Age related increase in internal jugular vein size parallels temporal development of periventricular white matter hyperintensities.

Age-related white matter hyperintensities are associated with cognitive impairment and dementia. Venous insufficiency has recently been proposed as a potential mechanism for the development of periventricular white matter hyperintensities based on the neuroanatomic distribution. The current study assesses age related changes of the internal jugular veins and its association with white matter hyperintensities. A retrospective study was performed assessing patients with computed tomography angiography (CTA) and magnetic resonance imaging (MRI) within a 4-week window. The size of the internal jugular veins, straight sinus, vein of Galen and internal cerebral veins were measured on the CT angiography. A normalized neck venous ratio was developed. Burden of white matter hyperintensities were quantified on MRI using periventricular/deep Fazekas scores. Association was assessed using correlation analysis and multrivariate linear modeling, and differences between groups were assessed using t test, ANOVA or Kruskal-Wallis test, using p < 0.05 for significance. One hundred eighty-two patients were included with a mean age of 65.2 ± 16.8 (51.6% females). Age was correlated with the normalized neck venous ratio (rs  = 0.25, p < 0.001), and, with both, the periventricular Fazekas (rs  = 0.63, p < 0.001) and the deep Fazekas (rs  = 0.57, p < 0.001) grades. The periventricular Fazekas score was positively correlated with the normalized neck venous ratio (rs  = 0.21, p = 0.003), but not significant on multivariate analysis accounting for age. The internal jugular veins demonstrate age related increase in size, paralleling the progression of periventricular white matter hyperintensities. Age remains the strongest predictor of white matter hyperintensities. Further work is needed to evaluate any causal role of venous changes on white matter hyperintensities.

Canadian Association of Radiologists Recommendations for the Safe Use of MRI During Pregnancy.

The use of magnetic resonance imaging (MRI) during pregnancy is associated with concerns among patients and health professionals with regards to fetal safety. In this work, the Canadian Association of Radiologists (CAR) Working Group on MRI in Pregnancy presents recommendations for the use of MRI in pregnancy, derived from literature review as well as expert panel opinions and discussions. The working group, which consists of academic subspecialty radiologists and obstetrician-gynaecologists, aimed to provide updated, evidence-based recommendations addressing safety domains related to energy deposition, acoustic noise, and gadolinium-based contrast agent use based on magnetic field strength (1.5T and 3T) and trimester scanned, in addition to the effects of sedative use and occupational exposure.

Long-term sequelae of herpes simplex virus encephalitis-related white matter injury: correlation of neuropsychological outcome and diffusion tensor imaging.

The pathophysiology of the memory impairment following Herpes Simplex virus encephalitis is not yet established and understood. This study attempts to elucidate the role of white matter injury and its impact on neuropsychological outcome in patients with history of Herpes Simplex virus encephalitis. This is a single-institution prospective study assessing 9 patients and 15 matched controls utilizing a combination of MRI with diffusion tensor imaging and neuropsychological testing. Tract-based spatial statistics analysis was performed and correlated with neuropsychological outcomes. Significantly decreased fractional anisotropy (FA) values were noted in corpus callosum, corona radiata, left posterior thalamic radiation, cingulum, superior longitudinal fasciculus, fornix, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinated fasciculus. Impaired facial recognition significantly correlated with reduction in FA of right uncinate fasciculus, right inferior longitudinal fasciculus, and splenium genu of corpus callosum. FA value of left cingulum significantly correlated with logical memory, auditory verbal learning. FA value of fornix correlated with visual recognition; FA value of left uncinate fasciculus with auditory verbal learning and delayed recall. In conclusion, this study demonstrates microstructural abnormalities involving several white matter tracts corresponding to neuropsychological deficits.

Multimodal MRI for MRgFUS in essential tremor: post-treatment radiological markers of clinical outcome.

