Robert M. Cohen

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss.

Alzheimers disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The “amyloid cascade hypothesis” posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Ocular Changes in TgF344-AD Rat Model of Alzheimer's Disease

PURPOSE Alzheimers disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed. METHODS Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response and luminance threshold recording from the superior colliculus. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques. RESULTS As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature. CONCLUSIONS In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was observed further in human AD retina. Along with Ab deposition, the inflammatory response was manifested by microglial recruitment and complement activation. Further studies are needed to elucidate the significance and mechanisms of these pathological changes [corrected].

Incorporating multidimensional patient-reported outcomes of symptom severity, functioning, and quality of life in the Individual Burden of Illness Index for Depression to measure treatment impact and recovery in MDD.

CONTEXT The National Institute of Mental Health Affective Disorders Workgroup identified the assessment of an individuals burden of illness as an important need. The Individual Burden of Illness Index for Depression (IBI-D) metric was developed to meet this need. OBJECTIVE To assess the use of the IBI-D for multidimensional assessment of treatment efficacy for depressed patients. DESIGN, SETTING, AND PATIENTS Complete data on depressive symptom severity, functioning, and quality of life (QOL) from depressed patients (N = 2280) at entry and exit of level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (12-week citalopram treatment) were used as the basis for calculating IBI-D and self-rating scale changes. RESULTS Principal component analysis of patient responses at the end of level 1 of STAR*D yielded a single principal component, IBI-D, with a nearly identical eigenvector to that previously reported. While changes in symptom severity (Quick Inventory of Depressive Symptomatology-Self Report) accounted for only 50% of the variance in changes in QOL (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) and 47% of the variance in changes in functioning (Work and Social Adjustment Scale), changes in IBI-D captured 83% of the variance in changes in QOL and 80% in functioning, while also capturing 79% of the variance in change in symptom severity (Quick Inventory of Depressive Symptomatology-Self Report). Most importantly, the changes in IBI-D of the 36.6% of remitters who had abnormal QOL and/or functioning (mean [SD], 2.98 [0.35]) were significantly less than the changes in IBI-D of those who reported normal QOL and functioning (IBI-D = 1.97; t = 32.6; P < 10(-8)) with an effect size of a Cohen d of 2.58. In contrast, differences in symptom severity, while significant, had a Cohen d of only 0.78. CONCLUSIONS Remission in depressed patients, as defined by a reduction in symptom severity, does not denote normal QOL or functioning. By incorporating multidimensional patient-reported outcomes, the IBI-D provides a single measure that adequately captures the full burden of illness in depression both prior to and following treatment; therefore, it offers a more accurate metric of recovery. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00021528.

Quality of life in major depressive disorder before/after multiple steps of treatment and one-year follow-up

This study examines the impact of major depressive disorder (MDD) and its treatment on quality of life (QOL).

Sexual Satisfaction and Quality of Life in Major Depressive Disorder Before and After Treatment With Citalopram in the STAR *D Study

OBJECTIVE Major depressive disorder (MDD) patients often experience impaired sexual satisfaction (ISS) and poor quality of life (QOL). Selective serotonin reuptake inhibitors (SSRIs), the first-line treatment for MDD, can cause sexual dysfunction, potentially worsening ISS and QOL. This study examined the impact of MDD and the SSRI citalopram on sexual satisfaction and QOL in level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (July 2001-September 2006). METHOD A retrospective analysis was conducted of the change in sexual satisfaction, as measured by item 9 of the Quality of Life Enjoyment and Satisfaction Questionnaire, the primary outcome measure, in 2,280 patients with DSM-IV-TR-defined MDD who were treated with citalopram for 12 weeks. The Quick Inventory of Depressive Symptomatology-Self Report was used to evaluate the impact of depression ratings on impaired sexual satisfaction and on QOL. RESULTS Impaired sexual satisfaction was present in 64.3% of MDD patients at pretreatment, but that percentage declined to 47.1% at posttreatment with citalopram (P < .0001). Those who achieved remission had less ISS and better QOL. The prevalence of ISS in remitters was 21.2% versus 61.3% in nonremitters (P < 10(-8)). The mean ± standard deviation score for remitters increased from 2.32 ± 1.16 to 3.44 ± 1.23 (P < 10(-8); Cohen d = 0.81 [large effect size]), whereas in nonremitters it increased only from 1.99 ± 1.08 to 2.19 ± 1.19 (P < 10(-8); Cohen d = 0.16). The difference between remitters and nonremitters was highly significant (P < 10(-8)). Regression analyses at pretreatment and posttreatment demonstrated significant associations between depressive symptoms and ISS (P < .0001) and between ISS and lower QOL (P < .0001) as well as an association between citalopram and increased probability of ISS and a poorer QOL in patients who continue to have moderate-to-severe depression. CONCLUSIONS A majority of MDD patients have impaired sexual satisfaction, a symptom associated with poor QOL. Despite the sexual side effects of the SSR citalopram, treating depression to full remission was associated with improvements in sexual satisfaction and QOL. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.

Low-level laser therapy for beta amyloid toxicity in rat hippocampus.

