The Utility of Addenbrooke’s Cognitive Examination III (ACE-III) in Differentiating Neurodegenerative Disorders with Psychotic Symptoms: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This publication presents cognitive screening tools named  Addenbrooke’s Cognitive Examination-III (ACE-III) and  Mini-ACE to assess  psychosis-related neurodegeneration. I have following suggestions to improve the quality of manuscript further:

1. Add more details about the description of Addenbrooke’s Cognitive Examination-III (ACE-III) and  Mini-ACE tests. 
2. Compare, in detail, ACE-III and Mini-ACE with MMSE, CDR rating, FAQ and NPI-Q scores.
3. How these criteria can be used to assess subjects of Parkinson's disease who are later converted to Alzheimer's disease?
4. The manuscript has fewer longitudinal studies. Try to include more.
5. Summarize studies in the form of tables.
6. Comment on the link between explainable AI, ACE-III and  Mini-ACE.

Author Response

We sincerely thank the Reviewer for the thoughtful and constructive comments, which significantly improved the quality and clinical relevance of the manuscript. We carefully revised the paper and addressed all suggested points as follows:

1. Additional description of ACE-III and Mini-ACE

We expanded the description of both ACE-III and Mini-ACE in Sections 3.1 and 3.2. The revised manuscript now includes detailed information regarding test structure, cognitive domains assessed, administration time, scoring, and clinical applicability in neurodegenerative and psychiatric populations.

2. Comparison of ACE-III and Mini-ACE with MMSE, CDR, FAQ, and NPI-Q

We substantially expanded the comparative discussion of cognitive, functional, and neuropsychiatric assessment tools. A new comparative table (Table 2) was added summarizing the principal characteristics, strengths, limitations, and clinical roles of ACE-III, Mini-ACE, MMSE, MoCA, CDR, FAQ, and NPI-Q in the differential diagnosis of neurodegenerative disorders with psychotic symptoms. Additional explanatory text was incorporated into Sections 7.1 and 7.2.

3. Assessment of Parkinson’s disease patients with later Alzheimer-type features

We expanded the section discussing Parkinson’s disease dementia (PDD) and longitudinal cognitive profiling. The revised manuscript now emphasizes that, in some patients, cognitive impairment may evolve from predominantly executive–attentional dysfunction toward more pronounced episodic memory deficits and more severe visuospatial impairment over time. We also highlight that such progression may reflect mixed or additional neurodegenerative pathology and underscores the importance of longitudinal multidomain cognitive assessment.

4. Inclusion of longitudinal studies

In response to this important suggestion, we added a dedicated section discussing longitudinal cognitive assessment and introduced a new summary table (Table 3) presenting selected longitudinal studies relevant to ACE-based assessment in psychosis-related neurodegeneration. The revised discussion now places greater emphasis on the diagnostic value of repeated cognitive evaluations and cognitive trajectories over time.

5. Summary of studies in tables

Several summary tables were added and expanded throughout the manuscript to improve clarity and facilitate comparison between neurodegenerative syndromes, cognitive profiles, psychotic features, and assessment instruments.

6. Relationship between explainable AI (XAI), ACE-III, and Mini-ACE

We expanded the “Future Perspectives” section by discussing the potential role of explainable artificial intelligence (XAI) in the interpretation of ACE-III and Mini-ACE domain-level cognitive profiles. The revised text highlights how transparent AI-based approaches may support clinically interpretable pattern recognition across neurodegenerative syndromes while complementing, rather than replacing, clinical judgment.

We believe these revisions have substantially strengthened the manuscript and greatly appreciate the Reviewer’s valuable suggestions.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Comments:

The manuscript title “The Utility of the Addenbrooke’s Cognitive Examination-III (ACE-III) in Differentiating Neurodegenerative Disorders with Psychotic Symptoms: A Narrative Review" provides a comprehensive overview of the very interesting topic of ACE-III. The author explains ACE-III and Mini-ACE differences between brain-related causes and also has considered neurodegenerative diseases like Alzheimer's disease (AD), dementia with Lewy bodies, Parkinson's disease and frontotemporal dementia. However, some points are too general; for example, the author has highlighted the need for more long-term studies, which is an important point, but adding a few details on what exactly these studies would make this point clearer to the reader. Apart from this, there are some areas that can be improved to enhance clarity, depth and critical analysis. The following points still have scope to improve to enhance the manuscript further.