BACKGROUND: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a promising non-invasive treatment option for medication-resistant essential tremor. However, it has been associated with variable efficacy and a relatively high incidence of adverse effects. OBJECTIVES: To assess the evolution of radiological findings after MRgFUS thalamotomy and to evaluate their significance for clinical outcomes. METHODS: Ninety-four patients who underwent MRgFUS between 2012 and 2017 were retrospectively evaluated. Lesion characteristics were assessed on routine MRI sequences, as well as with tractography. Relationships between imaging appearance, extent of white matter tract lesioning (59/94, on a 4-point scale) and clinical outcome were investigated. Recurrence was defined as >33% loss of tremor suppression at 3 months relative to day 7. RESULTS: Acute lesions demonstrated blood products, surrounding oedema and peripheral diffusion restriction. The extent of dentatorubrothalamic tract (DRTT) lesioning was significantly associated with clinical improvement at 1 year (t=4.32, p=0.001). Lesion size decreased over time (180.8±91.5 mm3 at day 1 vs 19.5±19.3 mm3 at 1-year post-treatment). Higher post-treatment oedema (t=3.59, p<0.001) was associated with larger lesions at 3 months. Patients with larger lesions at day 1 demonstrated reduced rates of tremor recurrence (t=2.67, p=0.019); however, lesions over 170 mm3 trended towards greater incidence of adverse effects (sensitivity=0.60, specificity=0.63). Lesion encroachment on the medial lemniscus (Sn=1.00, Sp=0.32) and pyramidal tract (Sn=1.00, Sp=0.12) were also associated with increased adverse effects incidence. CONCLUSION: Lesion size at day 1 predicts symptom recurrence, with fewer recurrences seen with larger lesions. Greater DRTT lesioning is associated with treatment efficacy. These findings may have implications for lesion targeting and extent. TRIAL REGISTRATION NUMBER: NCT02252380.

Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI.

Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution.

Spinal metastases: multimodality imaging in diagnosis and stereotactic body radiation therapy planning.

Due to increased effectiveness of cancer treatments and increasing survival rates, metastatic disease has become more frequent compared to the past, with the spine being the most common site of bony metastases. Diagnostic imaging is an integral part of screening, diagnosis and follow-up of spinal metastases. In this article, we review the principles of multimodality imaging for tumor detection with respect to their value for diagnosis and stereotactic body radiation therapy planning for spinal metastases. We will also review the current international consensus agreement for stereotactic body radiation therapy planning, and the role of imaging in achieving the best possible treatment plan.

A narrative review of oncologic emergencies in patients with head and neck cancers: initial management and the role of radiation therapy.

BACKGROUND AND OBJECTIVE: Head and neck cancers (HNCs) encompass a complex group of malignancies with high morbidity, often leading to critical emergencies such as pain crises, airway obstruction and hemorrhage. This review aims to outline an evidence-based approach to the multidisciplinary management of HNC oncologic emergencies with a focus on the role of emergent radiotherapy (RT). METHODS: A literature search was performed using Medline, Embase and the Cochrane Central Register of Controlled Trials databases with a focus on three common oncological emergencies using the following keywords: "head and neck cancer", "radiation OR radiotherapy", "pain", "bleeding OR haemorrhage", and "airway obstruction". All English language articles published up to April 2022 were screened to identify studies pertaining to the management of oncologic emergencies in HNC. KEY CONTENT AND FINDINGS: The management of oncologic emergencies in HNC present a unique set of challenges that require early recognition and aggressive treatment. In this narrative review, we summarize the evidence supporting the role of RT in the management of HNC patients presenting with pain crisis, malignant airway obstruction and acute haemorrhage. We demonstrate that while RT can be used as a primary or adjunct therapy, optimal management depends on the involvement of a multi-disciplinary team that includes head and neck surgeons, interventional radiology and palliative care. CONCLUSIONS: RT plays a critical role in the multidisciplinary management of HNC oncological emergencies. Further prospective and comparative studies are needed to assess optimal management strategies.

Cerebrovascular Reactivity and Concussion.

Cerebrovascular reactivity (CVR) reflects the change in cerebral blood flow in response to vasodilatory stimuli enabling assessment of the health of the cerebral vasculature. Recent advances in the quantitative delivery of CO2 stimuli with computer-controlled sequential gas delivery have enabled mapping of the speed and magnitude of response to flow stimuli. These CVR advances when applied to patients with acute concussion have unexpectedly shown faster speed and greater magnitude of responses unseen in other diseases that typically show the opposite effects. The strength of the CVR alterations have diagnostic potential in single subjects with AUC values in the 0.90-0.94 range.

