PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-13 (13)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Criteria for the diagnosis of corticobasal degeneration 
Neurology  2013;80(5):496-503.
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
doi:10.1212/WNL.0b013e31827f0fd1
PMCID: PMC3590050  PMID: 23359374
2.  Clinical, Biological, and Imaging Features of Monogenic Alzheimer's Disease 
BioMed Research International  2013;2013:689591.
The discovery of monogenic forms of Alzheimer's Disease (AD) associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/Aβ ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.
doi:10.1155/2013/689591
PMCID: PMC3860086  PMID: 24377094
3.  Cognitive Reserve in Granulin-Related Frontotemporal Dementia: from Preclinical to Clinical Stages 
PLoS ONE  2013;8(9):e74762.
Objective
Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+).
Methods
Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale.
Results
In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN.
Conclusions
This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages.
doi:10.1371/journal.pone.0074762
PMCID: PMC3767639  PMID: 24040338
4.  Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease 
The Journal of Clinical Investigation  2013;123(6):2523-2538.
A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer’s disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.
doi:10.1172/JCI65401
PMCID: PMC3668814  PMID: 23676497
5.  A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies 
Brain  2011;134(9):2548-2564.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
doi:10.1093/brain/awr160
PMCID: PMC3170529  PMID: 21752791
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
6.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy 
Nature genetics  2011;43(7):699-705.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component.
doi:10.1038/ng.859
PMCID: PMC3125476  PMID: 21685912
7.  Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration 
Brain  2011;134(9):2565-2581.
Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
doi:10.1093/brain/awr198
PMCID: PMC3170537  PMID: 21908872
frontotemporal dementia; frontotemporal lobar degeneration; voxel-based morphometry; MRI; neural network
8.  Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients 
The progranulin gene (PGRN) encodes a pleiotropic molecule with anti-inflammatory actions and neuronal protective effects. Accordingly, PGRN-deficient mice have been demonstrated to develop enhanced inflammation and progressive neurodegeneration. Loss of function mutations of the PGRN gene have been also reported to cause frontotemporal lobar degeneration (FTLD), a neurodegenerative disease leading to dementia generally in the presenium. Since neurodegeneration might be negatively impacted by chronic inflammation, the possible influence of PGRN defects on inflammatory pathways appears to be of great relevance for the understanding of neurodegeneration pathogenic processes in those patients. However, no data about the inflammatory profile of PGRN-defective subjects have been so far provided.
In this study, we analyzed serum levels of the pro-inflammatory mediators IL-6, TNF-α and IL-18 in FTLD patients with or without PGRN mutations, at both pre-symptomatic and symptomatic stages. We provide evidence that circulating IL-6 is increased in PGRN-mutated FTLD patients, as compared to both PGRN non-mutated FTLD patients and controls. In contrast, levels of IL-6 were not altered in asymptomatic subjects carrying the PGRN mutations. Finally, TNF-α and IL-18 serum levels did not differ among all groups of included subjects.
We conclude that the profile of circulating pro-inflammatory cytokines is altered in PGRN-related symptomatic FTLD. Thus, our findings point to IL-6 as a possible specific mediator and a potential therapeutic target in this monogenic disease, suggesting that an enhanced inflammatory response might be indeed involved in its progression.
doi:10.1186/1742-2094-8-65
PMCID: PMC3141503  PMID: 21645364
9.  The Usefulness of Biological and Neuroimaging Markers for the Diagnosis of Early-Onset Alzheimer's Disease 
The recent proposed criteria for Alzheimer's Disease (AD) have strongly claimed the usefulness of biological and neuroimaging markers for early identification AD. Cerebrospinal fluid (CSF) Tau/Abeta ratio, hippocampal atrophy, posterior cingulate, and neocortical associative area hypometabolism, or amyloid burden evaluated by PiB compound, held the premises to increase diagnostic accuracy in the preclinical disease stages. Despite many efforts to identify subjects at risk of developing AD, less attention has been paid to presenile AD diagnosis. A few data are already available in early onset AD, mainly obtained in cases of monogenic disorder. In this paper, we discuss the current literature on the role of biological and neuroimaging markers in presenile AD.
doi:10.4061/2011/296374
PMCID: PMC3087487  PMID: 21559247
10.  Latent profile analysis in frontotemporal lobar degeneration and related disorders: clinical presentation and SPECT functional correlates 
BMC Neurology  2007;7:9.
Background
Frontotemporal Lobar Degeneration (FTLD) thus recently renamed, refers to a spectrum of heterogeneous conditions. This same heterogeneity of presentation represents the major methodological limit for the correct evaluation of clinical designation and brain functional correlates. At present, no study has investigated clinical clusters due to specific cognitive and behavioural disturbances beyond current clinical criteria.
