Margaret E. Flanagan

Precision Medicine: Clarity for the Complexity of Dementia

Three key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of action of intervention(s) with an individuals molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease.

Clinical-pathologic correlations in vascular cognitive impairment and dementia

The most common causes of cognitive impairment and dementia are Alzheimers disease (AD) and vascular brain injury (VBI), either independently, in combination, or in conjunction with other neurodegenerative disorders. The contribution of VBI to cognitive impairment and dementia, particularly in the context of AD pathology, has been examined extensively yet remains difficult to characterize due to conflicting results. Describing the relative contribution and mechanisms of VBI in dementia is important because of the profound impact of dementia on individuals, caregivers, families, and society, particularly the stability of health care systems with the rapidly increasing age of our population. Here we discuss relationships between pathologic processes of VBI and clinical expression of dementia, specific subtypes of VBI including microvascular brain injury, and what is currently known regarding contributions of VBI to the development and pathogenesis of the dementia syndrome. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Resistance to Alzheimer Disease Neuropathologic Changes and Apparent Cognitive Resilience in the Nun and Honolulu-Asia Aging Studies

Two population-based studies key to advancing knowledge of brain aging are the Honolulu-Asia Aging Study (HAAS) and the Nun Study. Harmonization of their neuropathologic data allows cross comparison, with findings common to both studies likely generalizable, while distinct observations may point to aging brain changes that are dependent on sex, ethnicity, environment, or lifestyle factors. Here, we expanded the neuropathologic evaluation of these 2 studies using revised NIA-Alzheimers Association guidelines and compared directly the neuropathologic features of resistance and apparent cognitive resilience. There were significant differences in prevalence of Alzheimer disease neuropathologic change, small vessel vascular brain injury, and Lewy body disease between these 2 studies, suggesting that sex, ethnicity, and lifestyle factors may significantly influence resistance to developing brain injury with age. In contrast, hippocampal sclerosis prevalence was very similar, but skewed to poorer cognitive performance, suggesting that hippocampal sclerosis could act sequentially with other diseases to impair cognitive function. Strikingly, despite these observed differences, the proportion of individuals resistant to all 4 diseases of brain or displaying apparent cognitive resilience was virtually identical between HAAS and Nun Study participants. Future in vivo validation of these results awaits comprehensive biomarkers of these 4 brain diseases.

Flow-Related Aneurysm within Glioblastoma: A Case Report and Review of Literature

BACKGROUND Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, with a median survival of 13 months despite surgery and chemoradiation. GBMs are often hypervascular tumors caused by abnormal oversecretion of growth factors such as vascular endothelial growth factor. These angiogenic factors are hypothesized to promote increased blood flow and possibly secondary changes to arterial walls, thus facilitating the formation of flow-related aneurysms. CASE DESCRIPTION A 59-year-old woman presented with headaches, confusion, nausea and emesis. Computed tomography and magnetic resonance imaging revealed a hypervascular lesion, likely high-grade glioma, in the right frontal lobe, with a dilated vessel within the tumor. Cerebral angiography demonstrated a flow-related aneurysm on the right frontopolar artery supplying the tumor. The aneurysm was embolized with coils and the patient later underwent craniotomy for near total resection of the lesion without complications. Final pathology returned GBM with dilated vessels noted. CONCLUSIONS Hypervascular lesions, such as GBMs, may be associated with flow-related aneurysms on feeding arteries, but aneurysms within the gross tumor are unusual. Although rare, this finding needs to be recognized on preoperative imaging before tumor resection to prevent potentially catastrophic intraoperative complications.

Performance of a Condensed Protocol That Reduces Effort and Cost of NIA-AA Guidelines for Neuropathologic Assessment of Alzheimer Disease

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost. A 28 autopsy brain–retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings.

Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimers disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.

Localized crystal-storing histiocytosis of the posterior fossa: Crystal-storing histiocytosis

Crystal‐storing histiocytosis (CSH) is an uncommon histiocytic proliferation reported to involve diverse organs and tissues, but involvement of the central nervous system (CNS) is rare. In most cases CSH is identified in association with underlying lymphoproliferative, plasma cell diseases or rarely with various inflammatory or infectious conditions. CSH is characterized by the cytoplasmic accumulation of crystalline material in histiocytes, most commonly of kappa immunoglobulin light chain. We report a unique case of localized CSH involving the left cerebellum and caudal brain stem in a young man with a history of gout but without known lymphoproliferative or plasma cell disorders. Awareness of this entity is important diagnostically, but also to ensure appropriate management and follow‐up, particularly in the absence of apparent underlying malignancy.

