Selected References

Hypertensive Encephalopathies

Acute Hypertensive Encephalopathy, Posterior Reversible

Encephalopathy Syndrome

Fischer M et al: Posterior reversible encephalopathy syndrome. J Neurol. ePub, 2017

Hiremath SB et al: Susceptibility-weighted angiography and diffusion-weighted imaging in posterior reversible encephalopathy syndrome - is there an association between hemorrhage, cytotoxic edema, blood pressure and imaging severity? J Neuroradiol. ePub, 2017

Ollivier M et al: Neuroimaging features in posterior reversible encephalopathy syndrome: A pictorial review. J Neurol Sci. 373:188-200, 2017

Schweitzer AD et al: Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome. Neuroradiology. 59(4):379-386, 2017

Shankar J et al: Posterior reversible encephalopathy syndrome: a review. Can Assoc Radiol J. 68(2):147-153, 2017

Acute Hypertensive Encephalopathy and Malignant Hypertension

Thind G et al: Malignant hypertension as a rare cause of thrombotic microangiopathy. BMJ Case Rep. 2017, 2017

Timmermans SA et al: Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int. 91(6):1420-1425, 2017

Mitaka H et al: Malignant hypertension with thrombotic microangiopathy. Intern Med. 55(16):2277-80, 2016

Shi L: ED 08-4 Diagnosis and treatment of hypertensive emergency in children. J Hypertens. 34 Suppl 1 - ISH 2016 Abstract Book:e373e374, 2016

Glucose Disorders

Pediatric/Adult Hypoglycemic Encephalopathy

Shah P et al: Hyperinsulinaemic hypoglycaemia in children and adults. Lancet Diabetes Endocrinol. ePub, 2016

Neonatal/Infantile Hypoglycemia

De Leon DD et al: Congenital hypoglycemia disorders: new aspects of etiology, diagnosis, treatment and outcomes: highlights of the Proceedings of the Congenital Hypoglycemia Disorders Symposium, Philadelphia April 2016. Pediatr Diabetes. 18(1):3-9, 2017

Ferriero DM: The vulnerable newborn brain: imaging patterns of acquired perinatal injury. Neonatology. 109(4):345-51, 2016

Hyperglycemia-Associated Disorders

Siwakoti K et al: Cerebral edema among adults with diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome: incidence, characteristics, and outcomes. J Diabetes. 9(2):208-209, 2017

Soto-Rivera CL et al: Suspected cerebral edema in diabetic ketoacidosis: is there still a role for head CT in treatment decisions? Pediatr Crit Care Med. 18(3):207-212, 2017

Yu F et al: T2*-based MR imaging of hyperglycemia-induced hemichorea-hemiballism. J Neuroradiol. 44(1):24-30, 2017

Barrot A et al: Neuroimaging findings in acute pediatric diabetic ketoacidosis. Neuroradiol J. 29(5):317-22, 2016

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Malone JI: Diabetic central neuropathy: CNS damage related to hyperglycemia. Diabetes. 65(2):355-7, 2016

Umpierrez G et al: Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol. 12(4):222-32, 2016

Thyroid Disorders

Keller-Petrot I et al: Congenital hypothyroidism: role of nuclear medicine. Semin Nucl Med. 47(2):135-142, 2017

Kocova M et al: Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia? J Pediatr Endocrinol Metab. 29(3):297-303, 2016

Parathyroid and Related Disorders

Hyperparathyroidism

Sharata A et al: Management of primary hyperparathyroidism: can we do better? Am Surg. 83(1):64-70, 2017

Hypoparathyroid Disorders

Abate EG et al: Review of hypoparathyroidism. Front Endocrinol (Lausanne). 7:172, 2017

Tafaj O et al: Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Invest. 40(4):347-356, 2017

Simpson C et al: Pseudopseudohypoparathyroidism. Lancet. 385(9973):1123, 2015

Primary Familial Brain Calcification (Fahr Disease)

Batla A et al: Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes. Parkinsonism Relat Disord. 37:1-10, 2017

