Brain multi-contrast, multi-atlas segmentation of diffusion tensor imaging and ensemble learning automatically diagnose late-life depression.

We investigated the potential of machine learning for diagnostic classification in late-life major depression based on an advanced whole brain white matter segmentation framework. Twenty-six late-life depression and 12 never depressed individuals aged > 55 years, matched for age, MMSE, and education underwent brain diffusion tensor imaging and a multi-contrast, multi-atlas segmentation in MRIcloud. Fractional anisotropy volume, mean fractional anisotropy, trace, axial and radial diffusivity (RD) extracted from 146 white matter parcels for each subject were used to train and test the AdaBoost classifier using stratified 12-fold cross validation. Performance was evaluated using various measures. The statistical power of the classifier was assessed using label permutation test. Statistical analysis did not yield significant differences in DTI measures between the groups. The classifier achieved a balanced accuracy of 71% and an Area Under the Receiver Operator Characteristic Curve (ROC-AUC) of 0.81 by trace, and a balanced accuracy of 70% and a ROC-AUC of 0.80 by RD, in limbic, cortico-basal ganglia-thalamo-cortical loop, brainstem, external and internal capsules, callosal and cerebellar structures. Both indices shared important structures for classification, while fornix was the most important structure for classification by both indices. The classifier proved statistically significant, as trace and RD ROC-AUC scores after permutation were lower than those obtained with the actual data (P = 0.022 and P = 0.024, respectively). Similar results were obtained with the Gradient Boosting classifier, whereas the RBF-kernel Support Vector Machine with k-best feature selection did not exceed the chance level. Finally, AdaBoost significantly predicted the class using all features together. Limitations are discussed. The results encourage further investigation of the implemented methods for computer aided diagnostics and anatomically informed therapeutics.

A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders.

OBJECTIVE: Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed. DESIGN: A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised. RESULTS: In patients with Alzheimer's Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson's Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects. CONCLUSIONS: Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital.

Old-age mental telehealth services at primary healthcare centers in low- resource areas in Greece: design, iterative development and single-site pilot study findings.

BACKGROUND: Even though communities in low-resource areas across the globe are aging, older adult mental and cognitive health services remain mainly embedded in tertiary- or secondary hospital settings, and thus not easily accessible by older adults living in such communities. Here, the iterative development of INTegRated InterveNtion of pSychogerIatric Care (INTRINSIC) services addressing the mental and cognitive healthcare needs of older adults residing in low-resource areas of Greece is depicted. METHODS: INTRINSIC was developed and piloted in three iterative phases: (i) INTRINSIC initial version conceptualization; (ii) A 5-year field testing in Andros island; and (iii) Extending the services. The INTRINSIC initial version relied on a digital platform enabling videoconferencing, a flexible battery of diagnostic tools, pharmacological treatment and psychosocial support and the active involvement of local communities in service shaping. RESULTS: Ιn 61% of the 119 participants of the pilot study, new diagnoses of mental and/or neurocognitive disorders were established. INTRINSIC resulted in a significant reduction in the distance travelled and time spent to visit mental and cognitive healthcare services. Participation was prematurely terminated due to dissatisfaction, lack of interest or insight in 13 cases (11%). Based on feedback and gained experiences, a new digital platform, facilitating e-training of healthcare professionals and public awareness raising, and a risk factor surveillance system were created, while INTRINSIC services were extended to incorporate a standardized sensory assessment and the modified problem adaptation therapy. CONCLUSION: The INTRINSIC model may be a pragmatic strategy to improve access of older adults with mental and cognitive disorders living in low-resource areas to healthcare services.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

Differences in cause and 12-month follow-up outcome of parkinsonian symptoms in depressed older adults treated with antipsychotics: a case series.

BACKGROUND: Parkinsonian symptoms are common adverse effects of antipsychotics. Older adults are particularly vulnerable to drug-induced parkinsonism. Nonetheless, parkinsonian symptoms in seniors treated with antipsychotics cannot be straightforwardly attributed to antipsychotic medication. A comprehensive diagnostic workup is necessary in many cases in order to shed light on the cause of such symptoms in this patient population. CASE SERIES: Eight cases of hospitalized depressed older adults with parkinsonian symptoms, who were treated for at least one year with antipsychotics, are reported. Based on neurological consultation, structural brain imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT), Parkinson's disease was diagnosed in one case, idiopathic tremor in another, vascular parkinsonism in another one, while in another individual parkinsonian symptoms persisted at 12-month post-discharge follow-up even though his/her symptoms were classified as drug-induced on discharge. In four patients, parkinsonian symptoms were definitely drug-induced and no movement disturbances were reported at follow-up. CONCLUSIONS: Differences in the cause and outcome of parkinsonian symptoms in seniors treated with antipsychotics merit systematic and in-depth study considering the therapeutic and prognostic implications of an accurate detection of the cause of such symptoms. Familiarizing clinical psychiatrists with these differences could pave the way towards approaching seniors with severe, atypical and/or persistent parkinsonian symptoms in a more individualized diagnostic and therapeutic manner, and towards more cautious prescribing of antipsychotics in this age group.