Arachnoid granulations may be protective against the development of shunt dependent chronic hydrocephalus after aneurysm subarachnoid hemorrhage*.

BACKGROUND AND PURPOSE: Chronic hydrocephalus may develop as a sequela of aneurysmal subarachnoid hemorrhage, requiring long-term cerebrospinal fluid shunting. Several clinical predictors of chronic hydrocephalus and shunt dependence have been proposed. However, no anatomical predictors have been identified. MATERIALS AND METHODS: A retrospective cohort study was performed including 61 patients with aneurysmal subarachnoid hemorrhage. Clinical characteristics were noted for each patient including presentation World Federation of Neurosurgical Societies grade, modified Fischer grade, aneurysm characteristics, requirement for acute and chronic cerebrospinal fluid diversion, and 3-month modified Rankin scale. CT images were evaluated to determine the Evans' index and to enumerate the number of arachnoid granulations. Association between the clinical characteristics with ventriculoperitoneal shunt insertion and the 3-month modified Rankin scale were assessed. RESULTS: The initial Evans' index was positively associated with mFisher grade and age, but not the number of arachnoid granulations. 16.4% patients required insertion of a ventriculoperitoneal shunt. The number of arachnoid granulations were a significant negative predictor of ventriculoperitoneal shunt insertion [OR: 0.251 (95% CI:0.073-0.862; p = 0.028)]. There was significant difference in the number of arachnoid granulations between those with and without ventriculoperitoneal shunt (p = 0.002). No patient with greater than 4 arachnoid granulations required a ventriculoperitoneal shunt, irrespective of severity of initial grade. CONCLUSION: Arachnoid granulations may be protective against the development of shunt dependent chronic hydrocephalus after aneurysmal subarachnoid hemorrhage. This is irrespective of presenting hemorrhage severity. This is a potentially novel radiologic biomarker and anatomic predictor of shunt dependence.

Hypoperfusion Precedes Tau Deposition in the Entorhinal Cortex: A Retrospective Evaluation of ADNI-2 Data.

BACKGROUND AND PURPOSE: Tau deposition in the entorhinal cortex is the earliest pathological feature of Alzheimer's disease (AD). However, this feature has also been observed in cognitively normal (CN) individuals and those with mild cognitive impairment (MCI). The precise pathophysiology for the development of tau deposition remains unclear. We hypothesized that reduced cerebral perfusion is associated with the development of tau deposition. METHODS: A subset of the Alzheimer's Disease Neuroimaging Initiative data set was utilized. Included patients had undergone arterial spin labeling perfusion MRI along with [18F]flortaucipir tau PET at baseline, within 1 year of the MRI, and a follow-up at 6 years. The association between baseline cerebral blood flow (CBF) and the baseline and 6-year tau PET was assessed. Univariate and multivariate linear modeling was performed, with p<0.05 indicating significance. RESULTS: Significant differences were found in the CBF between patients with AD and MCI, and CN individuals in the left entorhinal cortex (p=0.013), but not in the right entorhinal cortex (p=0.076). The difference in maximum standardized uptake value ratio between 6 years and baseline was significantly and inversely associated with the baseline mean CBF (p=0.042, R²=0.54) in the left entorhinal cortex but not the right entorhinal cortex. Linear modeling demonstrated that CBF predicted 6-year tau deposition (p=0.015, R²=0.11). CONCLUSIONS: The results of this study suggest that a reduction in CBF at the entorhinal cortex precedes tau deposition. Further work is needed to understand the mechanism underlying tau deposition in aging and disease.

Segmentation of Brain Metastases Using Background Layer Statistics (BLAST).

