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The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

Despite genetic data from families harboring APP mutations in Alzheimer disease (AD)—or SNCA gene multiplication in familial Parkinson disease (PD)—Dr. Espay et al. emphasized the limited evidence that implicates these protein products in the pathogenesis of sporadic cases of AD/PD. Instead, the authors argued, such proteins may be epiphenomena or could represent the nervous system response to cellular stress. Using established Bradford Hill criteria to determine a cause-and-effect relationship of these proteins and their respective diseases, the authors challenged the “age-old” notion that such proteins play a proximate role in disease pathogenesis. By summarizing the available evidence, the authors concluded “human studies of protein aggregation in AD and PD do not meet a minimum set of Bradford Hill's criteria to support a causal role.” Dr. Nelson respectfully disagrees with the conclusions drawn by the authors, citing evidence that nondemented patients with “preclinical” disease already exhibit abnormal protein deposits in the CNS, whereas demented patients without histopathologic evidence of AD or PD demonstrate pathology consistent with other degenerative conditions. As such, abnormally misfolded and aggregated proteins are more likely to be deleterious rather than protective or reactive. In response, Dr. Espay et al. emphasize the lack of evidence supporting the benefit of antiaggregation therapy (so far) in the treatment of patients with preclinical disease. Targeting these proteins, or preventing their aggregation, may fail to address the occult, proximate causes underlying these conditions. Although the jury may still be out regarding this chicken or the egg dilemma, it stands to reason that we should consider alternative hypotheses in the pathogenesis of sporadic AD or PD, if only to avoid perpetuating confirmation bias. Despite genetic data from families harboring APP mutations in Alzheimer disease (AD)—or SNCA gene multiplication in familial Parkinson disease (PD)—Dr. Espay et al. emphasized the limited evidence that implicates these protein products in the pathogenesis of sporadic cases of AD/PD. Instead, the authors argued, such proteins may be epiphenomena or could represent the nervous system response to cellular stress. Using established Bradford Hill criteria to determine a cause-and-effect relationship of these proteins and their respective diseases, the authors challenged the “age-old” notion that such proteins play a proximate role in disease pathogenesis. By summarizing the available evidence, the authors concluded “human studies of protein aggregation in AD and PD do not meet a minimum set of Bradford Hill's criteria to support a causal role.” Dr. Nelson respectfully disagrees with the conclusions drawn by the authors, citing evidence that nondemented patients with “preclinical” disease already exhibit abnormal protein deposits in the CNS, whereas demented patients without histopathologic evidence of AD or PD demonstrate pathology consistent with other degenerative conditions. As such, abnormally misfolded and aggregated proteins are more likely to be deleterious rather than protective or reactive. In response, Dr. Espay et al. emphasize the lack of evidence supporting the benefit of antiaggregation therapy (so far) in the treatment of patients with preclinical disease. Targeting these proteins, or preventing their aggregation, may fail to address the occult, proximate causes underlying these conditions. Although the jury may still be out regarding this chicken or the egg dilemma, it stands to reason that we should consider alternative hypotheses in the pathogenesis of sporadic AD or PD, if only to avoid perpetuating confirmation bias.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

Cerebral amyloid angiopathy (CAA), first described in 1927 as a congophilic angiopathy associated with amyloid plaque in brains of patients with Alzheimer dementia,1 has an association with large and small intracranial hemorrhages (ICH). The differential diagnosis of ICH therefore includes CAA, especially in older patients or those without hypertension. The widely used Boston Criteria for diagnosis of CAA in vivo rely on the hemorrhagic characteristics of the disease.2 The pathophysiology of ICH in CAA remains uncertain. Thus, its prognosis, risk stratification, and clinical management present a challenge. Additional imaging features of CAA have contributed potential new perspectives on pathophysiology. The report of ischemic lesions in CAA may represent a novel concept for most clinicians accustomed to thinking about CAA as a hemorrhagic disease. The observation that Alzheimer dementia brains with severe amyloid angiopathy had more prevalent infarcts3–5 prompted subsequent investigations suggesting that amyloid deposition in small and medium-sized cortical vessels may play an active role in ischemia through pathologic thickening of the vessel wall, producing reduction or obliteration of the vessel lumen.6,7 Cortical superficial siderosis (cSS), easy to detect with modern MRI, is a striking and common feature of CAA. How these additional imaging features fit into a larger model of CAA remains unclear. Are they an epiphenomenon or can they teach us about the disease? In the current issue of Neurology® , a pair of articles suggest that CAA might be a multifaceted vascular entity in its own right, and elucidation of these newer features may increase our understanding of its pathophysiology, leading to better prognosis and management.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption. In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

Objective: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD). Methods: Patients 11 months to 17 years after moderate–severe TBI underwent 11C-Pittsburgh compound B (11C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of 11C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with 11C-PiB BPND. Results: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased 11C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

We read with interest the article by Ennis et al.,1 which found cortisol dysregulation to be related to an increased risk for Alzheimer disease (AD), and built on the unresolved question of whether systemic homeostasis primarily contributes to AD expression or represents an epiphenomenon of the underlying brain pathology. Additional considerations might provide useful insights toward a better and more comprehensive understanding of this issue. Within their pleiotropic effects, corticosteroids can greatly influence metabolic functions as well as blood pressure levels and fluctuations, all of which play key roles in dementia onset and course.2 In the CNS, corticosteroid receptors are not uniformly localized and abnormal glucocorticoid signaling can result in cell type and site-specific differences.3 Accordingly, it would be of great interest to address the interrelationships among cortisol dysregulation, insulin resistance, and blood pressure variability,4 and to investigate the associations between cortisol exposure and the risk of non-AD dementias.5

Does low serum cholesterol trigger intracerebral hemorrhage? Such a link was first suggested by early epidemiologic studies, though this apparent relationship has appeared weaker in more recent prospective studies.1 But even if convincingly demonstrated by observational studies, does low cholesterol truly cause hemorrhagic stroke, or is it merely a marker or epiphenomenon of a hemorrhage-prone individual? Trials of cholesterol-lowering agents could potentially settle the causality question, but have also not yielded a clear-cut verdict. Recent studies of statin medications in patients with coronary artery disease have failed to reveal an increased risk of hemorrhagic stroke.2 One could argue, however, that since these studies were performed in patients with coronary heart disease, their interpretation may be limited. They were mainly conducted with middle-aged persons, while the population most at risk for stroke is older. Persons in these studies may also have been more likely to succumb to coronary disease and less likely to develop stroke at an older …

Over the years, the standard for ideal glycemic control in diabetic patients has moved closer and closer to achieving normal blood glucose levels. This evolution has been driven primarily by improvements in our technical ability to achieve more precise control. Through this process it has become clear that in diabetic patients, the better the glycemic control, the better the outcome. Hyperglycemia, however, is not confined to diabetics. It occurs in acutely ill patients with many disorders. In addition, hyperglycemic (diabetic and nondiabetic) patients have a worse outcome, be it in the setting of an acute myocardial infarction, intracerebral hemorrhage, acute ischemic stroke, head injury, or admission to a medical-surgical intensive care unit (ICU). What has remained unsettled is which is the horse and which is the cart: is hyperglycemia and epiphenomenon, simply a market of metabolic perturbations caused by the primary insult, or is it a bad actor directly contributing to morbidity and mortality? Van den Berghe et al. have recently provided compelling data that directly address this question. In 2001, …