, alpha1, alpha2 and alpha3 frequency bands. The MCI cohort was classified into four subgroups, based on the mean and standard deviations of the hippocampal volume of a normal elderly control sample. RESULTS: The group with moderate hippocampal atrophy showed the highest increase in the theta power on frontal regions, and of the alpha2 and alpha3 powers on frontal and temporo-parietal areas. The analysis of the individual alpha frequency markers showed that the values for the alpha markers were highest in the group with the smallest hippocampal volume, whereas in the group with moderate hippocampal atrophy, these values were lower than in the group with severe atrophy. CONCLUSIONS: The relationship between hippocampal atrophy and EEG activity changes in MCI subjects is not proportional to the hippocampal atrophy. Therefore, EEG markers could represent a new tool for differential diagnosis. SIGNIFICANCE: The hippocampal atrophy induces different brain synchronization/desynchronization patterns. EEG changes model the brain activity induced by a discrete change of the hippocampal volume. The changes in the EEG rhythmicity differ greatly from those in MCI patients with subcortical vascular damage.

Vascular damage and EEG markers in subjects with mild cognitive impairment.

OBJECTIVE: We evaluated the changes induced by cerebrovascular (CV) damage on brain rhythmicity recorded by electroencephalography (EEG) in a cohort of subjects with mild cognitive impairment (MCI). METHODS: We enrolled 99 MCI subjects (Mini-Mental State Examination [MMSE] mean score 26.6). All subjects underwent EEG recording and magnetic resonance imaging (MRI). EEGs were recorded at rest. Individual EEG frequencies were indexed by the theta/alpha transition frequency (TF) and by the individual alpha frequency (IAF) with power peak in the extended alpha range (5-14 Hz). Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands on the basis of the TF and IAF values. Subsequently, we divided the cohort in four sub-groups based on subcortical CV damage as scored by the age-related white matter changes scale (ARWMC). RESULTS: CV damage was associated with 'slowing' of TF proportional to its severity. In the spectral bandpower the severity of vascular damage was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with IAF and alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. CONCLUSIONS: EEG analysis may show physiological markers sensitive to CV damage. The appropriate use of this EEG index may help the differential diagnosis of different forms of cognitive decline, namely primary degenerative and secondary to CV damage. SIGNIFICANCE: The EEG neurophysiological approach, together with anatomical features from imaging, could be helpful in the understanding of the functional substrate of dementing disorders.

The Frontal Behavioural Inventory (Italian version) differentiates frontotemporal lobar degeneration variants from Alzheimer's disease.

The objective was to evaluate the construct validity of the Italian version of the Frontal Behavioural Inventory (FBI) and its usefulness in the differential diagnosis of dementias. Standard criteria were used in the clinical diagnosis of dementias in 83 patients and 33 agematched healthy volunteers. The FBI scale was translated from English into Italian language and back-translated. Cronbach's alpha, inter-rater and test-retest reliability, FBI convergent validity and discriminant analysis were calculated. FBI profile was compared between patients affected by frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). The FBI showed a high internal consistency and inter-rater reliability and it distinguished normal behavioural conditions from those presented in FTLD or AD. An 86.8% diagnostic accuracy was calculated by the discriminant analysis, selecting only age at disease onset and FBI, and particularly distinguishing behavioural variants within the FTLD spectrum. FTLD patients showed a characteristic behavioural profile. The FBI might be a reliable and useful diagnostic tool for dementias in clinical practice.

Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment.

BACKGROUND: The diagnosis of mild cognitive impairment (MCI) is clinically unhelpful, as many patients with MCI develop dementia but many do not. OBJECTIVE: To identify clinical instruments easily applicable in the clinical routine that might be useful to predict progression to dementia in patients with MCI assessed in the outpatient facility of a memory clinic. PARTICIPANTS AND METHODS: 52 dementia-free patients (mean (standard deviation) age 70 (6) years; 56% women) with MCI, and 65 healthy controls (age 69 (6) years; 54% women) underwent brain magnetic resonance scan with standardised visual assessment of medial temporal atrophy (MTA) and subcortical cerebrovascular lesions (SVLs). Follow-up assessment occurred 15.4 (SD 3.4) months after baseline to detect incident dementia and improvement, defined as normal neuropsychological performance on follow-up. RESULTS: Patients were classified into three groups according to the presence of memory disturbance only (MCI Mem), other neuropsychological deficits (MCI Oth) or both (MCI Mem+). MCI Mem and Mem+ showed MTA more frequently (31% and 47% v 5% and 14% of controls and MCI Oth, p<0.001). 11 patients developed dementia (annual rate 16.5%) and 7 improved on follow-up. The only independent predictor of progression was MTA (odds ratio (OR) 7.1, 95% confidence interval (CI) 1.4 to 35.0), whereas predictors of improvement were the absence of memory impairment (OR 18.5, 95% CI 2.0 to 171.3) and normal MRI scan (OR 10.0, 95% CI 1.7 to 60.2). CONCLUSION: Neuropsychological patterns identify groups of patients with MCI showing specific clinical features and risk of progression to dementia. MTA clinically rated with a visual scale is the most relevant predictor of progression and improvement.