BACKGROUND AND PURPOSE: Accurate segmentation of brain metastases is important for treatment planning and evaluating response. The aim of this study was to assess the performance of a semiautomated algorithm for brain metastases segmentation using Background Layer Statistics (BLAST). MATERIALS AND METHODS: Nineteen patients with 48 parenchymal and dural brain metastases were included. Segmentation was performed by 4 neuroradiologists and 1 radiation oncologist. K-means clustering was used to identify normal gray and white matter (background layer) in a 2D parameter space of signal intensities from postcontrast T2 FLAIR and T1 MPRAGE sequences. The background layer was subtracted and operator-defined thresholds were applied in parameter space to segment brain metastases. The remaining voxels were back-projected to visualize segmentations in image space and evaluated by the operators. Segmentation performance was measured by calculating the Dice-Sørensen coefficient and Hausdorff distance using ground truth segmentations made by the investigators. Contours derived from the segmentations were evaluated for clinical acceptance using a 5-point Likert scale. RESULTS: The median Dice-Sørensen coefficient was 0.82 for all brain metastases and 0.9 for brain metastases of ≥10 mm. The median Hausdorff distance was 1.4 mm. Excellent interreader agreement for brain metastases volumes was found with an intraclass correlation coefficient = 0.9978. The median segmentation time was 2.8 minutes/metastasis. Forty-five contours (94%) had a Likert score of 4 or 5, indicating that the contours were acceptable for treatment, requiring no changes or minor edits. CONCLUSIONS: We show accurate and reproducible segmentation of brain metastases using BLAST and demonstrate its potential as a tool for radiation planning and evaluating treatment response.

Intracranial stenting compared to medical treatment alone for intracranial atherosclerosis patients: An updated meta-analysis.

Objective: Stroke is the second-leading cause of death globally. Intracranial atherosclerotic stenosis (ICAS) represents 10-15% of ischemic strokes in Western countries and up to 47% in Asian countries. Patients with ICAS have an especially high risk of stroke recurrence. The aim of this meta-analysis is to reassess recurrent stroke, transient ischemic attack (TIA), and other outcomes with stenting versus best medical management for symptomatic ICAS. Methods: The search protocol was developed a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The OVID Medline, Embase, Web of Science, and Cochrane Library databases were searched from inception to August 14th, 2022. Results: This Meta-analysis Included Four Randomized Controlled Trials (Rcts), With A Total Number Of 991 Patients. The Mean Age Of Participants Was 57 Years. The Total Number Of Intracranial Stenting Patients Was 495, And The Number Of Medical Treatment Patients Was 496. The Included Studies Were Published Between 2011 And 2022. Two Studies Were Conducted In The Usa, And The Other Two In China. All Included Studies Compared Intracranial Stenting To Medical Treatment For Icas. Conclusions: In patients with ischemic stroke due to symptomatic severe intracranial atherosclerosis, the rate of 30-day ischemic stroke, 30-day intracerebral hemorrhage, one-year stroke in territory or mortality favored the medical treatment alone without intracranial stenting. The risk of same-territory stroke at last follow-up, disabling stroke at last follow-up, and mortality did not significantly favor either group. Intracranial stenting for atherosclerosis did not result in significant benefit over medical treatment.

Venous dysfunction plays a critical role in "normal" white matter disease of aging.

A ubiquitous finding on MRI in older individuals, age-related cerebral white matter hyperintensities (WMHs) are associated with cognitive decline, dementia, disability, and death. Currently, these findings are thought to represent small infarcts secondary to lipohyalinotic arteriosclerosis. Commonly though, the anatomic distribution of WMHs is often non-arterial, and parallel the deep venous system. Furthermore, there is discrepant evidence for the role of conventional vascular risk factors such as hypertension, carotid atherosclerosis and diabetes for the development and progression of these. Interventions targeting conventional vascular risk factors lack consistency in preventing the progression of WMHs. There is evidence for age-related hemodynamic cervical venous dysfunction resulting in reduced internal jugular vein venous compliance, venous dilatation, and venous reflux. Similarly, venous collagenosis increases with age. Increased blood-brain barrier (BBB) permeability is also noted with aging. Both hemodynamic venous dysfunction, venous sclerosis, and increased BBB permeability are associated with WMHs. We propose that age-related WMHs are a sequalae of venous dysfunction. Venous dysfunction results initially in increased transmission of venous pressures to the brain. Subsequent BBB disruption leads to increased permeability with progression to end-stage findings of age-related WMHs.

In vivo detection of beta-amyloid at the nasal cavity and other skull-base sites: a retrospective evaluation of ADNI1/GO.

