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These observations could be linked with the fact that early AD can be associated with psychiatric symptoms. Nevertheless, our study does not provide information establishing a direct pathophysiological link between AD and psychiatric symptoms; thus, we could not confirm that psychiatric symptoms reveal AD pathology.
We also found age differences between our populations and the BNA populations, possibly due to the fact that BNA records all patients from all French memory clinics [ 31 ], while our study was carried out on a voluntary basis, and consequently we included a limited number of centres that perform CSF biomarker evaluations.
Biomarkers - the Future of Diagnosis in Psychiatry?
Our overall population and our study populations were significantly younger and more frequently diagnosed with AD than the BNA overall and psychiatric populations [ 16 ]. This difference is in accordance with the recommendations by French authorities and with the current use of CSF biomarkers that are used mainly in younger patients or in patients with atypical presentations [ 23 ].
Furthermore, CSF AD biomarkers are more discriminant in younger than in older patients with AD reinforcing the tendency to assess younger individuals [ 32 ]. Our population had a significantly higher rate of patients with AD than the BNA population, probably because CSF biomarker evaluations are performed when a neurodegenerative disease is strongly suspected. In the BNA population, all patients are recorded, including patients without any biomarkers. Our CSF biomarker results are in accord with those in the study by Blennow et al. Surprisingly, although pure depression revealing dementia with Lewy bodies DLB has been described previously [ 34 ], we did not find any patients with DLB.
This result could be explained by the small cohort, the translational methodology with a short follow-up in the retrospective part of the study, the lack of neuropathological confirmation, and possibly misdiagnoses. However, patients with DLB display some specific behavioural disorders, such as feeling of presence, illusions or visual hallucinations [ 36 ], that were not described in our population. In the complementary analysis, we made some very interesting observations. In the AD group, the first psychiatric symptoms occurred later in life than in the non-AD group, confirming that new onset of psychiatric symptoms later in life may be more suggestive of neurodegeneration.
We could hypothesise that, in the AD group, the psychiatric symptoms could be among the first symptoms of AD linked to the regional AD lesions. In contrast, in the other groups, the cognitive decline was associated either with neurodegeneration or with pure psychiatric disease or a chronic neuronal dysfunction of unknown pathophysiology. Note that all the results in the AD category are very homogeneous: The first psychiatric symptoms always occur late in life, and the delay between the first psychiatric symptoms and cognitive decline is always short.
The relationship seems more heterogeneous in the two other categories. These observations could suggest that there is a close link between the two. However, further, larger studies are needed to confirm these observations. In our results, clinical diagnosis and CSF biomarker results were concordant in about two-thirds of cases, a finding close to those of neuropathological studies [ 10 , 11 ].
Unlike post-mortem histological studies that reclassify the diagnosis after several years of evolution, a reclassification based on CSF biomarkers occurred quite often at the beginning of follow-up and may have therapeutic consequences. The distinction between AD and psychiatric disorders is essential because 1 the prognosis and management of the patient are different, 2 psychiatric symptoms in AD can be the expression of unmet clinical needs requiring specific treatment while avoiding antipsychotic drugs and 3 some treatments are not recommended in neurodegenerative diseases but are widely used in psychiatric disorders, such as anticholinergic drugs [ 37 — 39 ].
It clearly appears really helpful to get a precise differentiation between AD and pure psychiatric disorders to give and adapt an appropriate treatment and to avoid deleterious therapeutics and management. Some limitations of the present study have to be considered. First, there were two aspects of recruiting bias: 1 The participation of the memory clinics was on a voluntary basis, leading to overrepresentation of the clinics performing LP in routine clinical practice and in clinical research; and 2 patients were referred for cognitive disorders or atypical psychiatric disorders, probably explaining the high rate of patients with AD.
A similar study in psychiatric centres might produce different results according to the age and clinical characteristics of the patients as well as differences in diagnostic procedures used in psychiatric consultations.
In memory centres, clinicians have to be careful before concluding a diagnosis of psychiatric disorder and referring patients to a psychiatric centre. A second limitation is that, because of refusal or medical contraindications, LP could not be performed in all patients from the referring centres. Third, even though previous studies indicated a good correlation between CSF results and neuropathology [ 13 , 19 — 21 ], in this study we did not have pathological analysis available to confirm CSF findings. Further assessments using amyloid and tau PET imaging would certainly be worth trying.
