Presenile Dementia
Mary Ellen Quiceno, M.D.
Case #1
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33 y.o. reported memory loss in 2000.
In 2002, episodes of left-sided numbness &
weakness.
Febrile day prior to first admission in 2002 for
h/a, n/v, and left-sided weakness.
Abnormal MRI and LP.
Progressively worsened and developed
seizures, tremor, startle, and ataxia.
No family history.
Died a week after brain biopsy from pulmonary
embolism. Biopsy nondiagnostic.
MRI/MRA brain, spine.
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Subtle alteration of FLAIR signal in the basal
ganglia bilaterally and subtle diffuse
enhancement in the pons and thalami
(nonspecific findings, ?occult vascular
malformationscapillary telangiectasias).
No change on repeat brain scans done 12/02,
6/03. Developed atrophy.
Normal MRA.
C2 T2 hyperintensities (?myelomalacia or
demyelinization).
Case #2
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Mid-40’s Caucasian man with degenerative
dementia.
Institutionalized.
Parents deny history of dementia or psychiatric
disturbances in family.
Taking Haldol.
Exam: No chorea. Very disinhibited. Difficult to
examinerepeatedly says “I love you”.
Case #2 Diagnosis
Once Haldol stopped, chorea was seen.
 Family finally disclosed that patient was
adopted and HIS family history was
unknown.
 Tested positive for Huntington’s disease.
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Presenile Dementia
Presenile Dementia
Rare <40 years old.
 Overall prevalence of presenile dementias
in the 45 to 65 year old age group 1580/100,000.
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Presenile Dementia
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Age of onset and premorbid functioning.
 <65
y.o.
 Psychiatric history? Education? Level of functioning?
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Family history.
Clinical characteristics.
 Neurological
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dysfunction.
Other diseases or dysfunction (medical,
psychiatric).
Expected Age-related Cognitive
Changes
Bradyphrenia.
 Trouble with recall of names of
people/places.
 Decreased concentration.
 Language, vocabulary spared and may
improve.
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Why Age of Onset Matters
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Metabolic & genetic: very early.
 Can
have later onset of some metabolic d/o.
Anticipation with triplicate disorders.
 Differential differs between presenile and
senile dementias.
 Some disorders have more predictable
onset.
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Temporal Course of Disease
Slowly or rapidly progressive?
 Gradual and insidious, stepwise,
fluctuating, acute onset then static?
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Cognitive Profile
Onset with memory, frontal executive
dysfunction, other…
 Cortical.
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 Language,
 AD,
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memory, praxis.
FTD.
Frontal-subcortical.
 Slow,
poor attention, decreased verbal output,
apathy.
 Other dementias.
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Mixed.
Associated Features
Behavioral & Neurological
Personality & behavior changes.
 Depression & psychosis.
 Seizures.
 Myoclonus.
 Ataxia.
 Tremor.
 Parkinsonism.
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Differential
Diagnosis
Differential Diagnoses
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Neurodegenerative disorders.
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Vascular.
Infectious.
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Anti-Yo.
Autoimmune & Inflammatory.
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Syphilis, CJD, vCJD, HIV-related.
Tumor & Paraneoplastic disease.
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SCA, HD, DRPLA, Alzheimer’s disease, FTD, DLB & related
dementias.
MS, sarcoid.
Trauma.
Toxic & Metabolic.
Inherited Dementias
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AD
FTD
HD
SCA
Wilson’s
Prion
CADASIL
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Storage Disorders
 Lysosomal
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Niemann-Pick
MLD
 Peroxisomal
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ALD
 Lafora
Body Disease
 Mitochondrial d/o
Rapidly Progressive Dementias
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Reversible
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Irreversible
 NCSE
 CJD
 Drugs
 Rapidly
 Meningitis
 Whipple’s
 Tumor
progressive
variants of AD
Dementia-Plus Syndromes
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Cognitive impairment in the setting of
more wide-spread neurological
disturbance.
 Ataxia:
HD, DRPLA, Wilson’s, SCA, Prion
 EPS: FTDP-17, HD, Wilson’s
 Psychiatric: FTD, HD, Wilson’s
More Common
Dementias
Most Common
Senile & Presenile Dementias
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SENILE
 Alzheimer’s
ds. 70-80%?
 Lewy Body ds.
 Vascular ds.
 FTD.
 Other.
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PRESENILE
 Alzheimer’s
ds 30%
 Vascular ds 15%
 FTD 13%
 LBD 4%
 Other 25%
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HD, MS, CBGD, Prion
disease, PD.
Alzheimer’s disease
May manifest in 4th decade.
 Autosomal dominant with complete
penetrance.
 Presenilin 1 on chromosome 14.