Beta amyloid (Aβ) is well accepted to play a central role in the pathogenesis of Alzheimers disease (AD). The present work evaluated the therapeutic effects of low-level laser irradiation (LLI) on Aβ-induced neurotoxicity in rat hippocampus. Aβ 1-42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and 2-minute daily LLI treatment was applied transcranially after Aβ injection for 5 consecutive days. LLI treatment suppressed Aβ-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: (1) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aβ-induced extensive fragmentation; (2) suppressed Aβ-induced collapse of mitochondrial membrane potential; (3) reduced oxidized mitochondrial DNA and excessive mitophagy; (4) facilitated mitochondrial homeostasis via modulation of the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and of mitochondrial antioxidant expression; (5) promoted cytochrome c oxidase activity and adenosine triphosphate synthesis; (6) suppressed Aβ-induced glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity; (7) enhanced the total antioxidant capacity of hippocampal CA1 neurons, whereas reduced the oxidative damage; and (8) suppressed Aβ-induced reactive gliosis, inflammation, and tau hyperphosphorylation. Although development of AD treatments has focused on reducing cerebral Aβ levels, by the time the clinical diagnosis of AD or mild cognitive impairment is made, the brain is likely to have already been exposed to years of elevated Aβ levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aβ-induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis, and tau pathology, LLI could represent a new promising therapeutic strategy for AD.

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a suitable model of locus coeruleus pathology and dysfunction early in Alzheimer’s disease progression, and suggest that a substantial window of opportunity for locus coeruleus/ norepinephrine-based therapeutics exists.

Predicting relapse in major depressive disorder using patient-reported outcomes of depressive symptom severity, functioning, and quality of life in the individual burden of illness index for depression (IBI-D)

BACKGROUND Patients with Major Depressive Disorder (MDD) often experience unexpected relapses, despite achieving remission. This study examines the utility of a single multidimensional measure that captures variance in patient-reported Depressive Symptom Severity, Functioning, and Quality of Life (QOL), in predicting MDD relapse. METHODS Complete data from remitted patients at the completion of 12 weeks of citalopram in the STAR*D study were used to calculate the Individual Burden of Illness index for Depression (IBI-D), and predict subsequent relapse at six (n=956), nine (n=778), and twelve months (n=479) using generalized linear models. RESULTS Depressive Symptom Severity, Functioning, and QOL were all predictors of subsequent relapse. Using Akaike information criteria (AIC), the IBI-D provided a good model for relapse even when Depressive Symptom Severity, Functioning, and QOL were combined in a single model. Specifically, an increase of one in the IBI-D increased the odds ratio of relapse by 2.5 at 6 months (β=0.921 ± 0.194, z=4.76, p<2 × 10(-6)), by 2.84 at 9 months (β=1.045 ± 0.22, z=4.74, p<2.2 × 10(-6)), and by 4.1 at 12 months (β=1.41 ± 0.29, z=4.79, p<1.7 × 10(-6)). LIMITATIONS Self-report poses a risk to measurement precision. Using highly valid and reliable measures could mitigate this risk. The IBI-D requires time and effort for filling out the scales and index calculation. Technological solutions could help ease these burdens. The sample suffered from attrition. Separate analysis of dropouts would be helpful. CONCLUSIONS Incorporating patient-reported outcomes of Functioning and QOL in addition to Depressive Symptom Severity in the IBI-D is useful in assessing the full burden of illness and in adequately predicting relapse, in MDD.

Patient-reported outcomes of quality of life, functioning, and depressive symptom severity in major depressive disorder comorbid with panic disorder before and after SSRI treatment in the star*d trial.

Panic disorder (PD) is highly comorbid with major depressive disorder (MDD) with potential impact on patient‐reported outcomes of quality of life (QOL), functioning, and depressive symptom severity.

Patient-reported functioning in major depressive disorder

Objectives: Compared with the general population, patients with major depressive disorder (MDD) report substantial deficits in their functioning that often go beyond the clinical resolution of depressive symptoms. This study examines the impact of MDD and its treatment on functioning. Methods: From the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, we analyzed complete data of 2280 adult outpatients with MDD at entry and exit points of each level of antidepressant treatment and again 12 months post treatment. Functioning was measured using the Work and Social Adjustment Scale (WSAS). Results: The results show that only 7% of patients with MDD reported within-normal functioning before treatment. The proportion of patients achieving within-normal functioning (WSAS) scores significantly increased after treatment. However, the majority of patients (>60%) were still in the abnormal range on functioning at exit. Although remitted patients had greater improvements compared with nonremitters, a moderate proportion of remitted patients continued to experience ongoing deficits in functioning after treatment (20–40%). Follow-up data show that the proportions of patients experiencing normal scores for functioning after 12 months significantly decreased from the end of treatment to the follow-up phase, from 60.1% to 49% (p < 0.0001), a finding that was particularly significant in nonremitters. Limitations of this study include the reliance on self-report of functioning and the lack of information on patients who dropped out. Conclusion: This study points to the importance of functional outcomes of MDD treatment as well as the need to develop personalized interventions to improve functioning in MDD.