An artificial intelligence-derived metabolic network predicts psychosis in Alzheimer's disease.

Psychosis in Alzheimer’s Disease

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Phenomenological Distinctions Needed in DSM-V: Delirium, Subsyndromal Delirium, and Dementias

Effects of sex, educational background, and chronic kidney disease grading on longitudinal cognitive and functional decline in patients in the Japanese Alzheimer's Disease Neuroimaging Initiative study

The study aimed to evaluate and quantify the temporal link between cognitive and functional decline, and assess the impact of the apolipoprotein E4 (APOE-e4) genotype on Alzheimer's disease (AD) progression. A nonlinear mixed-effects Emax model was developed using longitudinal data from 659 patients with dementia due to AD sourced from the Alzheimer's disease neuroimaging initiative (ADNI) database. A cognitive decline model was first built using a cognitive subscale of the AD assessment scale (delayed word recall) as the endpoint, followed by a functional decline model, using the functional assessment questionnaire (FAQ) as the endpoint. Individual and population cognitive decline from the first model drove a functional decline in the second model. The impact of the APOE-e4 genotype status on the dynamics of AD progression was evaluated using the model. Mixed-effects Emax models adequately quantified population average and individual disease trajectories. The model captured a higher initial cognitive impairment and final functional impairment in APOE-e4 carriers than non-carriers. The age at cognitive decline and diagnosis of dementia due to AD was significantly lower in APOE-e4 carriers than that of non-carriers. The average [standard deviation] time shift between cognitive and functional decline, i.e. the time span between half of the maximum cognitive decline and half of the maximum functional decline, was estimated as 1.5 [1.6] years. The present analysis quantifies the temporal link between a cognitive and functional decline in AD progression at the population and individual level, and provides information about the potential benefits of pre-clinical AD treatments on both cognition and function.

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Psychosis in Alzheimer’s Disease is Associated with Frontal Metabolic Impairment and Accelerated Decline in Working Memory: Findings from the Alzheimer's Disease Neuroimaging Initiative

INTRODUCTIONCerebrospinal fluid (CSF) α‐synuclein (α‐syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co‐pathology in Alzheimer's disease.METHODSA total of 1637 cross‐sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α‐syn seeds, and phosphorylated tau181 (p‐tau181), along with global and domain‐specific cognition in stable SAA+, stable SAA−, and those who converted to SAA+ from SAA−.RESULTSSAA+ individuals had faster cognitive decline than SAA−, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p‐tau181 status. CSF Aβ42, p‐tau181, and α‐syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α‐syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.DISCUSSIONThese results highlight the interplay between amyloid and α‐syn and their association with disease progression.HighlightsSeed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset.Thirty‐four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA− to SAA+, that is, ≈ 5% conversion.SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline.SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers.Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA.SAA kinetic parameters were associated with clinical features and progression.

Association between Cerebrospinal Fluid sTREM2 Levels and Depression: The Alzheimer's Disease Neuroimaging Initiative Study.

Brain reserve, cognitive reserve, and education are thought to protect against late-life cognitive decline, but these variables have not been directly compared to one another in the same model, using future cognitive and functional decline as outcomes. We sought to determine whether the influence of these protective factors on executive function (EF) and daily function decline was dependent upon Alzheimer's disease (AD) pathology severity, as measured by the total tau to beta-amyloid (T-τ/Aβ1-42) ratio in cerebrospinal fluid (CSF). Participants were 1201 older adult volunteers in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Brain reserve was defined using a composite index of structural brain volumes (total brain matter, hippocampus, and white matter hyperintensity). Cognitive reserve was defined as the variance in episodic memory performance not explained by brain integrity and demographics. At higher levels of T-τ/Aβ1-42, brain and cognitive reserve predicted slower decline in EF. Only brain reserve attenuated decline at lower levels of T-τ/Aβ1-42. Education had no independent association with cognitive decline. These results point to a hierarchy of protection against aging- and disease-associated cognitive decline. When pathology is low, only structural brain integrity predicts rate of future EF decline. The ability of cognitive reserve to predict future EF decline becomes stronger as CSF biomarker evidence of AD increases. Although education is typically thought of as a proxy for cognitive reserve, it did not show any protective effects on cognition after accounting for brain integrity and the residual cognitive reserve index.

