Authors: Andreas Charidimou, Gregoire Boulouis, Matthew P Frosch...

BACKGROUND

Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations.

METHODS

In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy.

FINDINGS

The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard.

INTERPRETATION

The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations.

FUNDING

US National Institutes of Health (R01 AG26484).

Topics: Aged; Amyloid beta-Peptides; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Humans; Magnetic Resonance Imaging; Middle Aged; Neuropathology; Retrospective Studies

PubMed: 35841910
DOI: 10.1016/S1474-4422(22)00208-3

Authors: Jill M Lawrence, Kayla Schardien, Brian Wigdahl...

In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.

Topics: Humans; Astrocytes; Microglia; Central Nervous System; Blood-Brain Barrier; Chemokines; Neurotoxicity Syndromes

PubMed: 36915214
DOI: 10.1186/s40478-023-01526-9

Review

Authors: Ann C McKee, Thor D Stein, Patrick T Kiernan...

Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE). Most instances of CTE occur in association with the play of sports, but CTE has also been reported in association with blast injuries and other neurotrauma. Symptoms of CTE include behavioral and mood changes, memory loss, cognitive impairment and dementia. Like many other neurodegenerative diseases, CTE is diagnosed with certainty only by neuropathological examination of brain tissue. CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths. Severely affected cases show p-tau pathology throughout the brain. Abnormalities in phosphorylated 43 kDa TAR DNA-binding protein are found in most cases of CTE; beta-amyloid is identified in 43%, associated with age. Given the importance of sports participation and physical exercise to physical and psychological health as well as disease resilience, it is critical to identify the genetic risk factors for CTE as well as to understand how other variables, such as stress, age at exposure, gender, substance abuse and other exposures, contribute to the development of CTE.

Topics: Brain; Brain Injury, Chronic; DNA-Binding Proteins; Humans; Neuropathology; tau Proteins

PubMed: 25904048
DOI: 10.1111/bpa.12248

Review

Authors: D P Devanand

PURPOSE OF REVIEW

The purpose is to review the results and clinical implications of recent studies of neuropathology in relation to neuropsychiatric symptoms (NPS) in Alzheimer's disease and related dementias, and discuss new therapeutic approaches based on evidence from clinical trials.

RECENT FINDINGS

In a large autopsy series from a national consortium, multiple neuropathologies of dementia subtypes were common and increased severity of specific NPS during life was associated with greater severity of neuropathology across diagnoses. Based on three clinical trials, brexpiprazole, which is an antipsychotic with dopamine and serotonin receptor partial agonism properties, was recently approved for the treatment of agitation in Alzheimer's dementia by the U.S. Food and Drug Administration (FDA). Its therapeutic profile indicates modest efficacy with high safety. Brexpiprazole has not been compared to other antipsychotics that are commonly prescribed to treat agitation in dementia, though none of them have been approved for this indication. Other drugs that showed positive results in Phase 2 trials are being tested in Phase 3 trials. These include cannabinoids and drug combinations that inhibit dextromethorphan metabolism peripherally, thereby increasing its bioavailability in the brain. Apathy is common in several types of dementia, and there is initial evidence that treatment with methylphenidate, a psychostimulant, may be efficacious with good tolerability.

SUMMARY

Greater understanding of the associations between NPS and dementia subtypes can improve clinical management of these disorders. In addition to the approval of brexpiprazole to treat agitation in Alzheimer's dementia, there is optimism about other medications based on ongoing clinical trials. Along with short-term improvement, altering the adverse impact on NPS on long-term prognosis remains an important challenge for the field.

Topics: United States; Humans; Alzheimer Disease; Quinolones; Thiophenes; Apathy; Antipsychotic Agents

PubMed: 37639488
DOI: 10.1097/WCO.0000000000001199

Review

Authors: Dennis W Dickson

INTRODUCTION

Parkinson's disease (PD) is characterized by bradykinesia, rigidity, postural instability and tremor. Several pathologic processes can produce this syndrome, but neurodegeneration accompanied by neuronal inclusions composed of α-synuclein (Lewy bodies) is considered the typical pathologic correlate of PD.

