Cerebral blood flow, amyloid burden, and cognition in cognitively normal individuals.

PURPOSE: The role of cerebral blood flow (CBF) in the early stages of Alzheimer's disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD). METHODS: We included 187 cognitively normal individuals with SCD from the SCIENCe project (65 ± 8 years, 39% F, MMSE 29 ± 1). Each underwent a dynamic (0-70 min) [18F]florbetapir PET and T1-weighted MRI scan, enabling calculation of mean binding potential (BPND; specific amyloid binding) and R1 (measure of relative (r)CBF). Eighty-three individuals underwent a second [18F]florbetapir PET (2.6 ± 0.7 years). Participants annually underwent neuropsychological assessment (follow-up time 3.8 ± 3.1 years; number of observations n = 774). RESULTS: A low baseline R1 was associated with steeper decline on tests addressing memory, attention, and global cognition (range betas 0.01 to 0.27, p < 0.05). High BPND was associated with steeper decline on tests covering all domains (range betas - 0.004 to - 0.70, p < 0.05). When both predictors were simultaneously added to the model, associations remained essentially unchanged. Additionally, we found longitudinal associations between R1 and BPND. High baseline BPND predicted decline over time in R1 (all regions, range betasBP×time - 0.09 to - 0.14, p < 0.05). Vice versa, low baseline R1 predicted increase in BPND in frontal, temporal, and composite ROIs over time (range betasR1×time - 0.03 to - 0.08, p < 0.05). CONCLUSION: Our results suggest that amyloid accumulation and decrease in rCBF are two parallel disease processes without a fixed order, both providing unique predictive information for cognitive decline and each process enhancing the other longitudinally.

Neuropsychiatric Symptoms as Predictor of Poor Clinical Outcome in Patients With Vascular Cognitive Impairment.

OBJECTIVE: Examine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury. DESIGN/SETTING: TRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.5 years). PARTICIPANTS: Five hundred and seventy-five memory clinic patients with vascular brain injury on MRI (i.e. possible Vascular Cognitive Impairment [VCI]). Severity of cognitive impairment ranged from no objective cognitive impairment to mild cognitive impairment (MCI) and dementia. MEASUREMENTS: We used Neuropsychiatric Inventory (total score and score on hyperactive, psychotic, affective, and apathetic behavior domains) to measure NPS. We assessed the association between NPS and institutionalization, mortality and cognitive deterioration (increase ≥0.5 on Clinical Dementia Rating scale) with Cox proportional hazards models and logistic regression analyses. RESULTS: NPS were present in 89% of all patients, most commonly in the hyperactive and apathetic behavior domain. Across the whole cohort, affective behavior was associated with institutionalization (HR: 1.98 [1.01-3.87]), mainly driven by the dementia subgroup (HR: 2.06 [1.00-4.21]). Apathetic behavior was associated with mortality and cognitive deterioration (HR: 2.07 [1.10-3.90],OR: 1.67 [1.12-2.49], respectively), mainly driven by the MCI subgroup (HR: 4.93 [1.07-22.86],OR: 3.25 [1.46-7.24], respectively). Conversely, hyperactive behavior was related to lower mortality (HR: 0.54 [0.29-0.98]), again particularly driven by the MCI subgroup (HR:0.17 [0.04-0.75]). Psychotic behavior was associated with cognitive deterioration in patients with no objective cognitive impairment (OR: 3.10 [1.09-8.80]) and with institutionalization in MCI (HR: 12.45 [1.28-121.14]). CONCLUSION: NPS are common and have prognostic value in memory clinic patients with possible VCI. This prognostic value depends on the severity of cognitive impairment.

Diversity in Alzheimer's disease drug trials: The importance of eligibility criteria.

INTRODUCTION: To generalize safety and efficacy findings, it is essential that diverse populations are well represented in Alzheimer's disease (AD) drug trials. In this review, we aimed to investigate participant diversity in disease-modifying AD trials over time, and the frequencies of participant eligibility criteria. METHODS: A systematic review was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records. RESULTS: In the 101 included AD trials, participants were predominantly White (median percentage: 94.7%, interquartile range: 81.0-96.7%); and this percentage showed no significant increase or decrease over time (2001-2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific Mini-Mental State Examination scores (90.1%; no significant increase/decrease over time) may have led to a disproportionate exclusion of ethnoracially diverse individuals. DISCUSSION: Ethnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations are provided to broaden eligibility criteria.

