Massimo Franceschi

White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimers disease using diffusion tensor magnetic resonance imaging (DT-MRI). Background: Although Alzheimers disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimers disease associated white matter damage is still unclear. Methods: Conventional and DT-MRI scans were obtained from16 patients with Alzheimers disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D̅), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured. Results: D̅ was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimers disease than in the corresponding regions from healthy controls. D̅ and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D̅ (r=0.92, p<0.001) and FA (r=0.78; p<0.001). Conclusions: White matter changes in patients with Alzheimers disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET.

Objectives: To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Method: After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4−] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons. Results: All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4− patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination. Conclusion: Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype.

EEG coherence in Alzheimer's disease

EEG coherence can be used to evaluate the functionality of cortical connections and to get information about the synchronization of the regional cortical activity. We studied EEG coherence in patients affected by clinically probable Alzheimers disease (AD) in order to quantify the modifications in the cortico-cortical or cortico-subcortical connections. The EEGs were recorded in 10 AD patients (with mild or moderate degrees of dementia) and in 10 normal age-matched subjects, at rest and eye-closed, from 16 electrodes with linked-ears reference. Spectral parameters and coherence were calculated by a multichannel autoregressive model using 50 artifact-free epochs, 1 s duration each. Alpha coherence was significantly decreased in 6 patients, the decrease being more accentuated in the area near the electrode taken into account; a significant delta coherence increase was found in a few patients between frontal and posterior regions. The AD group showed a significant decrease of alpha band coherence, in particular in temporo-parieto-occipital areas, more evident in patients with a more severe cognitive impairment. These abnormalities could reflect two different pathophysiological changes: the alpha coherence decrease could be related to alterations in cortico-cortical connections, whereas the delta coherence increase could be related to the lack of influence of subcortical cholinergic structures on cortical electrical activity.

A PET Follow-up Study of Recovery after Stroke in Acute Aphasics ☆

The neural correlates of recovery from aphasia are largely unknown. Several different sources of evidence, from clinical studies to neurophysiological investigations, have suggested a contribution of the contralateral, undamaged hemisphere in recovery from aphasia. Eight patients with unilateral left hemispheric stroke were submitted to a standard language examination and to a [18F]FDG PET study in the recent phase after stroke (within 2 weeks) and 6 months later. All patients had a substantial recovery of specific aspects of language functions at the follow-up. Analysis of regional glucose metabolism showed hypometabolism in structurally unaffected regions both in the left and in the right hemisphere (diaschisis), in the acute stage. Glucose metabolism increased significantly on both sides in all patients at the second PET study. Regional analysis showed significant positive correlations between changes in metabolic values in several cortical and subcortical regions in the right hemisphere and changes in language performance at follow-up. The present findings show that an extensive, bihemispheric depression of metabolism is found in the acute stage after stroke in aphasic patients. Language recovery in the first months after aphasia onset is associated with regression of functional depression (diaschisis) in structurally unaffected regions, in particular in the right hemisphere.

Quantification of tissue damage in AD using diffusion tensor and magnetization transfer MRI

The authors measured mean diffusivity (D̄) and magnetization transfer ratio (MTR) of the brain from 18 patients with AD and 16 healthy control subjects. The peak heights of cortical gray matter (cGM) D̄ (p < 0.001) and MTR (p < 0.001) histograms were lower and average cGM D̄ (p < 0.01) higher in patients with AD than in control subjects. A composite MR score based on brain volume and cGM MTR peak height was correlated with patient cognitive impairment (r = 0.65, p = 0.003). This preliminary study presents a novel approach to quantify AD-related tissue damage in-vivo.

The contribution of voxel-based morphometry in staging patients with mild cognitive impairment

Objective: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). Methods: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). Results: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. Conclusions: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

Metabolic Impairment in Human Amnesia: A PET Study of Memory Networks

Human amnesia is a clinical syndrome exhibiting the failure to recall past events and to learn new information. Its “pure” form, characterized by a selective impairment of long-term memory without any disorder of general intelligence or other cognitive functions, has been associated with lesions localized within Papezs circuit and some connected areas. Thus, amnesia could be due to a functional disconnection between components of this or other neural structures involved in long-term learning and retention. To test this hypothesis, we measured regional cerebral metabolism with 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and positron emission tomography (PET) in 11 patients with “pure” amnesia. A significant bilateral reduction in metabolism in a number of interconnected cerebral regions (hippocampal formation, thalamus, cingulate gyrus, and frontal basal cortex) was found in the amnesic patients in comparison with normal controls. The metabolic impairment did not correspond to alterations in structural anatomy as assessed by magnetic resonance imaging (MRI). These results are the first in vivo evidence for the role of a functional network as a basis of human memory.

Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration

In patients with the frontal variant of frontotemporal lobar degeneration (fv‐FTLD), behavioral abnormalities may vary from apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form). These clinical presentations may be related to specific regional cerebral dysfunction and to deficit in the serotoninergic system. We studied cerebral glucose uptake using 18F‐fluorodeoxyglucose and positron emission tomography in 18 patients fulfilling clinical criteria for fv‐FTLD and showing, respectively, an apathetic or disinhibited behavioral syndrome. In eight of these patients, we also evaluated the 5‐hydroxytryptamine‐2A receptor cerebral receptor distribution with [11C]MDL and positron emission tomography. We found a reduction of frontal glucose metabolism in the whole group of fv‐FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). The in vivo measurements of [11C]MDL indicated a significant reduction of 5‐hydroxytryptamine‐2A receptors in orbitofrontal, frontal medial, and cingulate cortices. These 18F‐fluorodeoxyglucose positron emission tomography changes can be considered as specific functional markers of the different behavioral presentations in fv‐FTLD. The serotoninergic system dysfunction provides a rationale for therapeutic trials with selective serotonin reuptake inhibitors. Ann Neurol 2005;57:216–225

Protein misfolding in Alzheimer's and Parkinson's disease: Genetics and molecular mechanisms

The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimers disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinsons disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding.

Cognitive Processes in Insulin-dependent Diabetes

Cognitive processes in a group of neurologically asymptomatic patients with relativelysevere but uncomplicated insulin-dependent diabetes mellitus (IDDM) were studied. In comparison with a homogeneous group of normoglycemic controls, the diabetic group performed significantly worse in global memory, abstract reasoning, and eye-hand coordination tests. The two groups scored similarly in intelligence, concentration and attention, spatial, visual, and psychomotor tests. The neuropsychological deficits did not correlate with the duration or the severity of the disease. Whether these mild neuropsychological deficits are transient or stable or whether they are caused by central nervous system vascular or metabolic dysfunctions or by the emotional influence of the chronic illness on the intellectual and educational development of patients remains unclear. Our findings need to be cautiously interpreted and perhaps could not be extended to diabetic patients with better metabolic control.