Hascalovici JR et al: Diffuse symmetric cerebral calcifications: an emerging clinical pivot. Can J Neurol Sci. 44(2):190-191, 2017

Seizures and Related Disorders

Normal Anatomy of the Temporal Lobe

Dekeyzer S et al: "Unforgettable" - a pictorial essay on anatomy and pathology of the hippocampus. Insights Imaging. 8(2):199-212, 2017

Mesial Temporal (Hippocampal) Sclerosis

Asadi-Pooya AA et al: Prevalence and incidence of drug-resistant mesial temporal lobe epilepsy in the United States. World Neurosurg. 99:662-666, 2017

Stefanits H et al: Seven-Tesla MRI of hippocampal sclerosis: an in vivo feasibility study with histological correlations. Invest Radiol. ePub, 2017

Shih YC et al: Hippocampal atrophy is associated with altered hippocampus-posterior cingulate cortex connectivity in mesial temporal lobe epilepsy with hippocampal sclerosis. AJNR Am J Neuroradiol. 38(3):626-632, 2017

AlQassmi A et al: Benign mesial temporal lobe epilepsy: a clinical cohort and literature review. Epilepsy Behav. 65:60-64, 2016

Status Epilepticus

Cabrera Kang CM et al: Survey of the diagnostic and therapeutic approach to new-onset refractory status epilepticus. Seizure. 46:24-30, 2017

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Shimogawa T et al: The initial use of arterial spin labeling perfusion and diffusion-weighted magnetic resonance images in the diagnosis of nonconvulsive partial status epileptics. Epilepsy Res. 129:162-173, 2017

Cytotoxic Lesions of the Corpus Callosum

Fong CY et al: Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) due to dengue virus. J Clin Neurosci. 36:7375, 2017

Starkey J et al: Cytotoxic lesions of the corpus callosum that show restricted diffusion: mechanisms, causes, and manifestations. Radiographics. 37(2):562-576, 2017

Bajaj BK et al: "Boomerang sign": an ominous-looking finding in reversible maladies. Neurol India. 64(2):330-1, 2016

Ka A et al: Mild encephalopathy with reversible splenial lesion: an important differential of encephalitis. Eur J Paediatr Neurol. 19(3):377-82, 2015

Malhotra HS et al: Boomerang sign: clinical significance of transient lesion in splenium of corpus callosum. Ann Indian Acad Neurol. 15(2):151-7, 2012

Osmotic Encephalopathy

Beh SC: Temporal evolution of the trident and piglet signs of osmotic demyelination syndrome. J Neurol Sci. 373:268-273, 2017

Diringer M: Neurologic manifestations of major electrolyte abnormalities. Handb Clin Neurol. 141:705-713, 2017

Heavy Metal Deposition Disorders

Conte G et al: Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. Eur Radiol. ePub, 2017

Fraum TJ et al: Gadolinium-based contrast agents: a comprehensive risk assessment. J Magn Reson Imaging. ePub, 2017

Hoggard N et al: T1 hyperintensity on brain imaging subsequent to gadolinium-based contrast agent administration: what do we know about intracranial gadolinium deposition? Br J Radiol. 90(1069):20160590, 2017

Dementias and Brain

Degenerations

Worldwide public health efforts to improve living conditions, prevent disease, and enhance medical treatment have resulted in a 30-year increase in life expectancy over the past century. Individuals over 65 years of age now represent 13% of the population, and people aged 85 years and older are the fastest growing segment of the population.

One in three adults over 85 years suffers from Alzheimer disease or other forms of dementia. Despite the global increase in both the incidence and prevalence of Alzheimer disease, it is the only leading cause of death that we are currently unable to prevent or cure. New treatments to slow disease progression are being developed; most rely on early identification of at-risk individuals before clinical symptoms emerge.