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 APP
on chr. 21 (Down’s), PS-2 on chr. 1
 Creates abnormally aggregated b-amyloid
Neuropathology the same in
Presenile and Senile Onset AD
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Neuritic plaques
 extracellular
 b-amyloid
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Neurofibrillary tangles
 intracellular
 tau
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protein
Basal forebrain nuclei
 leads
to Ach deficit
Clinically Similar
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Early involvement of
medial temporal lobe.
 hippocampus
and
entorhinal cortex
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Parietal lobe
dysfunction.
Myoclonus may be
more prominent in
familiar forms.
Naming may be
spared until late in
familiar forms.
Frontotemporal Lobar
Degenerations (FTLD)
Onset 20-75 years of age.
 Male predominance.
 Half have family history (may be heterogeneous).
 Various genetic mutations known.
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 Chr.
17 tau gene mutation most common.
FTD with parkinsonism.
 Clinically variable within families.
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FTLD types
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Pick’s disease.
3
repeat tau isoform aggregates
FTD: behavioral, PPA, SD.
 CBGD.
 FTD associated with MND.
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 Ubiquitin
positive, tau negative inclusions
FTD
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Behavioral Onset
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 First
attributed to
depression, referred to
psychiatrist.
 Personality change,
blunted affect, loss of
motivation.
 Frontal atrophy on
MRI (may be missed).
Semantic Dementia
 Progressive
fluent
aphasia.
 Mistaken for AD.
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Progressive Aphasia
 Non-fluent
aphasia.
 Paraphasic errors.
 Orofacial apraxia.
FTD
Vascular Dementia
Usual risk factors, plus unusual cardiac,
hematological, metabolic, and genetic
causes.
 CADASIL (cerebral autosomal dominant arteriopathy with
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subcortical infracts and leukoencephalopathy).
 Mean
age of presentation in 50-60’s.
 Can present in 20’s with migraines w/aura and
MRI changes.
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Consider MRI in migraineurs w/ atypical auras,
family hx.
 Chr.
19 mutation on Notch 3 gene
CADASIL
Cerebral non-atherosclerotic, nonamyloid
angiopathy of white matter and basal
ganglia
 Stroke 84%, dementia 80%, migraine with
aura or mood disorders in 20%
 Slow stepwise deterioration of cognitive
and neurological function
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 Frontal
dysfunction, pseudobulbar palsy, gait
problems, incontinence
MRI in 2 patients with CADASIL
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The top MRIs are
from a 30 year-old
with migraine w/aura
and CADASIL
The bottom MRIs are
from a 57 year-old
with migraine, stroke,
and dementia.
Lewy Body Dementia
Rare in presenile populations.
 Dementia.
 Fluctuating cognitive impairment or
consciousness.
 Visual hallucinations.
 Parkinsonism.
 Neuritic plaques and Lewy bodies
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 a-synuclein
inclusions
Transmissible Spongiform
Encephalopathies (Prion)
Diffuse brain spongiosis.
 Deposition of abnormal PrP (prion protein).
 90% sporadic, others acquired or inherited.
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 Post-translational
conversion of the native prion
protein in sporadic forms, causing accumulation
in neurons.
 Mutations to PRNP gene on chr. 20 in inherited
cases.
Sporadic & Inherited Prion D/Os
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CJD incidence
1/1,000,000(?)
nvCJD = BSE
 Genetic
susceptibility
in 40% of UK residents
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Rapid dementia in
60’s w/death <6 mo.
Insomnia,
amotivation,
myoclonus, ataxia,
cortical blindness.
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Familial CJD
 similar
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to sporadic
Fatal Familial
Insomnia
 insomnia
&
dysautonomia
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GerstmannStraussler-Scheinker
syndrome
 ataxia,
dementia
Hyperintensity in the basal ganglia
and cortical ribboning are distinct
imaging features of sporadic CJD.
MRI differences in CJD, nvCJD
MRI of nvCJD patients is associated with
hyperintensity of the pulvinar (posterior
nuclei) of the thalamus
 MRI of sporadic CJD is associated with
high signal changes in the putamen and
caudate head.
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Summary
Alzheimer’s disease
 Vascular dementia
 FTLD
 Prion disorders
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Less Common
Dementias
Wilson’s Disease
Autosomal recessive disorder of copper
transport
 Prevalence of 1/50,000 in UK.
 Tremor, dystonia, chorea, ataxia,
dysarthria, psychiatric & cognitive
changes.
 Low serum copper and ceruloplasim levels
with increased 24o urinary Cu excretion.
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Huntington’s Disease
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Family history may NOT be known.
 Suicide,
institutionalization.
 Chorea may be suppressed by antipsychotics
used by psychiatrist.
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Trinucleotide repeat (CAG) >35 on chr. 4
 AD
with complete penetrance.