The aim of this study was to identify clinical FTLD presentation, based on cognitive and behavioural profile, and to define their SPECT functional correlations.
Methods
Ninety-seven FTLD patients entered the study. A clinical evaluation and standardised assessment were preformed, as well as a brain SPECT perfusion imaging study. Latent Profile Analysis on clinical, neuropsychological, and behavioural data was performed. Voxel-basis analysis of SPECT data was computed.
Results
Three specific clusters were identified and named "pseudomanic behaviour" (LC1), "cognitive" (LC2), and "pseudodepressed behaviour" (LC3) endophenotypes. These endophenotypes showed a comparable hypoperfusion in left temporal lobe, but a specific pattern involving: medial and orbitobasal frontal cortex in LC1, subcortical brain region in LC2, and right dorsolateral frontal cortex and insula in LC3.
Conclusion
These findings provide evidence that specific functional-cluster symptom relationship can be delineated in FTLD patients by a standardised assessment. The understanding of the different functional correlates of clinical presentations will hopefully lead to the possibility of individuating diagnostic and treatment algorithms.
doi:10.1186/1471-2377-7-9
PMCID: PMC1884173  PMID: 17506892
11.  Functional correlates of Apolipoprotein E genotype in Frontotemporal Lobar Degeneration 
BMC Neurology  2006;6:31.
Background
It 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.
Methods
Fifty-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.
Results
ApoE 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).
Conclusion
The 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.
doi:10.1186/1471-2377-6-31
PMCID: PMC1569858  PMID: 16930470
12.  Artificial neural networks allow the use of simultaneous measurements of Alzheimer Disease markers for early detection of the disease 
Background
Previous studies have shown that in platelets of mild Alzheimer Disease (AD) patients there are alterations of specific APP forms, paralleled by alteration in expression level of both ADAM 10 and BACE when compared to control subjects. Due to the poor linear relation among each key-element of beta-amyloid cascade and the target diagnosis, the use of systems able to afford non linear tasks, like artificial neural networks (ANNs), should allow a better discriminating capacity in comparison with classical statistics.
Objective
To evaluate the accuracy of ANNs in AD diagnosis.
Methods
37 mild-AD patients and 25 control subjects were enrolled, and APP, ADM10 and BACE measures were performed. Fifteen different models of feed-forward and complex-recurrent ANNs (provided by Semeion Research Centre), based on different learning laws (back propagation, sine-net, bi-modal) were compared with the linear discriminant analysis (LDA).
Results
The best ANN model correctly identified mild AD patients in the 94% of cases and the control subjects in the 92%. The corresponding diagnostic performance obtained with LDA was 90% and 73%.
Conclusion
This preliminary study suggests that the processing of biochemical tests related to beta-amyloid cascade with ANNs allows a very good discrimination of AD in early stages, higher than that obtainable with classical statistics methods.
doi:10.1186/1479-5876-3-30
PMCID: PMC1198261  PMID: 16048651
13.  [alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients. 
Molecular Medicine  2002;8(2):67-74.
BACKGROUND: Members of membrane-bound disintegrin metalloproteinases (ADAMs) were shown to be capable of cleaving amyloid precursor protein (APP) at the alpha-cleavage site in different cell systems. One of the candidate alpha-secretases identified in this family is ADAM10. The present study addresses the following major questions: 1) Are the levels of an alpha-secretase candidate (i.e., ADAM10) reduced in accessible cells of Alzheimer Disease (AD) patients? 2) Are ADAM10 levels in the peripheral cells of AD patients related to a concomitant decrease in alpha APPs? MATERIALS AND METHODS: Western Blot analysis of ADAM10 is performed on platelet homogenates from 33 sporadic AD patients and on 26 age-matched control subjects. Moreover, the levels of alpha-secretase metabolite (alpha APPs) are tested both in platelets and cerebrospinal fluid (CSF) of the same pool of subjects by means of Western blot with a specific antibody. RESULTS: A significant decrease of platelet ADAM10 levels is observed in patients affected by probable AD when compared to control subjects and this is paralleled by a reduced level of alpha APPs released from platelets. Moreover, in the same pool of AD patients, alpha APPs levels were reduced concomitantly in CSF. CONCLUSIONS: ADAM10 is expressed in platelets. A reduced level of ADAM10 is observed in platelets obtained from AD patients compared to age-matched controls. Further, in the same pool of AD patients, a qualitatively and quantitatively similar decrease in alpha APPs is present both in thrombin-activated platelets and CSF, thus suggesting that alterations of APP processing might occur both in the neuronal compartment and peripheral cells.
PMCID: PMC2039975  PMID: 12080182

Results 1-13 (13)