Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

Utility of cortical tissue analysis in normal pressure hydrocephalus.

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer's disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aß + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer's disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex.

Antipsychotic Use Among 1144 Patients After Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- At acute phase and neurointensive care, patients with aneurysmal subarachnoid hemorrhage (aSAH) may become agitated or delirious. We found no previous studies on psychotic disorders or antipsychotic drug (APD) use by long-term aSAH survivors. We defined the APD use and its risk factors among 12-month survivors of aSAH in an Eastern Finnish population-based cohort with long-term follow-up. Methods- We analyzed APD use in 1144 consecutive patients with aSAH alive at 12 months of the Kuopio intracranial aneurysm patient and family database and their age, sex, and birth municipality matched controls (3:1; n=3432) from 1995 to 2013 and median follow-up of 9 years. Using the Finish nationwide health registries, we obtained drug purchase and hospital discharge data. Results- In total, 140 (12%) of the 1144 patients started APD use first time after aSAH (index date), in contrast to 145 (4%) of the 3432 matched population controls. The cumulative rate of starting APD was 6% at 1 year and 9% at 5 years, in contrast to 1% and 2% in the controls, respectively. The rates at 1 and 5 years were only 1% and 2% in the 489 patients with a good condition (modified Rankin Scale score, 0 or 1 at 12 months; no shunt, intracerebral hemorrhage, or intraventricular hemorrhage). Instead, the highest rate of APD use, 23% at 5 years was among the 192 patients shunted for hydrocephalus after aSAH. Eighty-eight (63%) of the 140 aSAH patients with APD use had also concomitant antidepressant or antiepileptic drug use. Conclusions- The 12-month survivors of aSAH were significantly more likely to be started on APD after aSAH than their matched population controls. These patients often used antidepressant and antiepileptic drugs concomitantly. The use of APDs strongly correlated with signs of brain injury after aSAH, with low use if no signs of significant brain injury were present.

Deep learning assisted quantitative analysis of Aß and microglia in patients with idiopathic normal pressure hydrocephalus in relation to cognitive outcome.

Neuropathologic changes of Alzheimer disease (AD) including Aß accumulation and neuroinflammation are frequently observed in the cerebral cortex of patients with idiopathic normal pressure hydrocephalus (iNPH). We created an automated analysis platform to quantify Aß load and reactive microglia in the vicinity of Aß plaques and to evaluate their association with cognitive outcome in cortical biopsies of patients with iNPH obtained at the time of shunting. Aiforia Create deep learning software was used on whole slide images of Iba1/4G8 double immunostained frontal cortical biopsies of 120 shunted iNPH patients to identify Iba1-positive microglia somas and Aß areas, respectively. Dementia, AD clinical syndrome (ACS), and Clinical Dementia Rating Global score (CDR-GS) were evaluated retrospectively after a median follow-up of 4.4 years. Deep learning artificial intelligence yielded excellent (>95%) precision for tissue, Aß, and microglia somas. Using an age-adjusted model, higher Aß coverage predicted the development of dementia, the diagnosis of ACS, and more severe memory impairment by CDR-GS whereas measured microglial densities and Aß-related microglia did not correlate with cognitive outcome in these patients. Therefore, cognitive outcome seems to be hampered by higher Aß coverage in cortical biopsies in shunted iNPH patients but is not correlated with densities of surrounding microglia.

Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort.

BACKGROUND AND OBJECTIVES: Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH). METHODS: We used a case-control study design implementing FinnGen data containing 473,691 Finns with genotypes and nationwide health records. Patients with NPH were selected based on ICD-10 G91.2 diagnosis. To select patients with idiopathic NPH (iNPH) for sensitivity analysis, we excluded patients with a potentially known etiology of the condition using an algorithm on their disease history. The controls were the remaining non-hydrocephalic participants. For a replication analysis, the NPH cohort from UK Biobank (UKBB) was used. RESULTS: We included 1,522 patients with NPH (mean age 72.2 years, 53% women) and 451,091 controls (mean age 60.5 years, 44% women). In the GWAS comparing patients with NPH with the controls, we identified 6 gene regions significantly (p < 5.0e-8) associated with NPH that replicated in a meta-analysis with UKBB (NPH n = 173). The top loci near the following genes were rs7962263, SLCO1A2 (odds ratio [OR] 0.71, 95% CI 0.65-0.78, p = 1.0e-14); rs798495, AMZ1/GNA12 (OR 1.29, 95% CI 1.20-1.39, p = 2.9e-12); rs10828247, MLLT10 (OR 0.77, 95% CI 0.71-0.83, p = 1.5e-11); rs561699566 and rs371919113, CDCA2 (OR 0.76, 95% CI 0.70-0.82, p = 1.5e-11); rs56023709, C16orf95 (OR 1.24, 95% CI 1.16-1.33, p = 3.0e-9); and rs62434144, PLEKHG1 (OR 1.23, 95% CI 1.14-1.32, p = 1.4e-8). In the sensitivity analysis comparing only patients with iNPH (n = 1,055) with the controls (n = 451,091), 4 top loci near the following genes remained significant: rs7962263, SLCO1A2 (OR 0.70, 95% CI 0.63-0.78, p = 2.1e-11); rs10828247, MLLT10 (OR 0.74, 95% CI 0.62-0.82, p = 4.6e-10); rs798511, AMZ1/GNA12 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8); and rs56023709, C16orf95 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8). DISCUSSION: We identified 6 loci significantly associated with NPH in the thus far largest GWAS in chronic hydrocephalus. The genes near the top loci have previously been associated with blood-brain barrier and blood-CSF barrier function and with increased lateral brain ventricle volume. The effect sizes and allele frequencies remained similar in NPH and iNPH cohorts, indicating the identified loci are risk determinants for iNPH and likely not explained by associations with other etiologies. However, the exact role of these loci is still unknown, warranting further studies.

