Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia.

We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia).Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory - Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia.We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative.Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures. OBJECTIVES: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia), but their brain structural correlates are unknown. We tested for associations between NPS and MRI-based cortical and subcortical morphometry in patients with MCI and AD dementia. DESIGN: Cross-sectional. SETTINGS: Conducted in Norway. PARTICIPANTS: Patients with MCI (n = 102) and AD dementia (n = 133) from the Memory Clinic and the Geriatric Psychiatry Unit at Oslo University Hospital. MEASUREMENTS: Neuropsychiatric Inventory ­ Questionnaire (NPI-Q) severity indices were reduced using principal component analysis (PCA) and tested for associations with 170 MRI features using linear models and false discovery rate (FDR) adjustment. We also tested for differences between groups. For transparency, we added analyses with selected NPI-Q items. RESULTS: PCA revealed four factors: elation, psychosis, depression, and motor behavior.FDR adjustment revealed a significant positive association (B = 0.20, pFDR < 0.005) between elation and thickness of the right caudal anterior cingulate cortex (ACC) across groups, and significant interactions between diagnosis and psychosis (B = −0.48, pFDR < 0.0010) on the left post-central volume and between diagnosis and depression (B = −0.40, pFDR < 0.005) on the thickness of the banks of the left superior temporal sulcus. Associations of apathy, anxiety, and nighttime behavior to the left temporal lobe were replicated. CONCLUSIONS: The positive association between elation and ACC thickness suggests that mechanisms other than atrophy underly elation. Interactions between diagnosis and NPS on MRI features suggest different mechanisms of NPS in our MCI and AD dementia samples. The results contribute to a better understanding of NPS brain mechanisms in MCI and AD dementia.

The effect of anxiety on cognition in older adult inpatients with depression: results from a multicenter observational study.

Late-life depression is associated with reduced cognitive function beyond normal age-related cognitive deficits. As comorbid anxiety frequently occur in late-life depression, this study aimed to examine the association between anxiety symptoms and cognitive function among older inpatients treated for depression. We hypothesized that there would be an overall additive effect of comorbid anxiety symptoms on dysfunction across cognitive domains. The study included 142 patients treated for late-life depression in hospital, enrolled in the Prognosis of Depression in the Elderly study. Anxiety symptoms were measured at admission using the anxiety subscale of the Hospital Anxiety and Depression Scale. Patients completed cognitive tasks at admission and discharge. Linear mixed and generalized linear mixed models were estimated to investigate the effect of anxiety, on continuous and categorical cognitive scores, respectively, while controlling for depression. Anxiety severity at admission was not associated with performance in any of the cognitive domains. Patients with more symptoms of anxiety at admission demonstrated a significant improvement in immediate recall during the hospital stay. Patients with a score above cutoff indicating clinically significant symptoms on the anxiety subscale performed better on general cognitive function, as measured by the Mini Mental Status Examination at admission, than those below cutoff for anxiety. In conclusion, comorbid anxiety symptoms had no additive effect on cognitive dysfunction in late-life depression in our sample of inpatients.

Impaired synaptic function is linked to cognition in Parkinson's disease.

OBJECTIVE: Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid-ß species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid-ß release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid-ß, and presynaptic deposits of α-synuclein. We expect a correlation between hypometabolism, CSF amyloid-ß, and the synapse related-markers CSF neurogranin and α-synuclein. METHODS: Thirty patients with mild-to-moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18F-fludeoxyglucose-PET, and a neuropsychological test battery (repeated for the patients after 2 years). RESULTS: All subjects had CSF amyloid-ß 1-42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aß, α-synuclein, and neurogranin. All PET CSF biomarker-based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mild-to-moderate Parkinson's disease compared to controls, correlated with amyloid-ß and α-synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group. INTERPRETATION: CSF Aß, α-synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aß and α-synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Isobaric Quantification of Cerebrospinal Fluid Amyloid-ß Peptides in Alzheimer's Disease: C-Terminal Truncation Relates to Early Measures of Neurodegeneration.

The amyloid beta (Aß) peptide is the main constituent of the plaques characteristic of Alzheimer's disease (AD). Measurement of Aß1-42 in cerebrospinal fluid (CSF) is a valuable marker in AD research, where low levels indicate AD. Although the use of immunoassays measuring Aß1-38 and Aß1-40 in addition to Aß1-42 has increased, quantitative assays of other Aß peptides remain rarely explored. We recently discovered novel Aß peptides in CSF using antibodies recognizing the Aß mid-domain region. Here we have developed a method using both Aß N-terminal and mid-domain antibodies for immunoprecipitation in combination with isobaric labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for relative quantification of endogenous Aß peptides in CSF. The developed method was used in a pilot study to produce Aß peptide profiles from 38 CSF samples. Statistical comparison between CSF samples from 19 AD patients and 19 cognitively healthy controls revealed no significant differences at group level. A significant correlation was found between several larger C-terminally truncated Aß peptides and protein biomarkers for neuronal damage, particularly prominent in the control group. Comparison of the isobaric quantification with immunoassays measuring Aß1-38 or Aß1-40 showed good correlation (r(2) = 0.84 and 0.85, respectively) between the two analysis methods. The developed method could be used to assess disease-modifying therapies directed at Aß production or degradation.