INTRODUCTION: Amyloid beta (Aß) is partially cleared from the CSF via skull base perivascular and perineural lymphatic pathways, particularly at the nasal cavity. In vivo differences in Aß level at the nasal cavity between patients with Alzheimer's disease (AD), subjects with mild cognitive impairment (MCI) and cognitively normal (CN) individuals have not been previously assessed. METHODS: This is a retrospective evaluation of subject level data from the ADNI-1/GO database. Standardized uptake value ratio (SUVR) maximum on 11C-Pittsburgh compound-B (PiB)-PET was assessed at the nasal cavity on 223 scans. Exploratory ROI analysis was also performed at other skull base sites. SUVR maximum values and their differences between groups (CN, MCI, AD) were assessed. CSF Aß levels and CSF Aß 42/40 ratios were correlated with SUVR maximum values. RESULTS: 103 subjects with 223 PiB-PET scans (47 CN, 32 AD and 144 MCI) were included in the study. The SUVR maxima at the nasal cavity were significantly lower in subjects with AD [1.35 (± 0.31)] compared to CN [1.54 (± 0.30); p = 0.024] and MCI [1.49 (± 0.33); p = 0.049]. At very low CSF Aß, less than 132 pg/ml, there was significant correlation with nasal cavity SUVR maximum. The summed averaged SUVR maximum values were significantly lower in subjects with AD [1.35 (± 0.16)] compared to CN [1.49 (± 0.17); p = 0.003] and MCI [1.40 (± 0.17); p = 0.017]. CONCLUSION: Patients with AD demonstrate reduced nasal cavity PiB-PET radiotracer uptake compared to MCI and CN, possibly representing reduced Aß clearance via perineural/perivascular lymphatic pathway. Further work is necessary to elucidate the true nature of this finding.

Bibliometric evaluation of systematic review and meta analyses published in the top 5 "high-impact" radiology journals.

INTRODUCTION: Meta-analyses provide high-level evidence and understanding their trends may provide understanding of the field as a whole. Bibliometric analysis was undertaken to understand research trends in a particular field or subfield and to assess citation as a measure of impact. METHODS: All journals categorised as "Radiology, Nuclear Medicine & Medical Imaging" under the Web of Science subject category were included. After analyzing impact factors of the journals in up to 2018, the top five journals were identified. The retrieved results were ordered by citation count based on Web of Science and Scopus. Specific parameters regarding the title, journal, publication year, authors, country of origin, institution and university, field of study and funding sources were analyzed. RESULTS: A total of 139 articles were identified. The mean number of citations per article was 25.3 and 22.6 in Scopus and Web of Science respectively, with four articles receiving 100 or more citations. European Radiology had the greatest number of top cited articles (n = 68; 49%). Most number of articles originated from South Korea (n = 60; 43%) and the commonest field of focus with the most common being oncology (n = 51; 27%). CONCLUSION: The top 5 high impact journals published a large number of meta-analysis and systematic reviews. The greatest number of top-cited articles were from South Korea, shifting away from the United States. Large number of studies focused on oncologic imaging, consistent with recent trends towards development of imaging biomarkers and personalized medicine. Author H index did not predict citation number or density.

The Initial Step Towards Establishing a Quantitative, Magnetic Resonance Imaging-Based Framework for Response Assessment of Spinal Metastases After Stereotactic Body Radiation Therapy.