Novel cerebrospinal fluid biomarkers correlating with shunt responsiveness in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer's disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-ß 1-42 (Aß1-42) to serve as predictors of shunt response. METHODS: We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC-MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness. RESULTS: We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = - 0.46, log2(fold change (FC)) = - 0.25, p < 0.001), ANXA4 (R = 0.46, log2(FC) = 0.32, p < 0.001), MIF (R = -0.49, log2(FC) = - 0.20, p < 0.001) and B3GAT2 (R = 0.54, log2(FC) = 0.20, p < 0.001). In addition, five biomarker candidates were selected based on their strong correlation with gait speed change 1 year after shunt installation: ITGB1 (R = - 0.48, p < 0.001), YWHAG (R = - 0.41, p < 0.01), OLFM2 (R = 0.39, p < 0.01), TGFBI (R = - 0.38, p < 0.01), and DSG2 (R = 0.37, p < 0.01). Concentrations of the CSF AD core biomarkers did not differ significantly with shunt responsiveness. CONCLUSION: FABP3, MIF, ANXA4, B3GAT2, ITGB1, YWHAG, OLFM2, TGFBI and DSG2 in CSF are promising prognostic biomarker candidates to predict shunt responsiveness in iNPH patients.

Early Alzheimer's disease pathology in human cortex is associated with a transient phase of distinct cell states.

Cellular perturbations underlying Alzheimer's disease are primarily studied in human postmortem samples and model organisms. Here we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of Alzheimer's disease pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the Early Cortical Amyloid Response-were prominent in neurons, wherein we identified a transient state of hyperactivity preceding loss of excitatory neurons, which correlated with the selective loss of layer 1 inhibitory neurons. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathological burden increased. Lastly, both oligodendrocytes and pyramidal neurons upregulated genes associated with amyloid beta production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

The CERAD Neuropsychological Battery in Patients with Idiopathic Normal Pressure Hydrocephalus Compared with Normal Population and Patients with Mild Alzheimer's Disease.

BACKGROUND: The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown. OBJECTIVE: To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer's disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB. METHODS: We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal cortical brain biopsies in iNPH patients' cognitive profiles were examined. RESULTS: The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p = 0.016) and Clock Drawing (p < 0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p < 0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results. CONCLUSION: At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients' results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone.

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-ß (Aß) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aß plaques in frontal cortical brain biopsy and 13 iNPH patients without Aß pathology. CSF Amyloid-ß42 (Aß42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. RESULTS: All biomarkers but Aß42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aß42 instead showed divergent longitudinal decrease between Aß-positive and -negative patients in L-CSF, and thereafter increase in Aß-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aß42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aß42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aß42 showed higher concentration in non-carriers of allele ɛ4. CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aß pathology, while NFL normalized toward its pre-shunt levels. Aß42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Lack of impact of polycystic kidney disease on the outcome of aneurysmal subarachnoid hemorrhage: a matched case-control study.

OBJECTIVE: The authors set out to study whether autosomal dominant polycystic kidney disease (ADPKD), an established risk factor for intracranial aneurysms (IAs), affects the acute course and long-term outcome of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The outcomes of 32 ADPKD patients with aSAH between 1980 and 2015 (median age 43 years; 50% women) were compared with 160 matched (age, sex, and year of aSAH) non-ADPKD aSAH patients in the prospectively collected Kuopio Intracranial Aneurysm Patient and Family Database. RESULTS: At 12 months, 75% of the aSAH patients with ADPKD versus 71% of the matched-control aSAH patients without ADPKD had good outcomes (Glasgow Outcome Scale score 4 or 5). There was no significant difference in condition at admission. Hypertension had been diagnosed before aSAH in 69% of the ADPKD patients versus 27% of controls (p < 0.001). Multiple IAs were present in 44% of patients in the ADPKD group versus 25% in the control group (p = 0.03). The most common sites of ruptured IAs were the anterior communicating artery (47% vs 29%, p = 0.05) and the middle cerebral artery bifurcation (28% vs 31%), and the median size was 6.0 mm versus 8.0 mm (p = 0.02). During the median follow-up of 11 years, a second aSAH occurred in 3 of 29 (10%) ADPKD patients and in 4 of 131 (3%) controls (p = 0.11). A fatal second aSAH due to a confirmed de novo aneurysm occurred in 2 (6%) of the ADPKD patients but in none of the controls (p = 0.027). CONCLUSIONS: The outcomes of ADPKD patients with aSAH did not differ significantly from those of matched non-ADPKD aSAH patients. ADPKD patients had an increased risk of second aSAH from a de novo aneurysm, warranting long-term angiographic follow-up.

