Lower cerebral blood flow is associated with faster cognitive decline in Alzheimer's disease

OBJECTIVE: To determine whether lower cerebral blood flow (CBF) is associated with faster cognitive decline in patients with Alzheimer's disease (AD). METHODS: We included 88 patients with dementia due to AD from the Amsterdam Dementia Cohort. Mean follow-up was 2 ± 1 years. Linear mixed models were used to determine associations of lower whole brain and regional pseudo-continuous arterial spin labelling measured CBF with rate of cognitive decline as measured with repeated mini-mental state examination (MMSE). Model 1 was adjusted for age, sex, and education. Model 2 was additionally adjusted for normalized gray matter volume, medial temporal lobe atrophy, white matter hyperintensities, microbleeds, and lacunes. Analyses were repeated after partial volume correction (PVC) of CBF. Statistical significance was set at p ≤ 0.05. RESULTS: Patients were 65 ± 7 years old, 44 (50 %) were women, and mean baseline MMSE was 22 ± 4. Annual decline (β[SE]) on the MMSE was estimated at -2.11 (0.25) points per year. Lower whole brain (β[SE]-0.50[0.25]; p ≤ 0.05) and parietal (β[SE]-0.59[0.25]; p < 0.05) CBF were associated with faster cognitive decline. PVC cortical CBF was not associated with cognitive decline. CONCLUSIONS: Lower CBF, in particular in the posterior brain regions, may have value as a prognostic marker for rate of cognitive decline in AD. KEY POINTS: • In AD, lower CBF is associated with more rapid cognitive decline. • Decreasing CBF does not reach a plateau early in AD. • PcASL-CFB has additive value to conventional structural MRI measures in AD

A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline

OBJECTIVES: Grey matter network disruptions in Alzheimer's disease (AD) are associated with worse cognitive impairment cross-sectionally. Our aim was to investigate whether indications of a more random network organization are associated with longitudinal decline in specific cognitive functions in individuals with subjective cognitive decline (SCD). EXPERIMENTAL DESIGN: We included 231 individuals with SCD who had annually repeated neuropsychological assessment (3 ± 1 years; n = 646 neuropsychological investigations) available from the Amsterdam Dementia Cohort (54% male, age: 63 ± 9, MMSE: 28 ± 2). Single-subject grey matter networks were extracted from baseline 3D-T1 MRI scans and we computed basic network (size, degree, connectivity density) and higher-order (path length, clustering, betweenness centrality, normalized path length [lambda] and normalized clustering [gamma]) parameters at whole brain and/or regional levels. We tested associations of network parameters with baseline and annual cognition (memory, attention, executive functioning, language composite scores, and global cognition [all domains with MMSE]) using linear mixed models, adjusted for age, sex, education, scanner and total gray matter volume. PRINCIPAL OBSERVATIONS: Lower network size was associated with steeper decline in language (β ± SE = 0.12 ± 0.05, p < 0.05FDR). Higher-order network parameters showed no cross-sectional associations. Lower gamma and lambda values were associated with steeper decline in global cognition (gamma: β ± SE = 0.06 ± 0.02); lambda: β ± SE = 0.06 ± 0.02), language (gamma: β ± SE = 0.11 ± 0.04; lambda: β ± SE = 0.12 ± 0.05; all p < 0.05FDR). Lower path length values in precuneus and fronto-temporo-occipital cortices were associated with a steeper decline in global cognition. CONCLUSIONS: A more randomly organized grey matter network was associated with a steeper decline of cognitive functioning, possibly indicating the start of cognitive impairment

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome

BACKGROUND/AIMS: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. METHODS: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. RESULTS: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). CONCLUSIONS: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process

Vascular Cognitive Impairment and cognitive decline; a longitudinal study comparing different types of vascular brain injury - The TRACE-VCI study

Background: Little is known about the trajectories of cognitive decline in relation to different types of vascular brain injury in patients presenting at a memory clinic with Vascular Cognitive Impairment (VCI). / Methods: We included 472 memory clinic patients (age 68 (±8.2) years, 44% female, MMSE 25.9 (±2.8), 210 (44.5%) dementia) from the prospective TRACE-VCI cohort study with possible VCI, defined as cognitive complaints and vascular brain injury on MRI and at least 1 follow-up cognitive assessment (follow-up time 2.5 (±1.4) years, n = 1172 assessments). Types of vascular brain injury considered lacune(s) (≥1; n = 108 patients (23%)), non-lacunar infarct(s) (≥1; n = 54 (11%)), white matter hyperintensities (WMH) (none/mild versus moderate/severe (n = 211 patients (45%)) and microbleed(s) (≥1; n = 202 patients (43%)). We assessed cognitive functioning at baseline and follow-up, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT) A and B, category naming task and MMSE. The association of different types of vascular brain injury with cognitive decline was evaluated with linear mixed models, including one type of vascular brain injury (dichotomized), time and vascular brain injury*time, adjusted for sex, age, dementia status (yes/no), education (Verhage scale) and medial temporal lobe atrophy (MTA) score (dichotomized as ≥ 1.5). / Results: Across the population, performance declined over time on all tests. Linear mixed models showed that lacune(s) were associated with worse baseline TMTA (Beta(SE)) (8.3 (3.8), p = .03) and TMTB (25.6 (10.3), p = .01), albeit with a slower rate of decline on MMSE, RAVLT and category naming. By contrast, patients with non-lacunar infarct(s) showed a steeper rate of decline on TMTB (29.6 (7.7), p = .00), mainly attributable to patients with dementia (62.9 (15.5), p = .00). / Conclusion: Although different types of vascular brain injury have different etiologies and different patterns, they show little differences in cognitive trajectories depending on type of vascular brain injury

