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-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”.

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 Huntington’s disease.

6. Presenile Dementia

7. Presenile Dementia • Rare <40 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. • <65 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, Alzheimer’s 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. AD FTD HD SCA Wilson’s Prion CADASIL Storage Disorders Lysosomal Niemann-Pick MLD Peroxisomal ALD Lafora Body Disease Mitochondrial d/o Inherited Dementias

17. Reversible NCSE Drugs Meningitis Whipple’s Tumor Irreversible CJD Rapidly progressive variants of AD Rapidly Progressive Dementias

18. Dementia-Plus Syndromes • 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

19. More Common Dementias

20. SENILE Alzheimer’s ds. 70-80%? Lewy Body ds. Vascular ds. FTD. Other. PRESENILE Alzheimer’s ds 30% Vascular ds 15% FTD 13% LBD 4% Other 25% HD, MS, CBGD, Prion disease, PD. Most CommonSenile & Presenile Dementias

21. Alzheimer’s disease • May manifest in 4th decade. • Autosomal dominant with complete penetrance. • Presenilin 1 on chromosome 14. • APP on chr. 21 (Down’s), 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 • Pick’s disease. • 3 repeat tau isoform aggregates • FTD: behavioral, PPA, SD. • CBGD. • FTD associated with MND. • Ubiquitin positive, tau negative inclusions

26. 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. FTD

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 50-60’s. • Can present in 20’s 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. CJD incidence 1/1,000,000(?) nvCJD = BSE Genetic susceptibility in 40% of UK residents Rapid dementia in 60’s w/death <6 mo. Insomnia, amotivation, myoclonus, ataxia, cortical blindness. Familial CJD similar to sporadic Fatal Familial Insomnia insomnia & dysautonomia Gerstmann-Straussler-Scheinker syndrome ataxia, dementia Sporadic & Inherited Prion D/Os

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 • Alzheimer’s disease • Vascular dementia • FTLD • Prion disorders

37. Less Common Dementias

38. 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.

39. Huntington’s Disease • Family history may NOT be known. • Suicide, institutionalization. • Chorea may be suppressed by antipsychotics used by psychiatrist. • 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.

40. Huntington’s Disease

41. Whipple’s 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 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. • secondary to surrounding chronic inflammation or to a primary vasculitic process

43. 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. Symptoms of CNS Whipple’s Ds

44. Myorhythmia • Pathognomonic for Whipple's disease • Oculomasticatory: Slow, smooth convergent-divergentpendular nystagmus associated with synchronous contractions ofthe jaw. • Oculo-facial-skeletal: nystagmus plus synchronous contractions of other bodyparts. • Occur in 20% and are always associated with a supranuclear vertical gaze palsy.

45. Guidelines for the diagnosis ofCNS Whipple’s 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 Whipple’s 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 Whipple’s • 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 Whipple’s Disease • 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 • 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

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.