Molecular Basis of Diseases of the Nervous System

Abstract The central nervous system (CNS) is composed of cellular components organized in a complex structure that is unlike other organ systems. At the macroscopic level, the parenchyma of the CNS can be categorized into two structurally and functionally unique components: gray and white matter. The CNS can be divided into a number of anatomic regions, each with specific neurologic or cognitive functions. Disease or damage to these regions produces neurologic or cognitive deficits that correlate with the anatomic location and extent of disease. There are several ways to divide these structures. The main divisions are the cerebrum, cerebellum, brainstem, and spinal cord. Developmental neuropathology encompasses a broad variety of cerebral malformations and functional impairments caused by disturbances of brain development, manifesting during ages from the embryonic period through adolescence and young adulthood. The neurologic and psychiatric manifestations of neurodevelopmental disorders range widely depending on the affected neural systems and include such diverse manifestations as epilepsy, mental retardation, cerebral palsy, breathing disorders, ataxia, autism, and schizophrenia. In terms of morbidity and mortality, the spectrum is extremely broad: the mildest neurodevelopmental disorders can be asymptomatic, whereas the worst malformations often lead to intrauterine or neonatal demise. This chapter focuses on the genetic disorders of brain development, caused by mutations of gene loci or chromosomal regions with important neurodevelopmental functions.

Application of the condensed protocol for the NIA-AA guidelines for the neuropathological assessment of Alzheimer's disease in an academic clinical practice

In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimers Association (NIA‐AA) Sponsored Guidelines for the neuropathological assessment of Alzheimers disease (AD), we previously developed a sensitive and cost‐reducing condensed protocol (CP) at the University of Washington (UW) Alzheimers Disease Research Center (ADRC) that consolidated the recommended NIA‐AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA‐AA protocols, but instead to make the NIA‐AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA‐AA guidelines.

WHAT WOULD BE THE LIKELY IMPACT OF AN INTERVENTION THAT SUCCESSFULLY PREVENTED NEOCORTICAL ACCUMULATION OF NEURITIC AMYLOID PLAQUES AND A HIGH BRAAK STAGE? THOUGHT EXPERIMENTS USING DATA FROM THE NUN STUDY (NS) AND THE HONOLULU-ASIA AGING STUDY

pathology; the other major pathological marker of Alzheimer’s Disease (AD). Our initial studies document that TLR9 signaling with the type B CpG ODN has a beneficial effect in 3xTg-AD mice with both plaque and tangle pathology without toxicity, suggesting that stimulating the innate immunity has the possible advantage of concurrently addressing both AD pathologies. Given the importance of tau related pathology, we felt it was critical to more precisely determine the effect of our novel approach in rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concomitant Ab pathology. Methods: The rTg4510 mice were injected with either the TLR9 agonist class B CpG ODN or saline at monthly intervals (from 3 to 11 months of age). After the treatment the mice were subjected to behavioral testing. Histological analyses commenced upon completion of the behavioral protocol. Animals were continuously monitored for signs of toxicity.Results:Administration of CpGODNwas effective at improving spatial working memory evaluated using the closed field symmetrical maze in rTg4510 mice. No difference between groups was found in any of the locomotor parameters. Histological evaluation of CpG ODN effect on hippocampal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG ODN-treated animals. Although the effect on tau pathology was modest, our findings confirmed that this type of immunomodulation has beneficial effects on tau related pathology, in contrast to number of other prior innate immunity stimulation approaches. Biochemical assessments of tau levels are underway. No differences were noted in the extent of CD45 microgliosis and GFAP astrogliosis in CpG ODN-treated animals compared to controls, at the end of the treatment. In addition, we have preliminary data showing that acute injection of CpG ODN leads to an induction of favorable microglia/macrophage activation in rTg4510 mice. Further characterization of immune responses is ongoing. Conclusions:Overall, the present findings, together with our earlier research, represent essential preclinical evidence validating the feasibility of TLR9 ligand CpG ODN as a disease modifying drug for AD.