Presenile Dementia

1
Presenile Dementia

• Mary Ellen Quiceno, M.D.

2
Case 1

• 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.

3
MRI/MRA brain, spine.

• 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).

4
Case 2

• Mid-40s 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.

5
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 Huntingtons disease.

6
Presenile Dementia
7
Presenile Dementia

• Rare lt40 years old.
• Overall prevalence of presenile dementias in the
  45 to 65 year old age group 15-80/100,000.

8
Presenile Dementia

• Age of onset and premorbid functioning.
• lt65 y.o.
• Psychiatric history? Education? Level of
  functioning?
• Family history.
• Clinical characteristics.
• Neurological dysfunction.
• Other diseases or dysfunction (medical,
  psychiatric).

9
Expected Age-related Cognitive Changes

• Bradyphrenia.
• Trouble with recall of names of people/places.
• Decreased concentration.
• Language, vocabulary spared and may improve.

10
Why Age of Onset Matters

• 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.

11
Temporal Course of Disease

• Slowly or rapidly progressive?
• Gradual and insidious, stepwise, fluctuating,
  acute onset then static?

12
Cognitive Profile

• Onset with memory, frontal executive dysfunction,
  other
• Cortical.
• Language, memory, praxis.
• AD, FTD.
• Frontal-subcortical.
• Slow, poor attention, decreased verbal output,
  apathy.
• Other dementias.
• Mixed.

13
Associated FeaturesBehavioral Neurological

• Personality behavior changes.
• Depression psychosis.
• Seizures.
• Myoclonus.
• Ataxia.
• Tremor.
• Parkinsonism.

14
Differential Diagnosis
15
Differential Diagnoses

• Neurodegenerative disorders.
• SCA, HD, DRPLA, Alzheimers disease, FTD, DLB
  related dementias.
• Vascular.
• Infectious.
• Syphilis, CJD, vCJD, HIV-related.
• Tumor Paraneoplastic disease.
• Anti-Yo.
• Autoimmune Inflammatory.
• MS, sarcoid.
• Trauma.
• Toxic Metabolic.

16
Inherited Dementias

• AD
• FTD
• HD
• SCA
• Wilsons
• Prion
• CADASIL

• Storage Disorders
• Lysosomal
• Niemann-Pick
• MLD
• Peroxisomal
• ALD
• Lafora Body Disease
• Mitochondrial d/o

17
Rapidly Progressive Dementias

• Reversible
• NCSE
• Drugs
• Meningitis
• Whipples
• Tumor

• Irreversible
• CJD
• Rapidly progressive variants of AD

18
Dementia-Plus Syndromes

• Cognitive impairment in the setting of more
  wide-spread neurological disturbance.
• Ataxia HD, DRPLA, Wilsons, SCA, Prion
• EPS FTDP-17, HD, Wilsons
• Psychiatric FTD, HD, Wilsons

19
More Common Dementias
20
Most CommonSenile Presenile Dementias

• SENILE
• Alzheimers ds. 70-80?
• Lewy Body ds.
• Vascular ds.
• FTD.
• Other.

• PRESENILE
• Alzheimers ds 30
• Vascular ds 15
• FTD 13
• LBD 4
• Other 25
• HD, MS, CBGD, Prion disease, PD.

21
Alzheimers disease

• May manifest in 4th decade.
• Autosomal dominant with complete penetrance.
• Presenilin 1 on chromosome 14.
• APP on chr. 21 (Downs), PS-2 on chr. 1
• Creates abnormally aggregated b-amyloid

22
Neuropathology the same in Presenile and Senile
Onset AD

• Neuritic plaques
• extracellular
• b-amyloid
• Neurofibrillary tangles
• intracellular
• tau protein
• Basal forebrain nuclei
• leads to Ach deficit

23
Clinically Similar

• Early involvement of medial temporal lobe.
• hippocampus and entorhinal cortex
• Parietal lobe dysfunction.
• Myoclonus may be more prominent in familiar
  forms.
• Naming may be spared until late in familiar forms.

24
Frontotemporal Lobar Degenerations (FTLD)

• Onset 20-75 years of age.
• Male predominance.
• Half have family history (may be heterogeneous).
• Various genetic mutations known.
• Chr. 17 tau gene mutation most common.
• FTD with parkinsonism.
• Clinically variable within families.

25
FTLD types

• Picks disease.
• 3 repeat tau isoform aggregates
• FTD behavioral, PPA, SD.
• CBGD.
• FTD associated with MND.
• Ubiquitin positive, tau negative inclusions

26
FTD

• Behavioral Onset
• 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.
• Progressive Aphasia
• Non-fluent aphasia.
• Paraphasic errors.
• Orofacial apraxia.