Innovative technologies, such as tau imaging and novel MR sequences for connectivity analyses, represent new, exciting frontiers in the early identification of dementing disorders. A detailed discussion of these experimental techniques is beyond the scope of this book. While some illustrative case examples are included here, the overall purpose of this chapter is to discuss normal and abnormal brain aging changes on imaging modalities that are generally available to practicing neuroradiologists.

Understanding the biology and imaging of normal aging is a prerequisite to understanding the pathobiology of degenerative brain diseases. Therefore, we first delineate normal age-related changes in brain structure and function.

We then turn our attention to dementias and brain degenerative disorders. Dementia is a loss of brain function that affects memory, thinking, language, judgment, and behavior. Dementia has many causes but most often occurs secondary to degenerative processes in the brain.

Neurodegeneration occurs when neurons in specific parts of the brain, spinal cord, or peripheral nerves die. Although dementia always involves brain degeneration, not all neurodegenerative disorders are dementing illnesses. Some neurodegenerative disorders (e.g., Parkinson disease) can have associated dementia, but most do not.

Chapter 33

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(33-1) Axial graphic depicts a normally aging brain in an 80y patient. Note the widening of sulci and ventricles in the absence of any parenchymal abnormalities.

The Normal Aging Brain

Introduction to the Normal Aging Brain

Terminology

Age-related changes take place in virtually all parts of the brain and occur at all ages. The term "normal aging brain" as used in this chapter refers to the spectrum of normal agerelated neuroimaging findings as delineated by the Rotterdam Scan Study (RSS). The RSS is a continuing population-based longitudinal study that began in the 1990s and includes advanced MR sequences. The population includes persons 45 years and older who are scanned every 3- 4 years.

The term "successfully aging brain" previously referred to patients whose anatomic imaging studies do not demonstrate markers of small vessel ("microvascular") disease, such as white matter (WM) hyperintensities with arteriolosclerosis and lipohyalinosis, silent lacunar infarcts, and microbleeds.

Recent studies of functional connectivity have demonstrated that the brain's intrinsic networks undergo progressive disgregation (i.e., separation and parting) from clinically normal aging across progressive states of cognitive impairment to full-blown Alzheimer disease (AD). Functional imaging definitions of successful brain aging therefore include older individuals whose brain connectivity maps are considered normal.

(33-2) NECT scan in a 100y, independent, cognitively normal man who had a ground-level fall shows mildly enlarged ventricles and sulci with no evidence of white matter lesions.

Various methods to determine cognitive status in the elderly include the designation of "clinically normal (CN)" on the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition.

Genetics

Genetic factors affect brain aging and contribute to agerelated cognitive decline. Apolipoprotein E (specifically APOE- ε4) and six novel risk-associated single-nucleotide polymorphisms (SNPs) on chromosome 17q25 are genetic variants that are robustly associated with brain pathology on MR.

Epigenetic dysregulation has also been identified as a pivotal player in aging as well as age-related cognitive decline and degenerative disorders. Major epigenetic mechanisms including DNA methylation and demethylation, chromatin remodeling, and noncoding RNAs are involved in normal aging and in the pathophysiology of the most common neurodegenerative diseases.

Biomarkers

The National Institute on Aging-Alzheimer's Association (NIAAA) criteria for normal aging vs. preclinical AD use five biomarkers to classify individuals as either amyloid-β-positive or amyloid-β-negative and as neurodegeneration-positive or neurodegeneration-negative. Biomarkers of fibrillary β- amyloid deposition are high ligand retention on amyloid PET and low levels of amyloid-β42 in the CSF.

The biomarkers of AD-related neurodegeneration are high levels of tau in CSF, brain hypometabolism as assessed by 18F FDG PET, and atrophy as determined by anatomic MR.

Pathology

Gross Pathology. Overall brain volume decreases with advancing age and is indicated by a relative increase in the size of the CSF spaces. Widened sulci with proportionate enlargement of the ventricles are common (33-1). Although minor thinning of the cortical mantle occurs with aging, the predominant neuroanatomic changes occur in the subcortical WM.