Diabetes is associated with familial idiopathic normal pressure hydrocephalus: a case-control comparison with family members.

BACKGROUND: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families. METHODS: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann-Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses. RESULTS: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1-12.9, p = 0.030). CONCLUSIONS: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.

Prevalence of Schizophrenia in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a progressive and potentially treatable neurodegenerative disease affecting elderly people, characterized by gait impairment and ventricular enlargement in brain imaging. Similar findings are seen in some patients with schizophrenia (SCZ). OBJECTIVE: To determine the prevalence of SCZ among patients suffering from probable or possible iNPH and the specific effects of comorbid SCZ on the outcome of the cerebrospinal fluid (CSF) shunting. METHODS: All medical records of the 521 iNPH patients in the NPH registry were retrospectively analyzed from 1991 until 2017. The prevalence of comorbidity of SCZ was determined and compared to that of general aged (≥65 yr) population in Finland. RESULTS: We identified a total of 16 (3.1%) iNPH patients suffering from comorbid SCZ. The prevalence of SCZ among the iNPH patients was significantly higher compared to the general population (3.1% vs 0.9%, P < .001). All iNPH patients with comorbid SCZ were CSF shunted and 12 (75%) had a clinically verified shunt response 3 to 12 mo after the procedure. The CSF shunt response rate did not differ between patients with and without comorbid SCZ. CONCLUSION: SCZ seems to occur 3 times more frequently among iNPH patients compared to the general aged population in Finland. The outcome of the treatment was not affected by comorbid SCZ and therefore iNPH patients suffering from comorbid SCZ should not be left untreated. These results merit validation in other populations. In addition, further research towards the potential connection between these chronic conditions is warranted.

Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer's disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. OBJECTIVE: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. METHODS: 335 shunted iNPH-patients (median 74 years) were followed until death (n = 185) or 6/2015 (n = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). CONCLUSION: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD.

Copy number loss in SFMBT1 is common among Finnish and Norwegian patients with iNPH.

OBJECTIVE: To evaluate the role of the copy number loss in SFMBT1 in a Caucasian population. METHODS: Five hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of SFMBT1 was determined using quantitative PCR. RESULTS: The copy number loss in intron 2 of SFMBT1 was detected in 10% of Finnish (odds ratio [OR] = 1.9, p = 0.0078) and in 21% of Norwegian (OR = 4.7, p < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in SFMBT1 were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between SFMBT1 copy number loss carriers and noncarriers. CONCLUSIONS: This is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of SFMBT1 among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.

Why Does the Health-Related Quality of Life in Idiopathic Normal-Pressure Hydrocephalus Fail to Improve Despite the Favorable Clinical Outcome?

OBJECTIVE: Occasionally, a favorable clinical disease-specific outcome does not reflect into improved generic health-related quality of life (HRQoL) in patients with idiopathic normal-pressure hydrocephalus (iNPH) at 1 year after the installation of a cerebrospinal fluid shunt. Our aim was to identify factors causing this discrepancy. METHODS: The 1-year HRQoL outcomes of 141 patients with iNPH were evaluated with the generic 15D instrument, in which the minimum clinically important change/difference on the 0-1 scale has been estimated to be ±0.015. A 12-point iNPH grading scale (iNPHGS) was used as a clinical disease-specific outcome measure, in which a 1-point decrease is considered to be clinically important. We identified 29 (21%) patients with iNPH from our prospective study whose HRQoL deteriorated or remained the same despite of a favorable iNPHGS outcome. We analyzed this discrepancy using patients' clinical variables and characteristics. RESULTS: Multivariate binary logistic regression analysis indicated that a greater (worse) iNPHGS score at baseline (adjusted odds ratio [OR], 1.7; 95% confidence interval [CI] 1.3-2.3; P < 0.001), comorbid chronic pulmonary disease (40% vs. 20%; adjusted OR 17.8; 95% CI 3.6-89.9; P < 0.001), and any comorbid nonmetastatic tumor (62% vs. 17%; adjusted OR 11.5; 95% CI 1.5-85.3; P = 0.017) predicted discrepancy between iNPHGS and 15D outcomes. CONCLUSIONS: Frail patients suffering from certain pre-existing comorbidities may not experience improvement in generic HRQoL despite of a favorable clinical disease-specific response. Acknowledging the comorbidity burden of the patient may help clinicians and the patients to understand the conflict between patient-reported and clinical outcomes.