METHODS

The neuropathologic features of PD are reviewed based upon personal experience and review of the literature. Molecular pathology of PD is summarized from cell biological and animal studies.

RESULTS

The pathologic feature that correlates with signs and symptoms of PD is neuronal loss in the substantia nigra with dopaminergic denervation of the striatum. Neuronal degeneration in the substantia nigra preferentially affects the ventrolateral cell group that projects to posterolateral putamen and is accompanied by formation of Lewy bodies composed of aggregated α-synuclein. Some patients with PD are found at autopsy to have other pathologic processes, such as multiple system atrophy, progressive supranuclear palsy and cerebrovascular disease (vascular Parkinsonism). The peripheral autonomic nervous system is also affected. The triggering event in PD is unknown, but recent studies suggest a role for loss of nuclear membrane integrity. Once α-synuclein aggregates forms, evidence supports cell-to-cell propagation.

CONCLUSION

PD is a multisystem synucleinopathy caused by poorly characterized genetic and environmental factors that produces degeneration in selectively vulnerable neuronal populations.

Topics: Brain; Humans; Neuropathology; Parkinson Disease

PubMed: 28780180
DOI: 10.1016/j.parkreldis.2017.07.033

Meta-Analysis

Authors: Lieke Jäkel, Anna M De Kort, Catharina J M Klijn...

Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer's disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA.

Topics: Alzheimer Disease; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Cognitive Dysfunction; Humans; Immunotherapy; Magnetic Resonance Imaging; Neuropathology; Prevalence

PubMed: 34057813
DOI: 10.1002/alz.12366

Review

Authors: Anthony T Lee, Edward F Chang, Mercedes F Paredes...

Advances in large-scale single-unit human neurophysiology, single-cell RNA sequencing, spatial transcriptomics and long-term ex vivo tissue culture of surgically resected human brain tissue have provided an unprecedented opportunity to study human neuroscience. In this Perspective, we describe the development of these paradigms, including Neuropixels and recent brain-cell atlas efforts, and discuss how their convergence will further investigations into the cellular underpinnings of network-level activity in the human brain. Specifically, we introduce a workflow in which functionally mapped samples of human brain tissue resected during awake brain surgery can be cultured ex vivo for multi-modal cellular and functional profiling. We then explore how advances in human neuroscience will affect clinical practice, and conclude by discussing societal and ethical implications to consider. Potential findings from the field of human neuroscience will be vast, ranging from insights into human neurodiversity and evolution to providing cell-type-specific access to study and manipulate diseased circuits in pathology. This Perspective aims to provide a unifying framework for the field of human neuroscience as we welcome an exciting era for understanding the functional cytoarchitecture of the human brain.

Topics: Humans; Brain; Neuropathology; Neurophysiology; Neurosciences; Single-Cell Analysis; Single-Cell Gene Expression Analysis; Transcriptome; Workflow; Animals

PubMed: 38898291
DOI: 10.1038/s41586-024-07405-0

Review

Authors: Fernando Gonzalez-Ortiz, Przemysław R Kac, Wagner S Brum...

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.

Topics: Humans; Alzheimer Disease; tau Proteins; Cognitive Dysfunction; Biomarkers; Neuropathology; Amyloid beta-Peptides

PubMed: 36927491
DOI: 10.1186/s13024-023-00605-8

Authors: Dominik Sturm, David Capper, Felipe Andreiuolo...

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

Topics: Adolescent; Humans; Child; Multiomics; Glioma; Neuropathology; DNA Methylation; Mutation; Brain Neoplasms

PubMed: 36928815
DOI: 10.1038/s41591-023-02255-1

Review

Authors: Thomas Koeglsperger, Svenja-Lotta Rumpf, Patricia Schließer...

BACKGROUND

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing.

METHODS

Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD.

RESULTS

Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons.

CONCLUSIONS

Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Topics: Humans; Parkinson Disease; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neuropathology; alpha-Synuclein

PubMed: 37173733
DOI: 10.1186/s13024-023-00622-7