Comorbid amyloid-ß pathology affects clinical and imaging features in VCD.

INTRODUCTION: To date, the clinical relevance of comorbid amyloid-ß (Aß) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. METHODS: We included 218 VCD patients with available cerebrospinal fluid Aß42 levels. Patients were divided into Aß+ mild-VCD (n = 84), Aß- mild-VCD (n = 68), Aß+ major-VCD (n = 31), and Aß- 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: Aß- patients showed more depressive symptoms than Aß+. In the major-VCD group, Aß- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aß+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aß- patients had more WMH than Aß+ patients, whereas conversely, in the major-VCD group, Aß+ patients had more WMH. Atrophy patterns did not differ between Aß+ and Aß- VCD group. DISCUSSION: Comorbid Aß pathology affects the manifestation of VCD, but effects differ by severity of VCD.

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes.

OBJECTIVE: We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD). METHODS: We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini-Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models. RESULTS: Fifty-seven (23%) subjects were CSF-amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF-amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69-84%; plasma Abeta42: AUC = 66%, 95% CI: 58-74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77-89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4-2.3). INTERPRETATION: Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656-666.

Impact of white matter hyperintensity location on depressive symptoms in memory-clinic patients: a lesion­symptom mapping study

Background: We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion­symptom mapping. Methods: We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumptionfree voxel-based lesion­symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis. Results: Voxel-based lesion­symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (ß = 0.26, p < 0.05), but not in mild cognitive impairment or dementia. Limitations: We observed a lack of convergence of findings between voxel-based lesion­symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts. Conclusion: This lesion­symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity.

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 (ß ± 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: ß ± SE = 0.06 ± 0.02); lambda: ß ± SE = 0.06 ± 0.02), language (gamma: ß ± SE = 0.11 ± 0.04; lambda: ß ± 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.

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 (ß[SE]) on the MMSE was estimated at -2.11 (0.25) points per year. Lower whole brain (ß[SE]-0.50[0.25]; p ≤ 0.05) and parietal (ß[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.

The effect of hippocampal function, volume and connectivity on posterior cingulate cortex functioning during episodic memory fMRI in mild cognitive impairment.

OBJECTIVES: Diminished function of the posterior cingulate cortex (PCC) is a typical finding in early Alzheimer's disease (AD). It is hypothesized that in early stage AD, PCC functioning relates to or reflects hippocampal dysfunction or atrophy. The aim of this study was to examine the relationship between hippocampus function, volume and structural connectivity, and PCC activation during an episodic memory task-related fMRI study in mild cognitive impairment (MCI). METHOD: MCI patients (n = 27) underwent episodic memory task-related fMRI, 3D-T1w MRI, 2D T2-FLAIR MRI and diffusion tensor imaging. Stepwise linear regression analysis was performed to examine the relationship between PCC activation and hippocampal activation, hippocampal volume and diffusion measures within the cingulum along the hippocampus. RESULTS: We found a significant relationship between PCC and hippocampus activation during successful episodic memory encoding and correct recognition in MCI patients. We found no relationship between the PCC and structural hippocampal predictors. CONCLUSIONS: Our results indicate a relationship between PCC and hippocampus activation during episodic memory engagement in MCI. This may suggest that during episodic memory, functional network deterioration is the most important predictor of PCC functioning in MCI. KEY POINTS: • PCC functioning during episodic memory relates to hippocampal functioning in MCI. • PCC functioning during episodic memory does not relate to hippocampal structure in MCI. • Functional network changes are an important predictor of PCC functioning in MCI.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease.

INTRODUCTION: We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD). METHODS: We included 161 AD, 95 MCI, and 143 SCD patients from the Amsterdam Dementia Cohort. We used 3-T pseudo-continuous arterial spin labeling to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and five cognitive domains. Associations were investigated using linear regression analyses. RESULTS: In the whole sample, reduced overall and regional CBF was associated with impairment in all cognitive domains. We found significant interactions between diagnosis and CBF for language and between diagnosis and parietal CBF for global cognition and executive functioning. Stratification showed that decreased CBF was associated with worse performance in AD patients but not in MCI or SCD. DISCUSSION: Our results suggest that CBF may have potential as a functional marker of disease severity.

