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DEMENTIA Sangam Kanekar, MD Assistant Professor Dept of Radiology and Neurology Penn State Milton S Hershey Medical Center Hershey, PA, USA Why is Dementia important ? 1. More than 24.3 million people are currently estimated to have dementia, and 4.6 million new cases are diagnosed each year. The number of aged 65 and older are climbing. 2. Worldwide, a new case of dementia arises every seven seconds. 3. Every atrophy seen on imaging in adult patients, is not an Alzheimer’s disease. 4. With elderly population explosion and corresponding increase in neurodegenerative disorders, it is important for radiologist to familiarize with the various types of dementia and differentiate the reversible/preventable from irreversible causes, and guide the physician to provide the appropriate therapy. The economic impact of this problem is staggering. INTRODUCTION Definition: Dementia is an impairment in intellectual functioning in at least two spheres. One of the spheres is memory; the second may be any other area of cognition. Dementia is truly a devastating disease that robs patients of their personalities and their ability to interact. It is also the fourth or fifth most common cause of death, although it rarely appears on death certificates. Pathophysiology: Most causes of dementia lead to the death or metabolic dysfunction of neurons, producing losses in cognitive function. The location of the cell loss is a critical factor e.g. in Alzheimer’s disease cell loss is most prominent in the cortex, hippocampus, and amygdala, disrupting connections critical for memory and other cognitive function while in the multi infarct dementia, small strokes placed in strategic locations can lead to loss of memory, visuospatial abilities, language, and personality. Dementia can also occur because of a change in the overall chemical milieu of the brain. Imaging: Over the last decade an exponential increase has occurred in the number of neuroimaging studies and techniques to investigate dementia. Till now structural imaging was performed primarily to answer one question and that is whether DEMENTIA IS REVERSIBLE OR IRREVERSIBLE? But the newer technique has revolutionized imaging of dementia and today we can classify or differentiate various types on imaging and give a lead and direction to the clinician/neurologist. Etiology of Dementia Establishing a precise etiology of dementia is challenging for clinicians. However whenever possible allows for more focused treatment and for an accurate assessment of prognosis. Causes are multiple and makes it very difficult for neurologist to pin point the specific cause and therefore imaging and radiologist plays a very important role. Degenerative: Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease, progressive supranuclear palsy (PSP), multisystem degeneration, amyotrophic lateral sclerosis (ALS), corticobasal degeneration (CBD), multiple sclerosis (MS) Vascular: Stroke, chronic subdural hemorrhages, postanoxic injury, diffuse white matter disease Infectious: Human immunodeficiency virus (HIV) infection, neurosyphilis, progressive multifocal leukoencephalopathy (PMLE), CreutzfeldtJakob disease (CJD), tuberculosis (TB), sarcoidosis, Whipple's disease Neoplastic: Primary versus metastatic carcinoma, paraneoplastic syndrome Endocrine: Hypothyroidism, adrenal insufficiency, Cushing's syndrome, hypoparathyroidism/hyperparathyroidism, renal failure, liver failure Metabolic Thiamine deficiency (Wernicke's encephalopathy), vitamin B12 deficiency, inherited enzyme defects Toxins Chronic alcoholism, drugs/medication effects, heavy metals, dialysis dementia (aluminum) Trauma Other Normal pressure hydrocephalus (NPH), obstructive hydrocephalus Inflammatory: Vasculitis Classification of Dementia Although reversible causes will be found in less than 15% of new cases, a diagnosis may help a patient and his or her family to understand what the future holds for them and to make appropriate personal, medical, and financial plans. Therefore it is important for neurologist and radiologist to differentiate potentially reversible and irreversible dementia. Evaluation of the patient with dementing illness, particularly in the mild to moderate stages, must emphasize a search for potentially reversible causes. IRREVERSIBLE CORTICAL AD Down’s syndrome MCI FTLD SUBCORTICAL Parkinson’s disease Multiple systemic atrophy Progressive surpanuclear palsy Huntington’s Chorea Multi-infarct dementia Binswanger CADASIL Leukoenecephalopathy Metabolic Gliomatosis cerebri Amyotrophic lateral sclerosis Hallovorden Spatz REVERSIBLE/ PREVENTABLE MIXED Corticobasal degeneration Dementia with Lewy bodies Head injury Radiation injury Rasmussen’s encephalitis Classification of Dementia REVERSIBLE/ PREVENTABLE IRREVERSIBLE INFLAMMATORY INFECTIVE Meningoencephalitis