Author's response to reviews
Title: Functional Correlates of Apolipoprotein E Genotype in Pick's Complex
Authors:
Barbara Borroni ([email protected])
Daniela Perani ([email protected])
Silvana Archetti ([email protected])
Chiara Agosti ([email protected])
Barbara Paghera ([email protected])
Giuseppe Bellelli ([email protected])
Monica DiLuca ([email protected])
Alessandro Padovani ([email protected])
Version: 3 Date: 20 July 2006
Author's response to reviews: see over
UNIVERSITA’ DEGLI STUDI DI BRESCIA
Centro per lo Studio
Dipartimento Scienze Mediche e Chirurgiche
dell'Invecchiamento Cerebrale e delle
CLINICA NEUROLOGICA
Malattie Neurodegenerative
Brescia, July 30th, 2006
Dear Editor,
Please find enclosed our revised manuscript entitled “Functional Correlates of Apolipoprotein
E Genotype in Frontotemporal Lobar Degeneration” by Barbara Borroni and colleagues.
We have taken into consideration the points that were raised by the referees, and the manuscript
has been amended accordingly. As we explained in the response to Reviewer 1, we think that it
is better to show the results of the above manuscript without introducing Tau haplotype findings.
We hope that this opinion does not disappoint both the Editorial board and the reviewer.
We hope that in the present form the manuscript will be suitable for publication in BMC
Neurology.
For further communications, please contact the corresponding author:
Barbara Borroni, M.D.
Clinica Neurologica, c/o Spedali Civili di Brescia
Università degli Studi di Brescia
Tel. 030/3995631, Fax. 030/3995027
E-mail. [email protected]
Looking forward to learning your decision
Best regards,
Barbara Borroni, M.D.
Centro per lo Studio dell'Invecchiamento Cerebrale e delle Malattie Neurodegenerative
Clinica Neurologica-Spedali Civili
Telefono: 030-3995632, FAX: 030-3995027
e-mail: [email protected]
Review 1
We thank the review for the suggestion. As we previously explained to the Editor, the
background that prompted the two studies as well as the methodology used for SPECT data
analysis are different.
The first paper on ApoE genotype and functional correlates focuses the attention on the recent
literature reports that claim for the presence of memory deficits in FTD and related disorders. On
the other hand, the second one evaluated the role of Tau haplotype in FTD and related disorders,
starting from the evidence of epidemiological, genetic and in vitro studies.
Thus, we found some difficulties to merge these different aspects both in the introduction and in
the discussion of the results.
Secondly, the former is based on Statistical Parametric Mapping analysis of functional data, the
latter on Principal Component Analysis. This second sophisticated methodology can not be
properly applied when hippocampal regions want to be evaluated, being not suitable for the
analysis of functional data according to ApoE genotype.
Thus, for these above reasons, we think that it is better to show the results of ApoE genotype and
functional correlates on their own.
We hope that this opinion does not disappoint the reviewer.
We agree that the paper was too short and not informative in the previous version. Taking into
account the suggestions raised by the other reviewers, we has amended it accordingly.
UNIVERSITA’ DEGLI STUDI DI BRESCIA
Centro per lo Studio
Dipartimento Scienze Mediche e Chirurgiche
dell'Invecchiamento Cerebrale e delle
CLINICA NEUROLOGICA
Malattie Neurodegenerative
Review 2
We would like to thank the reviewer Prof. Pijenburg for her helpful comments. We have
amended the manuscript accordingly.
Major revisions
-
As correctly suggested, we used the term Pick’s Comlex instead of Frontotemporal Lobar
Degeneration throughout the manuscript.
-
We described in detail the patients excluded in the present study (n=3) because of posterior
parietal hypoperfusion and CSF pattern resembling AD. We indeed agree that CSF Tau and
Abeta dosage can not be considered an useful biomarker for FTD and related disorders, but
we decided to exclude two patients with typical AD CSF pattern to avoid confounds, even if
they behaved clinically as FTD. Further, we excluded one patients with typical AD
hypoperfusion pattern.
In the Result section we added:
“Fifty-five patients with the clinical diagnosis of PC entered the study from March 2003
through April 2005. Among them, three were subsequently excluded to avoid confounds: one
because of SPECT perfusion pattern involving temporo-parietal region and cingulate areas,
two because of low CSF Abeta levels, thus resembling AD pattern.”
Minor essential revisions
-
The last sentence of the Background in the Abstract was split up in shorter sentences.
-
Page 4 (line 12 and last sentence). We corrected the typos.
Centro per lo Studio dell'Invecchiamento Cerebrale e delle Malattie Neurodegenerative
Clinica Neurologica-Spedali Civili
Telefono: 030-3995632, FAX: 030-3995027
e-mail: [email protected]
-
Indeed, the questionnaires that are mentioned in the results section (FBI, IADL, BADL,
NPI…) are too long to be introduced in the Methods. We therefore added a more extensively
explanation of the above battery in the present version along with the reference for each one.