Cerebral perfusion in the predementia stages of Alzheimer's disease.

OBJECTIVES: To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer's disease (AD). METHODS: Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-ß (Aß) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex. RESULTS: Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aß and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aß and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD. CONCLUSION: The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression. KEY POINTS: • Decreasing CBF relates to more advanced AD stages in all supratentorial regions. • The reduction of CBF does not reach a bottom level. • ASL-CBF has potential as a measure for disease progression in AD.

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.

Impact of Imaging and Cerebrospinal Fluid Biomarkers on Behavioral Variant Frontotemporal Dementia Diagnosis within a Late-Onset Frontal Lobe Syndrome Cohort.

BACKGROUND: The criteria for behavioral variant frontotemporal dementia (bvFTD) incorporate MRI and [18F]-FDG-PET. Cerebrospinal fluid (CSF) analysis is merely advised for excluding Alzheimer's disease. AIMS: We aimed to assess the impact of biomarkers on diagnostic certainty and contingent changes of bvFTD diagnosis within the clinically relevant neuropsychiatric differential diagnosis of subjects with a late-onset frontal lobe syndrome (LOF). METHODS: We included 137 patients with LOF, aged 45-75 years, 72% males. Biomarker disclosure was considered contributing after any substantial difference in diagnostic certainty or a diagnostic change. Percentages of contributing biomarkers were compared between three major diagnostic groups (bvFTD, psychiatry, other neurological disorders). Certainty levels in stable diagnostic groups were compared to those with a diagnostic change. RESULTS: Biomarkers contributed in 53, 60 and 41% of the LOF patients for MRI, [18F]-FDG-PET and CSF, respectively. Biomarkers changed the diagnosis in 14% of cases towards bvFTD and in 13% from bvFTD into an alternative. Those that changed had a lower level of a priori diagnostic certainty compared to stable diagnoses. CONCLUSION: Our study not only supports the widely accepted use of MRI and [18F]-FDG-PET in diagnosing or excluding bvFTD, but also shows that CSF biomarkers aid clinicians in the diagnostic process.

Schizophrenia as a mimic of behavioral variant frontotemporal dementia.

Recently, the diagnostic criteria for the behavioral variant of frontotemporal dementia were revised. Although these criteria offer a relatively high sensitivity, their specificity is yet unknown. We describe a 54-year-old woman fulfilling criteria for both late-onset schizophrenia and probable behavioral variant frontotemporal dementia. Following an initial presentation with psychosis, she developed progressive apathy, compulsiveness, and executive dysfunction. Moreover, bilateral frontotemporal hypometabolism was seen on [(18)F]fludeoxyglucose-positron emission tomography. A post-mortem diagnosis of schizophrenia was established, given the clinical picture combined with the pathological exclusion of a neurodegenerative cause. Our case suggests that patients with other brain disorders may meet the current diagnostic criteria for probable frontotemporal dementia. Further clinicopathological validation of these criteria is needed to determine their exact specificity.

White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline.

BACKGROUND AND PURPOSE: In patients with subjective cognitive decline, we assessed whether small vessel disease was associated with clinical progression and cognitive decline. METHODS: We included 334 patients with subjective cognitive decline. Follow-up was 3±2 years. RESULTS: Fifty-three (16%) patients progressed clinically to mild cognitive impairment or dementia. White matter hyperintensities were associated with clinical progression and with annual decline on memory, attention, executive functioning, and global cognition. Microbleeds and lacunes were not associated with clinical progression or cognitive decline. CONCLUSIONS: In patients with subjective cognitive decline, patients with white matter hyperintensities are at increased risk of clinical progression and cognitive decline.

Identifying bvFTD Within the Wide Spectrum of Late Onset Frontal Lobe Syndrome: A Clinical Approach.