BACKGROUND: There are no established threshold values regarding the degree of growth on imaging when assessing response of spinal metastases treated with stereotactic body radiation therapy (SBRT). OBJECTIVE: To determine a magnetic resonance imaging-based minimum detectable difference (MDD) in gross tumor volume (GTV) and its association with 1-yr radiation site-specific (RSS) progression-free survival (PFS). METHODS: GTVs at baseline and first 2 post-SBRT scans (Post1 and Post2, respectively) for 142 spinal segments were contoured, and percentage volume change between scans calculated. One-year RSS PFS was acquired from medical records. The MDD was determined. The MDD was compared against optimal thresholds of GTV changes associated with 1-yr RSS PFS using Youden's J index, and receiver operating characteristic curves between timepoints compared to determine which timeframe had the best association. RESULTS: A total of 17 of the 142 segments demonstrated progression. The MDD was 10.9%. Baseline-Post2 demonstrated the best performance (area under the curve [AUC] 0.90). Only Baseline-Post2 had an optimal threshold > MDD at 14.7%. Due to large distribution of GTVs, volumes were split into tertiles. Small tumors (GTV < 2 cc) had optimal thresholds of 42.0%, 71.3%, and 37.2% at Baseline-Post1 (AUC 0.81), Baseline-Post2 (AUC 0.89), and Post1-Post2 (AUC 0.77), respectively. Medium tumors (2 ≤ GTV ≤ 8.3 cc) all demonstrated optimal thresholds < MDD, with AUCs ranging from 0.65 to 0.84. Large tumors (GTV > 8.3 cc) had 2 timepoints where optimal thresholds > MDD: Baseline-Post2 (13.3%; AUC 0.97) and Post1-Post2 (11.8%; AUC 0.66). Baseline-Post2 had the best association with RSS PFS for all tertiles. CONCLUSION: Given a MDD of 10.9%, for small GTVs, larger (>37%) changes were required before local failure could be determined, compared to 11% to 13% for medium/large tumors.

Multiple sclerosis is a systemic venous vasculopathy: A single unifying mechanism.

Multiple sclerosis (MS) is a potentially debilitating disease affecting the central nervous system (CNS) clinically characterized by progressive neurological deterioration. It is the most common condition under the umbrella of demyelinating disease, thought to occur as a result of a primary autoimmune insult. Various genetic and environmental risk factors have been implicated as potential triggers and/or predisposing factors; however, the exact mechanism of disease remains elusive. Diagnosis and management are based on clinical presentation, with adjunct imaging and biochemical assessment. Since the 19th century anatomical distribution of lesions in MS have been observed to demonstrate a characteristic periventricular, perivenular distribution; spinal cord and cortical lesions also demonstrate this perivenous preponderance. Venous abnormalities have long been observed on pathology characterized by irregular narrowing and dilatation with associated venous wall and perivenous infiltrates. Active CNS lesions are characterized by perivenular inflammatory infiltrates. There is accompanying global dysfunction of the blood-brain barrier, even within normal appearing tissue, with low levels of inflammatory change and tissue injury seen at pathology. Although several CNS antigens have been identified as potential candidates, including myelin related antigens, a specific pathogenic antigen remains elusive. Evaluation of the cerebrospinal fluid reveals characteristic oligoclonal bands, indicating a broad inflammatory response against a variety of CNS antigens. Antibodies have been identified against endothelial elements in sera of patients with MS, their role is not yet clearly elucidated. Emerging evidence suggests there may be a more systemic inflammatory process, heralded by a systemic preclinical prodrome. In light of such seemingly-discrepant clinical, anatomic, immunologic and pathologic findings we propose a unifying theory; specifically we propose that MS is a primary autoimmune vasculopathy, with a predilection of CNS venous structures. Characteristic CNS lesions are a secondary manifestation resulting from an inflammatory response to the uncovering of usually privileged CNS antigens.

Intersection between sleep and neurovascular coupling as the driving pathophysiology of Alzheimer's disease.

Alzheimer's disease (AD) is the commonest cause of dementia. There are tremendous personal and systemic costs associated with the disease. Although there has been significant progress in understanding the disease process, the precise pathophysiologic mechanism remains elusive. The amyloid hypothesis is the leading theory with impaired clearance of the amyloid beta (Aß) believed to be the underpinning disease process. However, what triggers and propagates the accumulation of Aß remains unclear. We propose that the impairment of neurovascular coupling triggers a cascade that ultimately leads to impaired Aß clearance. With aging there is a generalized decline in cerebral blood flow and impairment of cerebrovascular reactivity. With impairment of this neurovascular coupling, the normal bulk clearance of cerebrospinal fluid and interstitial fluid (ISF) becomes hindered. We postulate that this clearance process occurs during non-rapid eye movement slow wave sleep, driven by the tight neurovascular coupling, via a pump-like action. The impairment of ISF clearance results in change in the interstitial microenvironment from accumulation of metabolites, reactive oxygen species, metal ions and results in decreased pH. The changes in the microenvironment promotes the accumulation and aggregation of Aß, heralding the disease process.