INTRODUCTIONHearing loss is identified as one of the largest modifiable risk factors for cognitive impairment and dementia. Studies evaluating this relationship have yielded mixed results.METHODSWe investigated the longitudinal relationship between self‐reported hearing loss and cognitive/functional performance in 695 cognitively normal (CN) and 941 participants with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative.RESULTSWithin CN participants with hearing loss, there was a significantly greater rate of cognitive decline per modified preclinical Alzheimer's cognitive composite. Within both CN and MCI participants with hearing loss, there was a significantly greater rate of functional decline per the functional activities questionnaire (FAQ). In CN and MCI participants, hearing loss did not significantly contribute to the risk of progression to a more impaired diagnosis.DISCUSSIONThese results confirm previous studies demonstrating a significant longitudinal association between self‐reported hearing loss and cognition/function but do not demonstrate an increased risk of conversion to a more impaired diagnosis.CLINICAL TRIAL REGISTRATION INFORMATIONNCT00106899 (ADNI: Alzheimer's Disease Neuroimaging Initiative, clinicaltrials.gov), NCT01078636 (ADNI‐GO: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity, clinicaltrials.gov), NCT01231971 (ADNI2: Alzheimer's Disease Neuroimaging Initiative 2, clinicaltrials.gov), NCT02854033 (ADNI3: Alzheimer's Disease Neuroimaging Initiative 3, clinicaltrials.gov).HighlightsHearing loss is a potential modifiable risk factor for dementia.We assessed the effect of self‐reported hearing loss on cognition and function in the ADNI cohort.Hearing loss contributes to significantly faster cognitive and functional decline.Hearing loss was not associated with conversion to a more impaired diagnosis.

The aim of this study was to examine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting subsequent rates of functional and cognitive decline among subjects considered cognitively normal (CN) or clinically diagnosed with mild cognitive impairment (MCI). Analyses of 276 subjects, 92 CN subjects and 184 with MCI, who were enrolled in the Alzheimer's Disease Neuroimaging Initiative, were conducted. Functional decline was assessed using scores on the Functional Activities Questionnaire (FAQ) obtained over a period of 36months, while cognitive decline was determined using the Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) scores. PET images were analyzed using clinically routine brain quantification software. A dementia prognosis index (DPI), derived from a ratio of uptake values in regions of interest known to be hypometabolic in Alzheimer's disease to regions known to be stable, was generated for each baseline FDG-PET scan. The DPI was correlated with change in scores on the neuropsychological examinations to examine the predictive value of baseline FDG-PET. DPI powerfully predicted rate of functional decline among MCI patients (t=5.75, p < 1.0E-8) and pooled N + MCI patient groups (t = 7.02, p < 1.0E-11). Rate of cognitive decline on MMSE was also predicted by the DPI among MCI (t = 6.96, p < 1.0E-10) and pooled N + MCI (t = 8.78, p < 5.0E-16). Rate of cognitive decline on ADAS-cog was powerfully predicted by the DPI alone among N (p < 0.001), MCI (t = 6.46, p < 1.0E-9) and for pooled N + MCI (t = 8.85, p = 1.1E-16). These findings suggest that an index, derivable from automated regional analysis of brain PET scans, can be used to help predict rates of functional and cognitive deterioration in the years following baseline PET.

Predictive structural dynamic network analysis

Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

Determining the genetic architecture of late onset Alzheimer's disease remains an important research objective. One approach to the identification of novel genetic variants contributing to the disease is the classification of biologically meaningful subgroups within the larger late-onset Alzheimer's disease phenotype. The occurrence of psychotic symptoms in patients with late-onset Alzheimer's disease may identify one such group. We attempted to establish methods for the reliable assessment of psychotic symptoms in a large, geographically dispersed collection of families, multiply affected with late onset Alzheimer's disease, who were participants in the larger National Institute on Aging Late Onset Alzheimer's Disease Family Study; and to characterize the correlates and familial aggregation of psychosis within this cohort. We found that reliable assessments of psychotic symptoms during in-person or phone interviews were readily implemented. The presence of psychosis in late onset Alzheimer's disease was significantly associated with degree of cognitive impairment, and significantly, albeit modestly, correlated with the severity of other behavioural symptoms. Psychosis significantly aggregated within late onset Alzheimer's disease families suggesting that it may identify a genetically determined subgroup. Future studies should examine the linkage and association of psychosis with genetic variation within these families.