In the Method section we wrote:
“Global cognitive function assessment was made according to a standardised battery,
including the Mini-Mental State Examination (MMSE). The neuropsychological assessment
was made with the following tests: Raven Colored Progressive Matrices, Controlled Oral
Word Association Test and Category Fluency, Clock Drawing Test, Rey Complex Figure
Copy and Recall, Story Recall Test, Digit Span, Trail Making Test A and B, Token Test, and
De Renzi Imitation Test. Instrumental Activities of Daily Living (IADL), and Basic
Activities of Daily Living (BADL) were assessed as well. Behavioural and psychiatric
disturbances were evaluated by Neuropsychiatric Inventory (NPI), and Frontal Behavioual
Inventory (FBI).”
-
Results. We agree with the criticism raised by the reviewer. In the previous version, we
indeed described the patients as overall sample. In the present version we detailed the
neuropsychological characteristics in each diagnostic subgroup.
-
Page 7, line 9. yes, we do. We meant Short Story recall. We changed the sentence.
-
The last two sentences were rephrased, as follows:
“When the opposite comparison was considered, and the hypoperfusion in ApoE ε4- vs. ApoE ε4+
was evaluated, no voxels above the threshold were found. In order to exclude the effect of clinical
endophenotypes in determining the hypoperfusion pattern, the clinical diagnoses (fvFTD, SD,
PNFA, PSP and CBD) were introduced as nuisance variable in the analysis, and the results were
confirmed. Thus, we concluded that the SPECT hypoperfusion pattern was not due to a specific
clinical endophenotype, but only to ApoE genotype.”
UNIVERSITA’ DEGLI STUDI DI BRESCIA
Centro per lo Studio
Dipartimento Scienze Mediche e Chirurgiche
dell'Invecchiamento Cerebrale e delle
CLINICA NEUROLOGICA
-
Malattie Neurodegenerative
Page 10. line 4. hyppocampal was changed into hippocampal.
Centro per lo Studio dell'Invecchiamento Cerebrale e delle Malattie Neurodegenerative
Clinica Neurologica-Spedali Civili
Telefono: 030-3995632, FAX: 030-3995027
e-mail: [email protected]
Review 3
We would like to thank the reviewer Prof. Sjogren for his helpful comment. We amended the
manuscript accordingly.
Major revision
1.In the abstract and in the Result section we included quantified results.
As suggested, we added a table on relevant functional data finrdiongs.
2. On Page 4, we stated not only percentage but also the number of patients for which CSF was
taken, as suggested
3. In regard to terminology, as also suggested by the other reviewer, we changed the term FTLD
into Pick’s Complex throughout the manuscript.
4. The study was approved by the Ethical committee of our Hospital. All patients we asked
consented to participate in the study.
5-6. On Page 6, we added a paragraph entitled “Statistical Analysis.
7. On Page 7, we stated that the diagnoses was based on clinical criteria.
8. Results. We reported quantified results and level of significance.
9. As pointed out, we mentioned clearly in the Material and Methods that it is a cross.sectional
study. We are also involved in the follow-up visit of these patients, but this is an on-going study
and we do not have conclusive results yet.
10. On Page 15, legend to the figure, we stated that hypoperfusion pattern in ApoE4 positive is
shown.
Minor essential revision
1. Page2, abstract, we deleted "It has been demonstrated..."
UNIVERSITA’ DEGLI STUDI DI BRESCIA
Centro per lo Studio
Dipartimento Scienze Mediche e Chirurgiche
dell'Invecchiamento Cerebrale e delle
CLINICA NEUROLOGICA
Malattie Neurodegenerative
2. Page 4, DSM-IV was only applied to exclude major depressive disorder, bipolar disorder,
schizophrenia, substance use disorder, or mental retardation. We deleted the sentence because it
could be misleading.
3. Page 7. We re-wrote the Results, as well as the first paragraph, according to the suggestions of
the other reviewer. We described in detailed the excluded patients and the neuropsychological
characteristics.
4. As correctly suggested, we divided the results into paragraphs. We added the statistical
methods in the paragraph “Statistical Analysis” in the Methods.
5. Results. we changed the wordings “cognitive decline" into "impairment".
6. Discussion. We went much more into detail.
7. Conclusion. We clarified that ApoE ε4 genotype was associated with greater hippocampal
hypoperfusion.
8. Conclusion. We changed the Conclusion, stating what the main finding was first.
9. References. We added the references on ApoE4 in FTD.
Centro per lo Studio dell'Invecchiamento Cerebrale e delle Malattie Neurodegenerative
Clinica Neurologica-Spedali Civili
Telefono: 030-3995632, FAX: 030-3995027
e-mail: [email protected]