Chronic meningitis CNS vasculitidis fungal CNS-SLE TB Limbic encephalitis Lyme Multiple sclerosis Syphilis HIV Whipple’s disease NUTRITIONAL/ TOXIC/ HORMONAL METABOLIC Vit B 12 def Thiamine def PTH def Adrenal def Growth hormone def MASS LESION Drugs SDH Wilson’s disease NPH Alcohol Meningioma Radiation Liver/ kidney & pancreas diseases IRREVERSIBLE CORTICAL ALZHEIMER’S DISEASE (AD) Introduction: AD is the most common cause of dementia and the prevelance by 2050 will be more than triple. Currently, the diagnosis of AD relies upon clinical neurological assessment combined with CT or MRI to exclude other potential etiologies for the patient's dementia. Pathology: Brain atrophy with regional neuron and synapse loss, amyloid and neuritic plaques, and neurofibrillary tangles (NFTs) are the primary pathological features of the disease. Deposition of NFT appears to begin in the transentorhinal and entorhinal cortex (ERC), spreading from there to the hippocampus and to the temporal neocortex and beyond. Neuritic or senile plaques (NPs) like NFTs are found predominantly in the cerebral cortex and hippocampus while amyloid deposition is seen initially in the cortex, then in the hippocampus. The number of NPs and NFTs correlates with disease severity. Genetics: A family history of AD is a major risk factor. Familial AD (FAD) has two forms, autosomal dominant, which has early-onset (age 30s to 50s), and late-onset familial AD Fig: shows a senile plaque, neuritic type, Bielschowsky stain: shows dark black, swollen, distorted axons or dendrites called senile plaque. The brown clump in the center is amyloid Fig shows a dark black neurofibrillarytangle NFT stained with silver stain Ref: Neuropathology for medical students. Presented by William I. Rosenblum, MD ALZHEIMER’S DISEASE (AD) IRREVERSIBLE CORTICAL Fig: Alzheimer’s disease: Note parietal & temporal cortical atrophy with disproportionate hippocampal volume loss. Alzheimer’s disease (AD) is the most common cause of dementia and the third leading cause of death in the elderly in United States. Currently, the diagnosis of AD relies upon clinical neurological assessment combined with CT or MRI to exclude other potential etiologies for the patient's dementia. AD is an irreversible dementia of the elderly that has an insidious onset but eventually leads to severe debilitation and death. It currently affects more than 4 million people in the United States, and it is estimated that 14 million Americans will be afflicted by the year 2050. ALZHEIMER’S DISEASE (AD) IRREVERSIBLE CORTICAL Fig: Alzheimer’s disease: FDG-PET shows decrease FDG uptake in the bilateral temporal and parietal lobes in two different patients. Note: Current role of the imaging is to exclude treatable dementia. Imaging: No absolute diagnostic test exist for AD. Definitive diagnosis requires brain biopsy. Atrophy of the brain is the imaging hallmark of AD. There is parietal & temporal cortical atrophy with disproportionate hippocampal volume loss. The greatest volume loss are in the medial temporal lobe. Atrophy is also seen of the basal & lateral temporal, parietal neocortex, posterior cingulate, and prefrontal cortex. FDG-PET shows decrease uptake in these region bilaterally again most prominent in temporal & parietal lobes. MR Spectroscopy: shows NAA due to loss of neurons, and myoinositol (which is found predominately in astrocytes and is increased due to glial activation from neuritis plaques and phosphomonoesters in parietal lobes. IRREVERSIBLE CORTICAL AD WITH DOWN’S SYNDROME Fig. Down syndrome with AD: Severe bilateral temporal lobe atrophy. Sag T2 cervical spine shows atlantoaxial instability. TRISOMY 21/ (DS): develop a clinical syndrome of dementia that has the same clinical and neuropathologic characteristics of AD. The only difference is, the early age (40-50) of onset of dementia with DS. The reason for AD in individuals with DS is not known. There is a complex connection between chromosome 21 (inherited in triplicate in DS) and Alzheimer's disease. The amyloid precursor protein (APP), which is a part of the nerve fiber tangles that typically appear in Alzheimer's disease, is localized in chromosome 21. In people with DS, this results in excess production of APP and appears to cause acceleration of the brain changes that typify Alzheimer's disease. Imaging studies are identical to adult onset AD. IRREVERSIBLE CORTICAL Newer Imaging trends in AD DWI & DTI: Normally cell membrane and intracellular structure act to impede the diffussion of water molecule. Pathologic disruption of cell membrane that occurs in AD increases the ADC of water. Fractional Anisotropy is also abnormal in ADC. Hippocampal ADC values from DWI images were predictive of progression from MCI to AD. MR PERFUSION: Bilateral tempero-parietal decrease in the cerebral blood flow has been