OBJECTIVE: The behavioral variant of frontotemporal dementia (bvFTD) can be difficult to diagnose because of the extensive differential diagnosis, including many other diseases presenting with a frontal lobe syndrome. We aimed to identify the diagnostic spectrum causing a late onset frontal lobe syndrome and examine the quality of commonly used instruments to distinguish between bvFTD and non-bvFTD patients, within this syndrome. METHODS: A total of 137 patients fulfilling the criteria of late onset frontal lobe syndrome, aged 45 to 75 years, were included in a prospective observational study. Diagnoses were made after clinical and neuropsychological examination, and neuroimaging and cerebral spinal fluid results were taken into account. Baseline characteristics and the scores on the Mini-Mental State Exam (MMSE), frontal assessment battery (FAB), Frontal Behavioral Inventory (FBI), and Stereotypy Rating Inventory (SRI) were compared between the bvFTD and the non-bvFTD group. RESULTS: Fifty-five (40%) of the patients received a bvFTD diagnosis (33% probable and 7% possible bvFTD). Fifty-one patients (37%) had a psychiatric disorder, including 20 with major depressive disorder. Thirty-one patients received an alternative neurological, including neurodegenerative, diagnosis. MMSE and FAB scores were unspecific for a particular diagnosis. A score above 12 on the positive FBI subscale or a score above 5 on the SRI were indicative of a bvFTD diagnosis. CONCLUSION: A broad spectrum of both neurological and psychiatric disorders underlies late onset frontal lobe syndrome, of which bvFTD was the most prevalent diagnosis in our cohort. The commonly used MMSE and the FAB could not successfully distinguish between bvFTD and non-bvFTD, but this could be achieved with the more specific FBI and SRI.

Diagnostic impact of CSF biomarkers for Alzheimer's disease in a tertiary memory clinic.

BACKGROUND: We aimed to assess the impact of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease on decision making and patient management in a tertiary memory clinic. METHODS: We included all patients, for 1 year, visiting the VUmc Alzheimer Center for cognitive screening. Neurologists completed questionnaires before and after CSF disclosure. We assessed the change of diagnosis, diagnostic confidence, and impact on patient management. RESULTS: A total of 438 patients (age 63 ± 8 years, 39% women) were included, of whom 351 (80%) underwent lumbar puncture. After the disclosure of CSF 23/351 diagnoses (7%) were changed. Diagnostic confidence increased from 84% to 89% (P < .001). There were consequences for management in 44/351 patients (13%) with CSF, and 13/87 patients (15%) because of unavailable CSF. There was no effect of age on these results. CONCLUSIONS: CSF biomarkers aid clinicians with decision making during diagnostic work-up of cognitive disorders. This study may be useful for developing guidelines for the implementation of CSF biomarkers in daily practice.

Cerebral small vessel disease affects white matter microstructure in mild cognitive impairment.

Microstructural white matter deterioration is a frequent finding in mild cognitive impairment (MCI), potentially underlying default mode network (DMN) dysfunctioning. Thus far, microstructural damage in MCI has been attributed to Alzheimer's disease pathophysiology. A cerebrovascular role, in particular the role of cerebral small vessel disease (CSVD), received less interest. Here, we used diffusion tensor imaging (DTI) to examine the role of CSVD in microstructural deterioration within the normal appearing white matter (NAWM) in MCI. MCI patients were subdivided into those with (n = 20) and without (n = 31) macrostructural CSVD evidence on MRI. Using TBSS we performed microstructural integrity comparisons within the whole brain NAWM. Secondly, we segmented white matter tracts interconnecting DMN brain regions by means of automated tractography segmentation. We used NAWM DTI measures from these tracts as dependent variables in a stepwise-linear regression analysis, with structural and demographical predictors. Our results indicated microstructural deterioration within the anterior corpus callosum, internal and external capsule and periventricular white matter in MCI patients with CSVD, while in MCI patients without CSVD, deterioration was restricted to the right perforant path, a tract along the hippocampus. Within the full cohort of MCI patients, microstructure within the NAWM of the DMN fiber tracts was affected by the presence of CSVD. Within the cingulum along the hippocampal cortex we found a relationship between microstructural integrity and ipsilateral hippocampal volume and the extent of white matter hyperintensity. In conclusion, we found evidence of CSVD-related microstructural damage in fiber tracts subserving the DMN in MCI.