27
FTD
28
Vascular Dementia

• Usual risk factors, plus unusual cardiac,
  hematological, metabolic, and genetic causes.
• CADASIL (cerebral autosomal dominant arteriopathy
  with subcortical infracts and leukoencephalopathy)
  .
• Mean age of presentation in 50-60s.
• Can present in 20s with migraines w/aura and MRI
  changes.
• Consider MRI in migraineurs w/ atypical auras,
  family hx.
• Chr. 19 mutation on Notch 3 gene

29
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
• Frontal dysfunction, pseudobulbar palsy, gait
  problems, incontinence

30
MRI in 2 patients with CADASIL

• 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.

31
Lewy Body Dementia

• Rare in presenile populations.
• Dementia.
• Fluctuating cognitive impairment or
  consciousness.
• Visual hallucinations.
• Parkinsonism.
• Neuritic plaques and Lewy bodies
• a-synuclein inclusions

32
Transmissible Spongiform Encephalopathies (Prion)

• Diffuse brain spongiosis.
• Deposition of abnormal PrP (prion protein).
• 90 sporadic, others acquired or inherited.
• 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.

33
Sporadic Inherited Prion D/Os

• CJD incidence 1/1,000,000(?)
• nvCJD BSE
• Genetic susceptibility in 40 of UK residents
• Rapid dementia in 60s w/death lt6 mo.
• Insomnia, amotivation, myoclonus, ataxia,
  cortical blindness.

• Familial CJD
• similar to sporadic
• Fatal Familial Insomnia
• insomnia dysautonomia
• Gerstmann-Straussler-Scheinker syndrome
• ataxia, dementia

34
Hyperintensity in the basal ganglia and cortical
ribboning are distinct imaging features of
sporadic CJD.
35
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.

36
Summary

• Alzheimers disease
• Vascular dementia
• FTLD
• Prion disorders

37
Less Common Dementias
38
Wilsons 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.

39
Huntingtons Disease

• Family history may NOT be known.
• Suicide, institutionalization.
• Chorea may be suppressed by antipsychotics used
  by psychiatrist.
• Trinucleotide repeat (CAG) gt35 on chr. 4
• AD with complete penetrance.
• Sporadic mutations rare.
• 25,000 affected in US. 10/100,000 prev.
• Caudate atrophy seen on MRI.

40
Huntingtons Disease
41
Whipples Disease

• Caused by bacteria Tropheryma whippelii
• Classic clinical features
• chronic diarrhea with malabsorption, abdominal
  pain, relapsing-remitting 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.

42
Neuropathology of CNS Whipples 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.
• secondary to surrounding chronic inflammation or
  to a primary vasculitic process

43
Symptoms of CNS Whipples Ds

• Cognitive changes (71),
• Supranuclear gaze palsy,
• Altered consciousness are the commonest
  neurological findings.

• Oculomasticatory (OMM) and oculofacial skeletal
  myorhythmia (OFSM),
• Myoclonus,
• Ataxia,
• Hypothalamic dysfunction,
• Cranial nerve abnormalities,
• UMN dysfunction,
• Sensory deficits.

44
Myorhythmia

• Pathognomonic for Whipple's disease
• Oculomasticatory Slow, smooth convergent-divergen
  t pendular nystagmus associated with synchronous
  contractions of the jaw.
• Oculo-facial-skeletal nystagmus plus synchronous
  contractions of other body parts.
• Occur in 20 and are always associated with a
  supranuclear vertical gaze palsy.

45
Guidelines for the diagnosis ofCNS Whipples
Disease

• 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 non-CNS tissue.

46
CNS Whipples Disease

• 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.
• PCR may also be useful to monitor response to
  treatment and prognosis.

47
Testing for Whipples

• 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.

48
Treatment of Whipples Disease

• Ceftriaxone 2 g IV3/day plus ampicillin 2 g
  IV 3/day for 14 days
• Followed by oral TMP-SMX (160800 mg) twice daily
  for 1-2 years
• Ceftriaxone 2g IV BID plus streptomycin 1 g/day
  for 14 days
• Followed by oral TMP-SMX (160800 mg) twice daily
  for 1-2 years or cefixime 400 mg po qd for 1-2
  years

49
DRPLA (Dentatorubral-Pallidoluysian Atrophy)

• Ataxia, choreoathetosis, dementia, and
  psychiatric disturbance.
• Positive family hx (AD) and the detection of a
  CAG repeat (48-93) on chr. 12.
• Significant anticipation 28 yrs/gen w/ paternal
  transmission and 15 yrs/gen w/ maternal
  transmission.
• Age of onset is from 1 to 62 years with a mean
  age of onset of 30 years.