                       

• The authors do explain that neurodegenerative diseases follow recognizable pattern while psychiatric disorders are nonspecific. However, to make this claim strong, the paper needs a table or figure that shows these two patterns. For example, a table comparing how an AD patient typically scores versus how a schizophrenia patient typically scores.
• Explanation on “If a patient scores low, how could it be determined that it is due to permanent brain damage or just temporary confusion?”
• The author is encouraged to briefly discuss cases where a patient may have more than one brain disease at once. How should ACE-III findings be used in such a situation?
• Please expand your table 1 to include more common diseases such as Lewy body dementia (DLB) or Parkinson’s.
• To make this review more useful, I suggest adding a figure/table/flowchart, such as a diagnostic flowchart illustrating the clinical pathway, to make it more visually appealing.
• The limitation section is well explained; the author may also discuss the ceiling effect of ACE-III, particularly with the patients at very early-stage or mild cognitive impairment. Previous studies (eg. Bruno and Schurmann Vignaga, 2019) have shown that age, education, and IQ can significantly affect test scores and should be taken into account.
• The authors mention “biomarker-based diagnostic procedures” in the limitation section. It would make the paper clearer if they briefly mentioned which specific biomarkers are most relevant.

Overall, the paper is nicely written. However, it needs a little more explanation and visual presentation to show how the test scores look for different neurodegenerative diseases.

Comments on the Quality of English Language

May be improved.

Author Response

We sincerely thank the Reviewer for the careful reading of the manuscript and for the valuable and constructive comments. We greatly appreciate the positive evaluation of the manuscript and the suggestions that helped us improve its clarity, depth, and clinical relevance. We addressed the comments as follows:

1. Comparison between neurodegenerative and primary psychiatric cognitive patterns

In response to the Reviewer’s suggestion, we expanded the discussion regarding qualitative and domain-specific cognitive profiles observed in neurodegenerative disorders compared with primary psychotic disorders. We further developed Sections 7.3–7.5 to emphasize that neurodegenerative disorders typically present with relatively stable and syndrome-consistent cognitive profiles, whereas cognitive deficits in primary psychotic disorders are generally less specific, more variable, and often influenced by attentional fluctuations or symptom severity. We also expanded Tables 1 and 2 and added a diagnostic pathway figure to improve visualization of the differential diagnostic framework.

2. Distinguishing permanent neurodegenerative impairment from transient cognitive dysfunction

We added a dedicated subsection entitled “Interpretation of Reduced ACE-III Performance” (Section 7.1.1), discussing how longitudinal assessment, internal consistency of domain deficits, clinical context, and response over time may help differentiate progressive neurodegenerative impairment from transient cognitive disturbances related to delirium, acute psychosis, medication effects, or fluctuating psychiatric symptoms.

3. Mixed neuropathology and coexistence of multiple brain diseases

We expanded the discussion to address cases of mixed or overlapping neuropathology, including coexisting Alzheimer-type, Lewy body, and vascular pathology. The revised manuscript now emphasizes that ACE-III findings in such cases may demonstrate overlapping or atypical profiles and therefore require cautious interpretation integrated with biomarkers, neuroimaging, and longitudinal clinical evaluation.

4. Expansion of Table 1

Table 1 was substantially expanded and now includes dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), vascular dementia, atypical Alzheimer’s disease variants, and additional frontotemporal dementia phenotypes relevant to psychosis and ACE-III interpretation.

5. Addition of visual diagnostic presentation

To improve the clinical applicability and visual presentation of the review, we added Figure 1 presenting a simplified diagnostic pathway integrating cognitive screening, multidomain assessment, functional evaluation, neuropsychiatric assessment, and biomarker investigation.

6. Ceiling effects and demographic influences on ACE-III performance

We expanded the Limitations section to discuss ceiling effects, particularly in highly educated individuals and patients at very early disease stages or with mild cognitive impairment. We also addressed the influence of age, education, premorbid ability, and related demographic variables on ACE-III interpretation, including reference to the work of Bruno and Schurmann Vignaga (2019).

7. Clarification of biomarker-based diagnostic procedures

The manuscript now briefly specifies the most clinically relevant biomarkers used in neurodegenerative diagnostics, including cerebrospinal fluid amyloid-β and tau analysis, amyloid and tau PET imaging, and structural MRI assessing hippocampal atrophy and vascular changes.

8. Longitudinal studies

In response to the Reviewer’s suggestion, we added a dedicated section and a new summary table (Table 3) discussing selected longitudinal studies relevant to ACE-based cognitive assessment and psychosis-related neurodegeneration. We also expanded the discussion of longitudinal cognitive trajectories and their diagnostic significance.