Predicting clinical variable from MRI features: application to MMSE in MCI.

The ability to predict a clinical variable from automated analysis of single, cross-sectional T1-weighted (T1w) MR scans stands to improve the management of patients with neurological diseases. We present a methodology for predicting yearly Mini-Mental Score Examination (MMSE) changes in Mild Cognitive Impairment (MCI) patients. We begin by generating a non-pathological, multidimensional reference space from a group of 152 healthy volunteers by Principal Component Analyses of (i) T1w MR intensity of linearly registered Volumes of Interest (VOI); and (ii) trace of the deformation fields of nonlinearly registered VOIs. We use multiple regression to build linear models from eigenvectors where the projection eigencoordinates of patient data in the reference space are highly correlated with the clinical variable of interest. In our cohort of 47 MCI patients, composed of 16 decliners, 26 stable and 5 improvers (based on MMSE at 1 yr follow-up), there was a significant difference (P = 0.0003) for baseline MMSE scores between decliners and improvers, but no other differences based on age or sex. First, we classified our three groups using leave-one-out, forward stepwise linear discriminant analyses of the projection eigencoordinates with 100% accuracy. Next, we compared various linear models by computing F-statistics on the residuals of predicted vs actual values. The best model was based on 10 eigenvectors + baseline MMSE, with predicted yearly changes highly correlated (r = 0.6955) with actual data. Prospective study of an independent cohort of patients is the next logical step towards establishing this promising technique for clinical use.

An electronic memory aid to support prospective memory in patients in the early stages of Alzheimer's disease: a pilot study.

The use of an electronic memory aid (EMA) for patients with mild-to-moderate probable Alzheimer disease is examined in five outpatients aged 58-79 years. The ability to remember to carry out seven tasks at a particular time was evaluated in three experimental conditions: recall without an external memory aid, recall with a written list and recall with support available from an EMA. The use of an EMA significantly improved patients' prospective memory, while the written list and free recall were not useful. Future research that examines the value of using an EMA to help with tasks that are associated with prospective memory with a larger sample of patients within their own home context is suggested.

Amygdaloid atrophy in frontotemporal dementia and Alzheimer's disease.

Crude and corrected amygdaloid volumes were computed from magnetic resonance scans in ten patients with frontotemporal dementia (FTD), 25 patients with Alzheimer's disease (AD) and 27 controls. Amygdaloid atrophy was present in FTD (P<0.005) compared to controls, and a trend for increasing atrophy from controls, through FTD to AD (P for trend <0.00005) showed that FTD amygdaloid volumes were intermediate between controls and AD. Behavioral and Klüver-Bucy-like symptoms, characteristic of FTD, cannot be explained by amygdaloid atrophy alone.

Reality orientation therapy to delay outcomes of progression in patients with dementia. A retrospective study.

OBJECTIVE: To evaluate the impact of continued Reality Orientation Therapy (ROT) in delaying the outcomes of dementia progression. DESIGN: Retrospective study. Data collection was based on review of clinical charts and on telephone interviews performed with patients or primary caregivers. SETTING: Day hospital of the Alzheimer's Disease Unit, Brescia (Italy). SUBJECTS: Seventy-four patients enrolled in at least one cycle of ROT from 1994 to 1998 were studied. INTERVENTIONS: Rehabilitative intervention based on formal ROT. MAIN OUTCOME MEASURES: This study analysed the time to the occurrence of any of the following: cognitive decline on Mini-Mental State Examination scores, urinary incontinence as an index of functional decline, institutionalization, and death. RESULTS: Data on a 30-month period after the first ROT session were analysed. We compared 46 patients (treatment group) who completed from 2 to 10 ROT cycles (corresponding to 8-40 weeks of training; mean = 15.48) with 28 patients (control group) who completed only one ROT cycle (4 weeks). Treatment group showed higher estimated survival rates than control group on cognitive decline (p = 0.022) and institutionalization (p = 0.002). The relative risks for cognitive decline and institutionalization in the control group compared with treatment group were 0.60 (p = 0.014), and 0.42 (p = 0.021), respectively. CONCLUSIONS: Continued ROT classes during the early to middle stages of dementia may delay nursing home placement and slow down the progression of cognitive decline.

Analysis of alpha-2-macroglobulin-2 allele as a risk factor in Alzheimer's disease.

A correlation between a 5-nucleotide deletion polymorphism in the A2M gene and an enhanced risk of developing Alzheimer's disease (AD) was reported. We studied this polymorphism in sporadic AD patients and patients with frontotemporal dementia (FTD) by using an electrophoretical separation of PCR products on a Metaphor gel. Our results did not show any significant difference between A2M-2 allelic frequency (p = 0.89) or genotype frequency (p = 0.97) in the two different clinical series and in control subjects. The frequencies were not significantly different after stratification by APOE epsilon4 status.