COVID-19 Crisis Effects on Caregiver Distress in Neurocognitive Disorder.

BACKGROUND: The outbreak of the COVID-19 pandemic seems to have mental health implications for both people with neurocognitive disorder and their caregivers. OBJECTIVE: The study aimed to shed light on relations between caregiver mental reaction to the pandemic and caregiver distress related to neuropsychiatric symptoms, memory impairment progression, and functional impairment of people with neurocognitive disorder during the period of confinement in Greece. METHODS: The study included caregivers of patients with mild (N = 13) and major (N = 54) neurocognitive disorder. The caregiver-based telephone interview was based on items of the neuropsychiatric inventory questionnaire, the AD8 Dementia Screening Instrument, and the Bristol Activities of Daily Living Scale. Regarding the mental impact of the COVID-19 crisis on caregivers, four single questions referring to their worries in the last seven days were posed, in addition to the scales Generalized Anxiety Disorder 7-Item (GAD-7) and the 22-item Impact of Event Scale-revised (IES-R). A stepwise linear regression model was employed for studying the relationship between caregiver distress and demographic and clinical data and caregiver mental reaction to COVID-19 pandemic outbreak. RESULTS: Caregiver distress severity during the confinement period was influenced not only by memory deficits (p = 0.009) and neuropsychiatric symptoms (p < 0.001) of patients, but also by caregiver hyperarousal (p = 0.003) and avoidance symptoms (p = 0.033) and worries directly linked to the COVID-19 crisis (p = 0.022). CONCLUSION: These observations provide further evidence for the urgent need for support of caregivers of patients with neurocognitive disorder during the COVID-19 pandemic.

Unmet Needs in Pharmacological Treatment of Apathy in Alzheimer's Disease: A Systematic Review.

Background: Apathy is one of the most prevalent neuropsychiatric symptoms encountered in Alzheimer's disease (AD) and may be an early sign in the development of dementia persisting over the disease course. It has been associated with poor disease outcome, impaired daily functioning, and significant caregiver distress. Early diagnosis and timely treatment of apathy in AD are of great importance. However, approved agents for apathy are still missing. Methods: Within this context, we conducted an extensive electronic search in the databases included in the National Library of Medicine, PsychInfo, and Google Scholar for studies that have investigated the effect of pharmacological treatments in apathy in AD. There were no limitations regarding study design and all care settings were considered for inclusion. Structured measures for level of evidence and study quality were employed to evaluate the results. Results: A total of 1,607 records were identified; 1,483 records remained after the removal of duplicates and were screened; 166 full-text articles were selected and assessed for eligibility and a remaining 90 unique studies and relevant reviews were included in the qualitative synthesis. Acetylcholinesterase inhibitors, gingko biloba, and methylphenidate were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity in the studies and the small amount of studies where apathy was the primary outcome are limiting factors to assess for group effects. Conclusions: Pharmacological treatment of apathy in AD is an underexplored field. Standardized and systematic efforts are needed to establish a possible treatment benefit. Elucidating the pathophysiology of apathy and its components or subtypes will inform disease models and mechanistic drug studies that can quantify a benefit from specific agents for specific AD groups.

Acetyl Cholinesterase Inhibitors and Cell-Derived Peripheral Inflammatory Cytokines in Early Stages of Alzheimer's Disease.

BACKGROUND: Clinical and preclinical studies firmly support the involvement of the inflammation in the pathogenesis of Alzheimer's disease (AD). Despite acetylcholinesterase inhibitors (AChEI) being widely used in AD patients, there is no conclusive evidence about their impact on the inflammatory response. METHODS: This study investigates peripheral proinflammatory cytokines (interferon gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukins 1ß [IL-1ß] and 6 [IL-6]) by firstly comparing peripheral blood mononuclear cell (PBMC)-derived secretion in drug-naïve and AChEI-treated AD patients versus healthy controls. A subset of those drug-naïve AD patients, who were prescribed the AChEI donepezil, was followed-up for 6 months to investigate if donepezil suppresses proinflammatory cell-derived cytokine secretion. RESULTS: Patients with AD showed higher levels of PBMC-derived proinflammatory cytokines (IFN-γ, TNF-α, IL-1ß, and IL-6) in comparison with healthy controls. On reexamination, previously drug-naïve AD patients who received donepezil treatment for 6 months displayed a decrease in cell-derived IFN-γ, TNF-α, IL-1ß, and IL-6. CONCLUSIONS: Proinflammatory PBMC-derived cytokines were increased in patients with AD in comparison with healthy controls and donepezil-reduced proinflammatory cytokines when examining drug-naïve AD patients before and after AChEI treatment.