Microscopic Features. Physiologic brain aging is accompanied by ubiquitous degeneration of neurons and oligodendrocytes. Neuronal dysfunction—rather than frank neuronal loss—seems to predominate with a reduction in cell size (rather than number). Dendritic pruning and loss of synapses

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occur in selected areas (e.g., the hippocampus) but not globally.

The subcortical WM demonstrates decreased numbers of myelinated fibers, increased extracellular space, and gliosis. Perivascular (Virchow-Robin) spaces in the subcortical WM and basal ganglia enlarge.

Three histologic markers are associated with dementias: senile plaques (SPs), neurofibrillary tangles (NFTs), and

Lewy bodies. All can be identified to some extent in normal aging brains, so the border between normal and "preclinical" dementia is unclear. Decades may elapse between initial cortical accumulations of NFTs and SPs and the development of overt cognitive changes.

SPs are extracellular amyloid deposits that accumulate in cerebral gray matter. Nearly half of cognitively intact older individuals demonstrate moderate or frequent SP density.

(33-4) FLAIR in a normal 79y man shows enlargement of ventricles, sulci due to age-related volume loss. Smooth, thin periventricular hyperintense rim around lateral ventricles is normal. Note lack of lacunar infarcts, WM hyperintensities.

NFTs are caused by tau aggregations within neurons. The Braak pathoanatomic staging divides AD into six distinct stages based on the topographical distribution of NFTs. Braak stage 5 or 6 NFTs are found in 6% of cognitively normal cases.

Lewy bodies are intraneuronal clumps of α-synuclein and ubiquitin proteins. They are found in 5-10% of cognitively intact individuals.

Clinical Issues

Epidemiology and Demographics. Brain maturation continues well into the third decade of life, after which brain aging predominates. Although the incidence of dementias increases dramatically with aging, nearly two-thirds of patients over 85 years of age remain neurologically intact and cognitively normal.

Presentation. Most older people with memory loss do not have dementia. As we age, we all experience memory deficits. As Dr. Gary Small, director of the UCLA Longevity Center put it, "To forget where you placed your keys, that's normal. If you forget how to use your keys, that's a problem."

Imaging the Normal Aging Brain

Because age-associated brain pathology begins long before clinical symptoms develop, imaging plays an increasingly central role in evaluating older patients for early signs of dementia. Just as imaging findings reflect the dramatic changes in brain morphology that occur with fetal and postnatal development, others mirror normal alterations in the aging brain.

(33-5) T2* SWI in a 67y normal woman shows striking hypointensity in the globi pallidi and less prominent hypointensity in the putamina from iron deposition. (Both cases from Imaging in Neurology.)

CT Findings

The normal aging brain demonstrates mildly enlarged ventricles and widened sulci on NECT scans (33-2). Punctate calcifications in the medial basal ganglia are physiologic.

Curvilinear calcifications in the cavernous carotid arteries and vertebrobasilar system are common. The significance of macrovascular calcification as a marker of microvascular disease is debated.

A few scattered patchy WM hypodensities are common, but confluent subcortical hypointensities, especially around the atria of the lateral ventricles, are a marker of arteriolosclerosis.

CECT scans demonstrate no foci of parenchymal enhancement in normal aging brains.

MR Findings

T1WI. T1-weighted images show mild but symmetric ventricular enlargement and proportionate prominence of the subarachnoid spaces. The corpus callosum may appear mildly thinned on sagittal T1 scans. Prominent perivascular spaces are a normal finding. They are filled with interstitial fluid (not CSF) but behave like CSF on all imaging sequences.

T2/FLAIR. White matter hyperintensities (WMHs) and lacunar infarcts on T2/FLAIR scans are highly prevalent in the elderly. They are associated with cardiovascular risk factors such as diabetes and hyperlipidemia. "Successfully" aging brains may demonstrate a few scattered nonconfluent WMHs (a reasonable number is one WMH per decade).

Perivascular spaces increase in prevalence and size with aging and are seen on T2WI as well-delineated round, ovoid, or