well documented in AD using nuclear medicine. Similar changes have been also documented with FDG-PET and SPECT scan. Recent MRI technique ASL (arterial spine labeling) appeace promising and depicts the tempero-parietal decrease perfusion similar to FDG-PET. rCBV in temporal & parietal region AMYLOID IMAGING: The most significant advanced in imaging of dementia in recent years has been the development of amyloid labels such as Pittsburgh Compound B (PIB). PIB uptake is seen in most AD patients in precisely the same area as pathologic distribution of amyloid plaque in AD. Pittsburgh Compound B (PIB) IRREVERSIBLE CORTICAL Mild Cognitive Impairment (MCI) Definition: MCI: meant to refer to an abnormal process likely the prodromal stages of an dementing condition and as such is fundamentally different from the extremes of normal ageing. Data indicates that the overall prevelance of MCI including demented subjects is probably in the 12-15% range among individuals aged 65 and older and the incidence rate are in 1% per year range similar to those of AD. International conference for diagnostic criteria Stockholm 2003 MCI Criteria: Memory complaint, preferably qualified by an informant Memory impairment for age and education Preserved general cognitive function Intact activities of daily living Not demented DISEASE PROGRESSION C/F Path Treat Normal No disease No symptoms Presymptomatic AD Early brain changes but No symptoms Primary prevention MCI AD brain changes with mild symptoms Secondary prevention AD Moderate –severe symptoms Treatment IRREVERSIBLE CORTICAL Mild Cognitive Impairment (MCI) Predictors for progression: APOE4 carrier Atrophic hippocampi on MRI ? CSF increase tau and decrease Abeta levels ? FDG-PET temporoparietal hypometabolism ? + amyloid imaging PET scan Neuropathology of MCI: Medial temporal lobe atrophy Medial temporal lobe neurofibrillary tangles Sparse diffuse neocortical plaques ?Agryrophilic grains ? Vascular lesions It is apparent that patients who have a more severe memory impairment are more likely to progress more rapidly than those with less severe memory impairment. Note: Please note that most of the imaging and molecular research on MCI is in the infancy stage and needs validation in longitudinal clinical studies with pathological confirmation. IRREVERSIBLE CORTICAL FRONTOTEMPORAL DEMENTIA Fronto-temporal lobar degeneration formerly called Pick’s disease is a progressive neurodegenerative disease affecting the frontal and anterior temporal lobes. In 1998 concensus criteria for FTLD classified it into 3 syndromes: Frontotemporal dementia, semantic dementia and nonfluent aphasia. Fronto-temporal dementia (FTD) Semantic dementia (SD) Nonfluent aphasia (NFA) Alzheimer’s disease (AD) Atrophy Frontal>temporal (prefrontal cortex) Temporal>frontal (insula, amygdala) Left frontal. Insula, left perisylvian Biparietotemporal, hippocampal atrophy Behavioral symptoms Apathy, social withdrawal Deprression, emotional withdrawal Depression, social withdrawal Depression, delusion Cognitive Frontal dysfunction, diminish word output Long term memory loss, agnosia for faces Word finding difficulty, change in verbal fluency, apraxia of speech Short term memory deficite Neurologic symptoms Motor neuron disease, Parkinson’s like s/s Presents late Supranuclear gaze disturbances, rigidity, dystonia Parkinsonism later IRREVERSIBLE CORTICAL FRONTOTEMPORAL DEMENTIA Pathology: Gross specimen shows morphologic atrophy in the frontal and anterior temporal lobes, with microscopic changes of gliosis, inclusion bodies, swollen neurons, and microvacuolation. Symmetric atrophy is seen in FTD while atrophy is assymmetric in NFA (frontal lobes) and SD (temporal lobes). Most of the cortical atrophy is due to severe or complete loss of pyramidal cells in Layer III & II of the gray matter. Neurons also show swelling (ballooned or Pick’s cells) and inclusion within parikaryon, mostly in layer II called Pick’s bodies. Fig Pick’s disease: Axial CT & Coronal MRI images show striking atrophy of the frontal lobes bilaterally with normal parieto-occipital lobes. IRREVERSIBLE CORTICAL FRONTOTEMPORAL DEMENTIA Clinical features: As compared to AD patients, FTD have much more prominent personality and behavior changes such as apathy, euphoria, loss of social awareness. FTD is characterized by progressive impairment of executive function and speech. Unlike AD, memory and visuospatial skills are preserved till late. Imaging: Atrophy of the frontal and anterior temporal which is bilaterally symmetrical. The affected gyri becomes paper thin and gives a radiologic appearance of knife blade atrophy (“walnut or knife-edge”). The extrapyramidal nuclei especially the caudate nucleus, insular cortex, and anterior corpus callosum is affected. Fig Fronto-temoral dementia: Axial CT & Coronal MRI images show striking atrophy