A systematic review of non-pharmacological treatments for apathy in dementia.

OBJECTIVE: Apathy is one of the most frequent neuropsychiatric symptoms encountered in dementia. Early diagnosis and timely treatment of apathy in dementia are crucial because apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. DESIGN: Extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies which have investigated the effect of non-pharmacological treatments of apathy in dementia. Quality of the studies was appraised. RESULTS: A total of 1303 records were identified and 120 full-texts assessed. Forty-three unique studies were reviewed. A variety of interventions were found to be effective in reducing apathy in demented patients, particularly when provided in a multidisciplinary manner. However, quantification of the effect was limited by the marked methodological heterogeneity of the studies and the small number of studies where apathy was the primary outcome measure. CONCLUSIONS: Treatment of apathy in dementia is a complex and underexplored field. Certain studies suggest promise for a variety of non-pharmacological interventions. Standardized and systematic efforts primarily focusing on apathy may establish a benefit from individualized treatments for specific disease groups.

Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities

OBJECTIVE: Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of great importance, since apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. DESIGN: Within this context, we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies that have investigated the effect of pharmacological and nonpharmacological treatments of apathy in AD. RESULTS: Acetylcholinesterase inhibitors, gingko biloba, methylphenidate, and a variety of nonpharmacological interventions were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity of the studies and the small amount of studies where apathy was a primary outcome measure are limiting factors to evaluate for group effects. CONCLUSION: Treatment of apathy in AD is a complicated and an underexplored field. Standardized and systematic efforts primarily focused on the study of apathy in AD may establish a benefit from individualized treatment for specific disease groups that would stem from a combination of both pharmacological and nonpharmacological interventions.

A Review of Pharmacological Treatments for Depression in Alzheimer's Disease.

Depression in Alzheimer's disease (dAD) is one of the most common behavioral and psychological symptoms of dementia, with devastating consequences not only for the affected individuals, but for caregivers as well. So far, pharmacological treatment of dAD has been based on the "monoamine hypothesis". However, the reported moderate effects of approved antidepressants, as well as an increasing body of research evidence, suggest a more complex pathophysiologic mechanism. In the present paper, a systematic review of different treatments for dAD is presented that can inform the study of alternative neuropathological and neurobiological aspects of the disease aimed at the development of more effective treatment targets.

A review of neuroimaging findings of apathy in Alzheimer's disease.

BACKGROUND: Apathy is one of the most frequent "behavioral and psychological signs and symptoms of dementia" (BPSD) encountered in Alzheimer's disease (AD). There is a growing interest in the early diagnosis of apathetic elderly patients in the community since apathy has been associated with reduced daily functioning, caregiver distress, and poor outcome. The generalization of neuroimaging techniques might be able to offer help in this domain. METHODS: Within this context we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for neuroimaging findings of apathy in AD. RESULTS: Neuroimaging findings lend support to the notion that frontal-subcortical networks are involved in the occurrence of apathy in AD. CONCLUSIONS: Longitudinal studies comparing patients and normal individuals might allow us to infer on the association between apathy and neurodegenerative diseases and what can brain imaging markers tell us about the characterization of this association, thus revealing disease patterns, helping to distinguish clinically distinct cognitive syndromes, and allowing predictions.

Pregabalin augmentation of antidepressants in older patients with comorbid depression and generalized anxiety disorder-an open-label study.

OBJECTIVE: The objective of this 12-week open-label study was to evaluate the efficacy, safety, and tolerability of pregabalin as an adjunctive treatment to antidepressants in older patients suffering from depression and comorbid generalized anxiety disorder (GAD). METHODS: The initial sample of this open-label study consisted of 94 older patients fulfilling criteria for depression with comorbid GAD who were treated with antidepressants. Twenty of them who had received antidepressant monotherapy for an adequate time and shown partial response to the antidepressant prescribed, in terms of either anxiety or depressive symptomatology, followed the next phase. During the 12-week study period, pregabalin was gradually added to the previously prescribed antidepressant, reaching 225 mg/day over 4 weeks. Depression and anxiety scores as well as side effects were monitored. Within groups, differences of depression and anxiety scores at baseline and during the following 12 weeks of treatment were estimated with repeated-measure analysis of variance. RESULTS: A statistical significant reduction in depression scores was observed after the 4th week of treatment (p < 0.01), which further improved between the 8th and 12th weeks (p < 0.01). Concerning overall anxiety scores, a statistically significant improvement was noted between the 2nd and 4th weeks (p < 0.01), which further continued throughout the 8th (p < 0.05) and 12th weeks (p < 0.05). CONCLUSIONS: The present study demonstrated a good therapeutic response to pregabalin in patients with depression comorbid with GAD after a 12-week treatment period. Both anxiety and depressive symptomatology significantly improved, and minimal side effects were observed.