 Sporadic mutations rare.
25,000 affected in US. 10/100,000 prev.
 Caudate atrophy seen on MRI.
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Huntington’s Disease
Whipple’s Disease
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Caused by bacteria: Tropheryma whippelii
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Classic clinical features
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chronic diarrhea with malabsorption, abdominal pain, relapsingremitting migratory polyarthralgia, lymphadenopathy, weight loss,
hyperpigmentation of the skin, and fever of unknown origin.
CNS may be affected in 40%.
 Neurological presentation is rare (5%) and
is often followed by disease confined to
the CNS.
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Neuropathology of CNS
Whipple’s Disease
Disseminated or focal macrophagic
encephalitis or meningoencephalitis
favoring subpial and subependymal grey
matter.
 Mass lesions and obstructive
hydrocephalus can be found.
 Infarcts are also described.
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 secondary
to surrounding chronic inflammation or to a
primary vasculitic process
Symptoms of CNS Whipple’s Ds
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Cognitive changes
(71%),
Supranuclear gaze
palsy,
Altered
consciousness are
the commonest
neurological findings.
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Oculomasticatory (OMM)
and oculofacial skeletal
myorhythmia (OFSM),
Myoclonus,
Ataxia,
Hypothalamic
dysfunction,
Cranial nerve
abnormalities,
UMN dysfunction,
Sensory deficits.
Myorhythmia
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Pathognomonic for Whipple's disease
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Oculomasticatory: Slow, smooth convergentdivergent pendular nystagmus associated with
synchronous contractions of the jaw.
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Oculo-facial-skeletal: nystagmus plus
synchronous contractions of other body parts.
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Occur in 20% and are always associated
with a supranuclear vertical gaze palsy.
Guidelines for the diagnosis of
CNS Whipple’s Disease
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Definite diagnosis
 presence
of OMM or OFSM or a positive
biopsy or positive PCR analysis.
 Neurological signs are required when the
positive results have been obtained from nonCNS tissue.
CNS Whipple’s Disease
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The majority of intestinal (70%), brain (83%),
lymph node and vitreous fluid biopsies (89%)
performed are diagnostic.
 Electron
microscopy
 T whippelii DNA is found in normals.
 The analysis of preferably more than one tissue
substrate have been advised to maximize sensitivity
and specificity.
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PCR may also be useful to monitor response to
treatment and prognosis.
Testing for Whipple’s
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PCR in CSF can be negative in 20-30%.
 80%
with neurological symptoms and 70% of
patients without neurological symptoms have
yielded positive CSF PCR results in one
series.
CSF PCR may be more sensitive in the
presence of CSF pleocytosis.
 ESR, CSF & serum ACE concentrations
may be elevated.
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Treatment of Whipple’s Disease
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Ceftriaxone 2 g IV×3/day plus ampicillin
2 g IV ×3/day for 14 days
 Followed
by oral TMP-SMX (160+800 mg)
twice daily for 1-2 years
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Ceftriaxone 2g IV BID plus streptomycin 1
g/day for 14 days
 Followed
by oral TMP-SMX (160+800 mg)
twice daily for 1-2 years or cefixime 400 mg
po qd for 1-2 years
DRPLA (Dentatorubral-Pallidoluysian Atrophy)
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Ataxia, choreoathetosis, dementia, and
psychiatric disturbance.
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Positive family hx (AD) and the detection
of a CAG repeat (48-93) on chr. 12.
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Significant anticipation: 28 yrs/gen w/
paternal transmission and 15 yrs/gen w/
maternal transmission.
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Age of onset is from 1 to 62 years with a
mean age of onset of 30 years.
DRPLA
Described in Japanese and African
American families.
 Differential: HD and SCA 1, 2, 3, 6, 7.
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The history of ataxia as an early symptom
as well as atrophy of the cerebellum and
brainstem (particularly pontine
tegmentum) on imaging study is important
in the differential diagnosis.
Spinocerebellar Ataxias (SCA)
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Slowly progressive incoordination of gait
and often associated with poor
coordination of hands, speech, and eye
movements.
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Atrophy of the cerebellum.
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The hereditary ataxias are categorized by
mode of inheritance, gene, or
chromosome locus.
Spinocerebellar Ataxias
26 described.
 Triplicate repeats in 1, 2, 3, 6, 7, 8, 10, 12,
& 17.
 Difficult to distinguish clinically.
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 Some
have peripheral neuropathy, seizure,
dementia associated
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Genetic testing available for some SCAs.