of the frontal lobes bilaterally with normal occipital lobes. IRREVERSIBLE SUBCORTICAL IRREVERSIBLE SUBCORTICAL PARKINSONIAN SYNDROME PRIMARY PARKINSONIAN SYNDROME Parkinson disease PSP CBD SECONDARY PARKINSONIAN SYNDROME MSA After: Infarction, Infection Trauma, Drugs, Toxins IRREVERSIBLE SUBCORTICAL PARKINSONS DISEASE PARKINSON'S DISEASE WITH DEMENTIA: There are several forms of primary degenerative parkinsonism, including idiopathic PD, sporadic PD with superimposed pathological features of AD, familial PD (or parkinsonian syndromes), and Parkinson-ALS-dementia complex of Guam. In case of PD, dementia is a "subcortical pattern“. It is a primary disorder of pars compacta of substantia nigra. MR shows narrowing or disappearance of pars compacta on T2WI, in addition to the generalized atrophy. In addition there may be hypointensity of putamen due to iron deposition or hyperintensity in the globus pallidus and putamen. Note: Role of imaging in PD is to exclude treatable causes of bradikinesia, like tumors, hematoma or hydrocephalus MULTIPLE SYSTEMIC ATROPHY Introduction: MSA presents clinically as variable combination of parkinsonism, cerebellar ataxia, and/or autonomic failure. MSA is a neurodegenerative disorder often confused with Parkinson disease (PD). Pathology: In MSA there is neuronal loss and gliosis in the inferior olives, pons, cerebellum, substantia nigra, locus ceruleus, striatum, and intermediolateral column of the spinal cord. In MSA-PD type the nigrostriatal system is the main site of disease, but less severe degeneration can be widespread and normally includes the olivopontocerebellar system. In MSA-C type, the olivopontocerebellar system is mainly involved, along with loss of pontine neurons and transverse pontocerebellar fibers and atrophy of middle cerebellar peduncles (MCPs). MULTIPLE SYSTEMIC ATROPHY MSA-Parkinsonism (MSA-P) Formrely: striatonigral degeneration MSA-cerebellar type (MSA-C) Formrely: olivopontocerebellar degeneration MSA-Shy-Drager syndrome (SDS) MSA-Parkinsonism (MSA-P) Introduction: MSA-P is characterized clinically by parkinsonian symptoms with prominence of rigidity. Unlike PD MSA-P less then 15% of the cases show response to levodopa. Pathology: Atrophy of the strium as a result of neuronal loss, particularly of the small neurons with putamen more than caudate. Imaging: MR shows atrophy of the putamen and hypointensity especially along the postero-lateral margins of putamen on T2 WI due to deposition of iron . On FLAIR there may be hyperintense rim surrounding this hyponintesity due to accumulation of water associated with cell loss and gliosis. In addition abnormal increased diffusion on DWIADC is sen in putamen and middle cerebellar peduncle, because of neuronal loss and loss of fiber tracts. DD Alzheimer’s disease usually spares putamen. Due to similar reasons MR spectroscopy shows reduction in NAA/Cr ratio within putamen and base of the pons. IRREVERSIBLE SUBCORTICAL MSA-CEREBELLAR TYPE (MSA-C) Introduction: MSA-C can involve early childhood or old age. It presents with ataxia, first in the legs then the arms and handsand finally the bulbar manifestation. Pathology: the primary degeneration involves pontine nuclei with subsequent progressive antegrade degeneration of the pontocerebellar tracts and the cerebellar cortex hemispheric greater than vermian. Later in the disease the inferior olive losses its normal bulge because of neuronal loss and gliosis. Imaging: MR shows atrophy of the pons with flattening of the inferior part (loss of normal pregnant belly of pons). Atrophy is also seen of the cerebellar cortex (hemispheric greater than vermian), middle cerebellar peduncles and inferior olives. Degeneration of pontine neurons & transverse pontocerebellar fibers with normal signal intensity in the surrounding parenchyma gives a classical hot cross burn sign. MR spectroscopy shows reduction in NAA/Cr and Cho/Cr ratio in pons and cerebellum. “Hot cross bun” IRREVERSIBLE SUBCORTICAL PROGRESSIVE SURPANUCLEAR PALSY Introduction: PSP presents with the typical subcortical pattern of dementia, supranuclear opthalmoplegia, PD and pseudobulbar palsy. There are frontal lobe features that appear to be more prominent. Pathology: classical finding on gross pathology is atrophy/ thinning of the superior colliculus. Imaging shows dilatation of third ventricle, atrophy of midbrain, enlargement of interpeduncular cistern, atrophy of superior colliculi and high signal intensity in periaqueductal GM. Putamen may appear more hypointense than globus pallidus due to iron deposition. Note: Mandatory exclusion criteria on MRI includes brainstem infarction and lobar atrophy (NINDS & SPSP criteria). Fig Progressive supranuclear palsy (in two different patients) : Sagittal MRI images show striking atrophy of the tectal plate especially the superior colliculus.