Download Dept of Radiology and Neurology Penn State Milton S

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.