50
DRPLA

• Described in Japanese and African American
  families.
• Differential HD and SCA 1, 2, 3, 6, 7.
• 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.

51
Spinocerebellar Ataxias (SCA)

• Slowly progressive incoordination of gait and
  often associated with poor coordination of hands,
  speech, and eye movements.
• Atrophy of the cerebellum.
• The hereditary ataxias are categorized by mode of
  inheritance, gene, or chromosome locus.

52
Spinocerebellar Ataxias

• 26 described.
• Triplicate repeats in 1, 2, 3, 6, 7, 8, 10, 12,
  17.
• Difficult to distinguish clinically.
• Some have peripheral neuropathy, seizure,
  dementia associated
• Genetic testing available for some SCAs.

53
World-wide Incidence of SCAs
54
SCA 3 or Machado-Joseph disease

• 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)
• Minor (but more specific) clinical signs such as
  progressive external ophthalmoplegia, dystonia,
  action-induced facial and lingual
  fasciculation-like movements, and bulging eyes
• Autosomal dominant inheritance

55
Differential Diagnosis of Ataxias

• ataxia-telangiectasia,
• alcoholism,
• vitamin deficiency (E),
• Friedreichs ataxia,

• multiple sclerosis,
• vascular disease,
• primary or metastatic tumors,
• or paraneoplastic diseases associated with occult
  carcinoma of the ovary, breast, or lung.

56
Paraneoplastic Limbic Encephalitis (PLE)

• Represents an autoimmune response to tumor
  antigens
• Predominantly Neuronal nuclear (Anti-Hu) ab (50
  of cases)
• Lymphocytic infiltrate in CNS
• Can precede cancer diagnosis
• small cell lung cancer (80), testicular, breast
• Symptoms usually progress over the course of
  weeks to months, reaching a plateau of neurologic
  disability.

57
Symptoms of PLE

• 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.
• Focal neurologic disturbances such as aphasia,
  weakness, or numbness.
• Brainstem encephalitis
• Autonomic dysfunction in 1/4.
• Motor neuron dysfunction.
• Lambert-Eaton myasthenic syndrome occurs in
  10-16 of cases.

58
Symptoms of PLE

• Subacute Sensory Neuronopathy
• Seen in 70-80 of cases.
• Symptoms include
• 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.

59
Diagnosis of PLE

• Serum and CSF paraneoplastic antibody panel
• Anti-Hu or other PEM antibodies (anti-CV2,
  anti-Yo, anti-Ma1, anti-Ta or anti-Ma2) may be
  found.
• Cerebrospinal fluid
• Cell count, protein, glucose, oligoclonal bands,
  IgG synthesis rate, cytology, and PCR for herpes
  simplex virus and varicella zoster virus
• Evaluate for an underlying malignancy Serum
  tumor markers
• 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.

60
Mesial temporal hyperintensity demonstrated on
T2-weighted (left) and fluid-attenuated inversion
recovery (FLAIR, right) MRI
61
Treatment of Paraneoplastic Limbic Encephalitis

• Plasmapheresis
• IVIG
• Steroids or Cytoxan
• Monitor for cancer

62
Steroid-responsive Encephalopathies

• Heterogeneous group of disorders
• May represent underlying cerebral vasculitis
• Circulating autoantibodies
• Hashimotos Encephalopathy

63
Hashimotos Encephalopathy

• 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.

64
Approach to Diagnosis of Presenile Dementia
65
Approach to Diagnosis

• Observation
• History from family
• Explore different cognitive domains impact on
  daily functioning
• Psychiatric history
• Family history
• Physical and neuropsychological exams

66
Investigations for Determination of Diagnosis and
Recognition of Treatable Disorders

• EEG
• MRI brain
• Possible LP
• Possible brain or tissue biopsy
• CADASIL, vasculitis, Whipples, CJD
• Other...

• Blood Urine testing
• Drug screen
• TSH, B12, ?ESR
• Syphilis
• Vasculitides/CTD
• HIV, heavy metals, Cu/ceruloplasm

67
Treatable Causes of Cognitive Impairment

• Dont forget these
• Obstructive Sleep Apnea
• Depression
• Drugs alcohol (thiamine deficiency,Li toxicity,
  BZD)
• Epilepsy

68
Treatment

• Accurate diagnosis extremely important
• Supportive care for patient and family
• Treat psychiatric symptoms
• Acetylcholinesterase inhibitors and NMDA receptor
  antagonist
• Anti-epileptics