Small vessel disease lesion type and brain atrophy: The role of co‐occurring amyloid

Introduction: It is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co‐occurring Alzheimer's disease pathology affects this relation. / Methods: In 725 memory clinic patients with SVD (mean age 67 ± 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488). / Results: WMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid‐negative patients. SVD‐related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid‐negative patients. / Discussion: Amyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients

Comorbid amyloid-β pathology affects clinical and imaging features in VCD

INTRODUCTION: To date, the clinical relevance of comorbid amyloid-β (Aβ) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. METHODS: We included 218 VCD patients with available cerebrospinal fluid Aβ42 levels. Patients were divided into Aβ+ mild-VCD (n = 84), Aβ- mild-VCD (n = 68), Aβ+ major-VCD (n = 31), and Aβ- major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. RESULTS: Aβ- patients showed more depressive symptoms than Aβ+. In the major-VCD group, Aβ- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aβ+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aβ- patients had more WMH than Aβ+ patients, whereas conversely, in the major-VCD group, Aβ+ patients had more WMH. Atrophy patterns did not differ between Aβ+ and Aβ- VCD group. DISCUSSION: Comorbid Aβ pathology affects the manifestation of VCD, but effects differ by severity of VCD

Cerebral amyloid burden is associated with white matter hyperintensity location in specific posterior white matter regions

White matter hyperintensities (WMHs) are a common manifestation of cerebral small vessel disease. WMHs are also frequently observed in patients with familial and sporadic Alzheimer's disease, often with a particular posterior predominance. Whether amyloid and tau pathologies are linked to WMH occurrence is still debated. We examined whether cerebral amyloid and tau burden, reflected in cerebrospinal fluid amyloid-beta 1-42 (Aβ-42) and phosphorylated tau (p-tau), are related to WMH location in a cohort of 517 memory clinic patients. Two lesion mapping techniques were performed: voxel-based analyses and region of interest-based linear regression. Voxelwise associations were found between lower Aβ-42 and parieto-occipital periventricular WMHs. Regression analyses demonstrated that lower Aβ-42 correlated with larger WMH volumes in the splenium of the corpus callosum and posterior thalamic radiation, also after controlling for markers of vascular disease. P-tau was not consistently related to WMH occurrence. Our findings indicate that cerebral amyloid burden is associated with WMHs located in specific posterior white matter regions, possibly reflecting region-specific effects of amyloid pathology on the white matter

Prediction of poor clinical outcome in vascular cognitive impairment: TRACE-VCI study

INTRODUCTION: Prognostication in memory clinic patients with vascular brain injury (eg possible vascular cognitive impairment [VCI]) is often uncertain. We created a risk score to predict poor clinical outcome. METHODS: Using data from two longitudinal cohorts of memory clinic patients with vascular brain injury without advanced dementia, we created (n = 707) and validated (n = 235) the risk score. Poor clinical outcome was defined as substantial cognitive decline (change of Clinical Dementia Rating ≥1 or institutionalization) or major vascular events or death. Twenty‐four candidate predictors were evaluated using Cox proportional hazard models. RESULTS: Age, clinical syndrome diagnosis, Disability Assessment for Dementia, Neuropsychiatric Inventory, and medial temporal lobe atrophy most strongly predicted poor outcome and constituted the risk score (C‐statistic 0.71; validation cohort 0.78). Of note, none of the vascular predictors were retained in this model. The 2‐year risk of poor outcome was 6.5% for the lowest (0‐5) and 55.4% for the highest sum scores (10‐13). DISCUSSION: This is the first, validated, prediction score for 2‐year clinical outcome of patients with possible VCI

The natural history of primary progressive aphasia: beyond aphasia

Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration

Small Vessel Ischemic Disease of the Brain and Brain Metastases in Lung Cancer Patients

Brain metastases occur commonly in patients with lung cancer. Small vessel ischemic disease is frequently found when imaging the brain to detect metastases. We aimed to determine if the presence of small vessel ischemic disease (SVID) of the brain is protective against the development of brain metastases in lung cancer patients.A retrospective cohort of 523 patients with biopsy confirmed lung cancer who had received magnetic resonance imaging of the brain as part of their standard initial staging evaluation was reviewed. Information collected included demographics, comorbidities, details of the lung cancer, and the presence of SVID of the brain. A portion of the cohort had the degree of SVID graded. The primary outcome measure was the portion of study subjects with and without SVID of the brain who had evidence of brain metastases at the time of initial staging of their lung cancer.109 patients (20.8%) had evidence of brain metastases at presentation and 345 (66.0%) had evidence of SVID. 13.9% of those with SVID and 34.3% of those without SVID presented with brain metastases (p<0.0001). In a model including age, diabetes mellitus, hypertension, hyperlipidemia, and tobacco use, SVID of the brain was found to be the only protective factor against the development of brain metastases, with an OR of 0.31 (0.20, 0.48; p<0.001). The grade of SVID was higher in those without brain metastases.These findings suggest that vascular changes in the brain are protective against the development of brain metastases in lung cancer patients