We believe that these revisions substantially improved the manuscript and we are grateful for the Reviewer’s insightful comments and recommendations.

Reviewer 3 Report

Comments and Suggestions for Authors

The main strength of this manuscript lies in its clinically relevant and well-structured synthesis of the role of ACE-III as a multidomain cognitive tool for differentiating neurodegenerative disorders with psychotic features. The manuscript successfully integrates cognitive profiling with neuropsychiatric symptomatology, providing a practical and clinically applicable framework that can support diagnostic reasoning in complex cases.

Weaknesses 

1. Lack of explicit theoretical framework
In the Introduction and early conceptual sections (Sections 1, 3, and 4), although the manuscript describes cognitive profiles in detail, it does not explicitly integrate these findings within a coherent theoretical or neurobiological framework. This limits conceptual depth and mechanistic understanding. The authors should explicitly link ACE-III domain patterns to established models of neurodegeneration or cognitive network dysfunction.

2. Limited methodological transparency
A key limitation is the insufficient description of the review methodology in the Methods section (Section 2). The manuscript refers to a “selective examination of the literature” but does not specify search strategies, inclusion/exclusion criteria, or time frames. This reduces reproducibility and increases the risk of selection bias. The authors should include a structured description of the search strategy and study selection process.

3. Bibliographic selection may introduce bias
Also in the Methods section (Section 2), the reliance on “clinical relevance” as the main selection criterion introduces potential bias and limits representativeness. Additionally, there is an inconsistent balance between primary and secondary sources across sections. The authors should clarify selection criteria and ensure a more systematic and balanced use of the literature.

4. Lack of critical appraisal of included studies
Throughout the main body of the manuscript, particularly in Sections 3–7, the review remains predominantly descriptive, with limited critical evaluation of the cited studies. There is little discussion of methodological quality, limitations, or strength of evidence. The authors should incorporate a structured critical appraisal to improve scientific rigor.

5. Limited use of quantitative evidence
In Sections 3 and 7, claims regarding diagnostic utility and superiority of ACE-III are not supported by quantitative synthesis (e.g., sensitivity, specificity, effect sizes). This weakens the strength of the conclusions. The authors should include summarized quantitative findings from key studies or meta-analyses.

6. Overly extensive and unfocused section on psychosis
The section “5. Psychosis in Neurodegenerative Disorders” is excessively detailed relative to the main objective of the manuscript. While informative, it creates imbalance and dilutes the focus on ACE-III. This section should be condensed and more explicitly linked to cognitive assessment and differential diagnosis.

7. Interpretation not always clearly linked to cited evidence
In extended descriptive sections, especially Section 5, some interpretative statements are not directly tied to specific references or are supported by broad citations. This reduces traceability and scientific precision. The authors should ensure clearer linkage between claims and supporting evidence.

8. Limited comparative analysis with other cognitive tools
In Section 7.1, comparisons with MMSE and MoCA are presented but remain superficial and narrative. There is no structured or quantitative comparison of diagnostic performance. The authors should include a more detailed comparative analysis, ideally supported by data.

9. Overgeneralization of diagnostic interpretations
In Sections 7 and 9 (Discussion and Conclusions), the manuscript occasionally presents ACE-III as highly effective without sufficient qualification. This may lead to overgeneralization. The authors should better define the clinical contexts and limitations of its diagnostic utility.

10. Insufficient discussion of conflicting evidence
In the Discussion section (Section 8), the manuscript lacks engagement with conflicting or inconclusive findings in the literature. This reduces critical balance. The authors should incorporate and discuss divergent evidence.

11. Redundancy and repetition of key concepts
Across Sections 3, 4, 7, and 9, key ideas—particularly the emphasis on qualitative domain analysis—are repeated multiple times. This affects readability and conciseness. The manuscript would benefit from consolidation of these concepts.

12. Minor language and typographical issues
Throughout the manuscript, there are typographical errors and formatting inconsistencies (e.g., distorted characters such as “aĴention”). These issues reduce clarity and professionalism. A thorough language and formatting revision is recommended.

Comments on the Quality of English Language

The manuscript is generally written in clear and professional English, and the overall meaning is understandable. However, the quality of language could be improved to enhance clarity and precision. There are several typographical errors, formatting inconsistencies, and occasional awkward phrasing that affect readability. In particular, some words contain encoding issues (e.g., distorted characters in terms such as “attention”), and certain sentences are overly long or repetitive. A thorough proofreading and language editing process is recommended to ensure consistency, correct minor errors, and improve the overall flow of the text.