World-wide Incidence of SCAs
SCA 3 or Machado-Joseph disease
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The diagnosis of SCA3 is suggested in
individuals with the following findings
 Cerebellar
ataxia and pyramidal signs (type II
disease) associated in variable degree with a
dystonic-rigid extrapyramidal syndrome (type I
disease)
 Or peripheral amyotrophy (type III disease)
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Minor (but more specific) clinical signs such as
progressive external ophthalmoplegia, dystonia,
action-induced facial and lingual fasciculationlike movements, and bulging eyes
Autosomal dominant inheritance
Differential Diagnosis of Ataxias
 multiple
sclerosis,
 ataxia-telangiectasia,
 vascular
disease,
 alcoholism,
 primary
 vitamin
deficiency (E),
 Friedreich’s
ataxia,
or metastatic
tumors,
 or
paraneoplastic
diseases associated
with occult carcinoma
of the ovary, breast, or
lung.
Paraneoplastic Limbic Encephalitis
(PLE)
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Represents an autoimmune response to
tumor antigens
 Predominantly
Neuronal nuclear (Anti-Hu) ab
(50% of cases)
 Lymphocytic infiltrate in CNS
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Can precede cancer diagnosis
 small
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cell lung cancer (80%), testicular, breast
Symptoms usually progress over the course of
weeks to months, reaching a plateau of
neurologic disability.
Symptoms of PLE
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Memory loss, personality changes, anxiety or
depression, neuropsychiatric disturbances, partial or
generalized seizures, olfactory and gustatory
hallucinations, sleep disturbances, and abnormalities in
other homeostatic functions.
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Focal neurologic disturbances such as aphasia,
weakness, or numbness.
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Brainstem encephalitis
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Autonomic dysfunction in 1/4.
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Motor neuron dysfunction.
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Lambert-Eaton myasthenic syndrome occurs in 1016% of cases.
Symptoms of PLE
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Subacute Sensory Neuronopathy
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Seen in 70-80% of cases.
Symptoms include
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asymmetric focal numbness or paresthesias,
typically involving the face, trunk, and
proximal extremities.
 burning or lancinating dysesthesias of all
extremities may be noted at later stages.
Diagnosis of PLE
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Serum and CSF paraneoplastic antibody panel
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Anti-Hu or other PEM antibodies (anti-CV2, anti-Yo, anti-Ma1, anti-Ta or
anti-Ma2) may be found.
Cerebrospinal fluid
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Cell count, protein, glucose, oligoclonal bands, IgG synthesis
rate, cytology, and PCR for herpes simplex virus and
varicella zoster virus
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Evaluate for an underlying malignancy & Serum tumor markers
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Brain MRI may help to rule out the differential diagnoses. Usually,
MRI in a patient with PEM is unremarkable, although T2-weighted
hyperintensity may be noted in mesial temporal lobes and
associated limbic structures.
Mesial temporal hyperintensity demonstrated on T2-weighted (left) and
fluid-attenuated inversion recovery (FLAIR, right) MRI
Treatment of Paraneoplastic Limbic
Encephalitis
Plasmapheresis
 IVIG
 Steroids or Cytoxan
 Monitor for cancer
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Steroid-responsive Encephalopathies
Heterogeneous group of disorders
 May represent underlying cerebral
vasculitis
 Circulating autoantibodies
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Hashimoto’s Encephalopathy
Hashimoto’s Encephalopathy
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Seizures, stroke-like events, temporary
neurologic deficits, and a variety of psychiatric
disturbances from dementia to visual
hallucinations and frank psychosis.
Significantly elevated antithyroid antibody titers,
mainly anti-thyroid peroxidase (TPO) antibodies.
Pathogenetic hypotheses proposed so far
 excessive
thyrotropin-releasing hormone output,
 edema-induced cerebral dysfunction,
 global hypoperfusion,
 an autoimmune-mediated inflammatory attack of
cerebral vessels.
Approach to
Diagnosis of Presenile
Dementia
Approach to Diagnosis
Observation
 History from family
 Explore different cognitive domains &
impact on daily functioning
 Psychiatric history
 Family history
 Physical and neuropsychological exams
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Investigations for Determination
of Diagnosis and Recognition of
Treatable Disorders
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Blood & Urine testing
Drug screen
TSH, B12, ?ESR
Syphilis
Vasculitides/CTD
HIV, heavy metals,
Cu/ceruloplasm
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EEG
MRI brain
Possible LP
Possible brain or
tissue biopsy
 CADASIL,
vasculitis,
Whipple’s, CJD
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Other...
Treatable Causes of Cognitive
Impairment

Don’t forget these:
 Obstructive
Sleep Apnea
 Depression
 Drugs
& alcohol (thiamine deficiency,Li
toxicity, BZD)
 Epilepsy
Treatment
Accurate diagnosis extremely important
 Supportive care for patient and family
 Treat psychiatric symptoms
 Acetylcholinesterase inhibitors and NMDA
receptor antagonist
 Anti-epileptics
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