Barbara Paghera

Combined 99mTc-ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD

Identifying pre-clinical Alzheimers disease (AD) in subjects with mild cognitive impairment (MCI) is a major issue in clinical diagnosis. Establishing a combination of predictive markers from different fields of research might help in increasing the diagnostic accuracy. Aim of this study was to evaluate the potential role of 99mTc-ECD single photon emission computed tomography (SPECT) and memory scores in predicting conversion to AD in MCI subjects. Thirty-one MCI subjects underwent a clinical and neuropsychological examination, and a regional cerebral blood flow (rCBF) SPECT scan at baseline. Subjects had been followed periodically through 2 years in order to monitor the progression of cognitive symptoms. Canonical variate analysis of principal components was able to separate all subjects who converted to AD from those who remained stable, the former being characterized by a specific hypometabolic pattern, involving the parietal and temporal lobes, precuneus, and posterior cingulate cortex. Canonical correlation analysis of combined baseline memory deficits and rCBF SPECT images identified pre-clinical AD with a sensitivity and specificity of 77.8%. The pattern of hypoperfusion 99mTc-ECD SPECT and the severity of memory deficits predict the risk of progression to probable AD dementia in MCI subjects.

Adult crossed aphasia in dextrals revisited.

The clinical study of crossed aphasia in dextrals (CAD) may shed light on the discreteness and modularity of several cognitive functions, such as language, gestures and visual spatial abilities, with respect to hemispheric lateralisation. Since 1975 over 180 cases have been described, employing, however, different criteria of assessment and classification. The purpose of this paper is to review them and to propose a set of diagnostic criteria that may be useful to single out a series of reliable CAD cases on which research can be safely carried out. A detailed analysis of such series is dealt with in terms of a number of characteristics concerning both the language disorder and the associated nonverbal cognitive impairments.

Markers of Alzheimer's disease in a population attending a memory clinic.

New marker‐based criteria for the diagnosis of Alzheimers disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic.

The FTLD-modified Clinical Dementia Rating scale is a reliable tool for defining disease severity in Frontotemporal Lobar Degeneration: evidence from a brain SPECT study

Background:  Frontotemporal Lobar Degeneration (FTLD) is a heterogeneous disorder characterized by impairment in executive functions, behavioural disturbance and language deficit. Reliable scales of global impairment are under evaluation. A consortium of Mayo Clinic and University of California FTLD Centers has recently developed the FTLD‐modified Clinical Dementia Rating (CDR) scale to assess FTLD severity.

Assessment of the incremental diagnostic value of florbetapir F 18 imaging in patients with cognitive impairment: The incremental diagnostic value of amyloid PET with [18F]-florbetapir (INDIA-FBP) study

Importance Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. Objective To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. Design, Setting, and Participants The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. Main Outcomes and Measures Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. Results Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). Conclusions and Relevance Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Pre–clinical diagnosis of Alzheimer disease combining platelet amyloid precursor protein ratio and rCBF spect analysis

AbstractPlatelet Amyloid Precursor Protein ratio of different abnormal forms and 99mTc–ECD SPECT perfusion analysis were evaluated in Mild Cognitive Impairment (MCI) subjects who progressed to Alzheimer Disease (AD) and in stable MCI. We report that their combined evaluation increases the discriminative power of the analysis in identifying presymptomatic AD. The positive predictive value of these combined markers in identifying progressive MCI was 0.87, and the negative predictive value was 0.90. This observation suggests that the interplay of different markers should be considered for enhancing diagnostic accuracy of pre–clinical AD.

The Speech and Language FOXP2 Gene Modulates the Phenotype of Frontotemporal Lobar Degeneration

The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping (SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.

CSF Alzheimer's disease-like pattern in corticobasal syndrome: evidence for a distinct disorder

Background Corticobasal syndrome (CBS) has a heterogeneous neuropathological spectrum, ranging from the classical corticobasal degeneration to Alzheimers disease (AD). The neuropathology of CBS is still unpredictable. CSF tau/abeta ratio is a reliable marker of AD. Objective To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern. Methods 30 patients fulfilling current clinical criteria for CBS entered the study. Each patient underwent a clinical and standardised neuropsychological assessment, and CSF analysis (total tau and abeta42 dosages). CSF AD-like pattern and CSF non-AD like pattern (nAD-like) were identified. In 23 CBS cases, 99mTc-ECD single photon emission computed tomography (SPECT) scan was performed and analysed by statistical parametric mapping. Results CSF AD-like pattern was reported in six cases (20%). The two subgroups did not differ in demographic characteristics or global cognitive impairment. The AD-like group showed greater impairment of memory performances, language and psychomotor speed while the nAD-like group had more severe extrapyramidal syndrome with comparable apraxia scores. Voxel by voxel analysis on SPECT images demonstrated that CBS AD-like patients had greater hypoperfusion in the brain areas typically affected by AD—namely, precuneus, posterior cingulate and hippocampus, bilaterally—compared with nAD-like patients (p<0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients. Conclusions CSF AD-like profile in CBS is associated with earlier memory impairment and brain abnormalities typically found in classical AD. These findings argue for the usefulness of CSF testing to identify AD in CBS, and might suggest a different pharmacological approach on the basis of biological data.

FOXP2, APOE and PRNP new modulators in primary progressive aphasia

Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development.

Functional correlates of Apolipoprotein E genotype in Frontotemporal Lobar Degeneration

BackgroundIt has been recently demonstrated that in Frontotemporal Lobar Degeneration (FTLD) memory deficits at presentation are commoner than previously thought. Apolipoprotein E (ApoE) genotype, the major genetic risk factor in sporadic late-onset Alzheimer Disease (AD), modulates cerebral perfusion in late middle-age cognitively normal subjects. ApoE ε4 homozygous have reduced glucose metabolism in the same regions involved in AD.The aim of this study was to determine whether ApoE genotype might play a key-role in influencing the cerebral functional pattern as well as the degree of memory deficits in FTLD patients.MethodsFifty-two unrelated FTLD patients entered the study and underwent a somatic and neurological evaluation, laboratory examinations, a brain structural imaging study, and a brain functional Single Photon Emission Tomography study. ApoE genotype was determined.ResultsApoE genotype influenced both clinical and functional features in FTLD. ApoE ε4-carriers were more impaired in long-term memory function (ApoE ε4 vs. ApoE non ε4, 6.3 ± 3.9 vs. 10.1 ± 4.2, p = 0.004) and more hypoperfused in uncus and parahippocampal regions (x,y,z = 38,-6,-20, T = 2.82, cluster size = 100 voxels; -32,-12,-28, T= 2.77, cluster size = 40 voxels).ConclusionThe present findings support the view that ApoE genotype might be considered a disease-modifying factor in FTLD, thus contributing to define a specific clinical presentation, and might be of relevance for pharmacological approaches.