Author Response

We sincerely thank the Reviewer for the detailed, thoughtful, and highly constructive evaluation of our manuscript. We greatly appreciate the recognition of the manuscript’s clinical relevance and practical applicability. The comments provided substantially helped us improve the conceptual clarity, methodological transparency, critical balance, and overall structure of the review. We addressed the points as follows:

1. Lack of explicit theoretical framework

We expanded the Introduction and conceptual sections to explicitly relate ACE-III cognitive profiles to contemporary neurobiological and large-scale network models of neurodegeneration. The revised manuscript now discusses how domain-specific ACE-III patterns correspond to dysfunction within medial temporal, posterior cortical, frontostriatal, and frontal–temporal networks across Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease dementia, and frontotemporal dementia.

2. Limited methodological transparency

The Methods section was substantially revised and now includes a structured description of the literature search strategy, databases searched (PubMed, Scopus, and Web of Science), key search terms, publication time frame, and the general principles guiding study selection. We also clarified the narrative nature of the review and the rationale for inclusion of clinically relevant studies.

3. Potential bibliographic selection bias

We clarified that study selection was based on relevance to clinical application, cognitive profiling, psychosis, and differential diagnosis. We also revised the manuscript to improve the balance between primary studies, reviews, and meta-analyses throughout the text.

4. Lack of critical appraisal

We expanded the Discussion and Limitations sections to incorporate a more critical interpretation of the literature, including heterogeneity of methodologies, variability in study populations, limitations of available evidence, and reduced specificity of ACE-III in advanced or mixed pathology.

5. Limited quantitative evidence

The revised manuscript now includes additional quantitative information from key studies, including sensitivity and specificity findings for ACE-III and M-ACE in comparison with MMSE and MoCA, particularly in Sections 3 and 7.

6. Extensive section on psychosis

The section “Psychosis in Neurodegenerative Disorders” was revised and condensed to improve focus and readability. We strengthened the explicit links between psychotic symptomatology, cognitive profiles, and the clinical utility of ACE-III in differential diagnosis.

7. Linkage between interpretation and evidence

We carefully revised the manuscript to improve traceability between interpretative statements and supporting references. Additional citations were incorporated where necessary to strengthen scientific precision.

8. Comparative analysis with MMSE and MoCA

We expanded the comparative discussion of ACE-III, MMSE, and MoCA and added a dedicated comparative table summarizing the strengths, limitations, and clinical roles of these instruments alongside CDR, FAQ, and NPI-Q.

9. Potential overgeneralization of ACE-III utility

We revised the Discussion and Conclusions sections to better emphasize that ACE-III is a supportive multidomain cognitive profiling tool rather than a standalone diagnostic instrument. We also further clarified the contexts in which its diagnostic specificity may be limited, particularly in advanced disease stages, mixed pathology, and very early neurodegenerative presentations.

10. Insufficient discussion of conflicting evidence

The revised Discussion section now more explicitly addresses conflicting findings, heterogeneity across studies, and the limitations of current evidence, particularly regarding differentiation between dementia syndromes and psychosis-related presentations.

11. Redundancy and repetition

We carefully edited the manuscript to reduce redundancy, consolidate repeated concepts, and improve overall readability and conciseness while preserving key clinical messages.

12. Language and formatting issues

The manuscript underwent additional language editing and proofreading to correct typographical errors, formatting inconsistencies, and encoding issues, and to improve sentence structure and readability throughout the text.

We are grateful for the Reviewer’s insightful comments and believe that the revisions substantially strengthened the scientific rigor, clarity, and clinical value of the manuscript.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thanks for the hard work.

Reviewer 3 Report

Comments and Suggestions for Authors

We thank the authors for their careful and responsive revision of the manuscript. The changes made adequately address the issues raised during review and result in a clearer, more balanced, and methodologically transparent work. The revised version demonstrates improved conceptual coherence, a more critical and nuanced interpretation of the literature, and a strengthened clinical focus. Overall, the manuscript has been substantially improved and now provides a solid and well-positioned narrative review on the topic.

Comments on the Quality of English Language

The revised manuscript is written in clear, professional, and fluent English. The quality of the language has improved, and the text is generally well structured and easy to follow. The previous typographical, formatting, and encoding issues have been adequately addressed, and sentence flow and clarity are noticeably improved. Overall, the language quality is appropriate for publication.