Fourth, psychiatric evaluations were not done using standardized interviews that would have allowed us to take into account atypical features and age at onset of the psychiatric disorders. Fifth, complementary data were recorded retrospectively in a subgroup of patients allowing to obtain follow up information but disadvantage to provide blinded from CSF biomarker results information.
As the management and the prognosis of patients with psychiatric disorders and AD are really different, the results of the present study are very useful in underlining the importance of and need for complementary explorations when psychiatric disorders with cognitive decline are addressed in memory centres.
Furthermore, the improvement of AD diagnosis will be important in the future when appropriate effective therapies become available and are routinely proposed to patients with AD. Geda YE et al. Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study. Am J Psychiatry. Kokmen E et al. Albert MS et al. Alzheimers Dement.
Jorm AF. History of depression as a risk factor for dementia: an updated review. Aust N Z J Psychiatry. Amieva H et al. McKhann G et al.
General Commentary ARTICLE
Petersen RC et al. Doody RS et al. N Engl J Med. Rinne JO, Nagren K. J Alzheimers Dis.
Digital biomarkers of mood disorders and symptom change
Lim A et al. J Am Geriatr Soc. Schoonenboom NS et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Beach TG et al. J Neuropathol Exp Neurol. Magnin E et al. The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol. McKhann GM et al. Mouton-Liger F et al. J Neurol. Sperling RA et al. Brunnstrom H et al. Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
Strozyk D et al. Tapiola T et al. Arch Neurol. Engelborghs S. Rev Neurol Paris. In addition, these methodologies rely on sophisticated computational-multi disciplinary field of systems biology utilizing advanced bioinformatics processing tools that can interpret the high throughput molecular omics data relevant to neuropsychiatric research. Among the ultimate aims of such discipline is the identification of novel sensitive and disease-specific biomarker s.
The promise that systems biology can lead a progress in biological psychiatry returns to the very complex nature of psychiatric disorders. Such disorders involve multifactorial genetic and environmental interactions together with the dynamic nature of protein alterations affecting both cellular as well as structural changes on the neuronal levels. Therefore, assessing psychiatric disorders cannot be targeted at a single behavioral or cellular level but rather would require a holistic global approach that can assess different components of such disorders Fang and Casadevall, ; Westerhoff, This can lead the inquiry into the roots of such disorders and identify new diagnostic and assessment biomarkers.
However, the need for biomarker discovery and the implementation of systems biology techniques is not just because of the complexity of the disease. Having been said, there has been a pronounced worldwide joint effort in the advancing of biomarker studies that is evident by the surge of research and review articles focusing on the application of systems biology, bioinformatics, and biomarkers in neuropsychiatry. These studies have included the use of high-throughput genomic, epigenetics, proteomic, metabolomics, and other—bioinformatic computational algorithms tools as well as the use of animal models, in vitro and in vivo tissue cultures and in silico models.
These techniques have been applied on different aspects of neuropsychiatric disorders spanning: drug abuse, eating disorders, and other psychiatric disorders involving schizophrenia, bipolar disorder, and major depressive disorder etc. Kobeissy et al. The application of these techniques has provided several disease models of psychiatric diseases Tretter and Gebicke-Haerter, that have moved research and therapy forward as with the dopamine agonist model of schizophrenia that we reviewed in a separate publication Alawieh et al. However, success reported by using such techniques is still in its infancy due to the aforementioned complexity of psychiatric diseases as well as for other reasons.
This resulted in massive amount of data—majorly non-replicable and non-validated—with very low biological significance and clinical impact Kraemer et al. Therefore, there is now an uprising need for the integrative and predictive analysis as well as validation of the available data collected to infer the biological significance relevant to psychiatry.
Finally, the field of biomarker discovery in psychiatry, taking advantage of systems biology approach and the available bioinformatics tools, is believed to yield several advantages including early diagnosis that is critical to psychiatric diseases and accurate criteria for disease, diagnosis, classification, and stratification. It can also allow for advanced personalized therapy and can act, if appropriately, validated as surrogate end points that can eliminate several limitations and greatly advance clinical research Biomarkers Definitions Working Group, ; Zhang et al.
Alawieh, A. Systems biology, bioinformatics and biomarkers in neuropsychiatry. Avena, N. Food and addiction: implications and relevance to eating disorders and obesity. Drug Abuse Rev.
Hanipsych, biomarkers in psychiatry
Pubmed Abstract Pubmed Full Text. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Fang, F. Reductionistic and holistic science. Hayes, R. Glial fibrillary acidic protein: a promising biomarker in pediatric brain injury. Care Med.
Related Biomarkers for Psychiatric Disorders
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