ALZHEIMER’S DISEASE & OTHER DEMENTIAS : ALZHEIMER’S DISEASE & OTHER DEMENTIAS Fernando Entenza, MD General, Geriatric & Forensic Psychiatrist
CORTICAL DEMENTIAS : CORTICAL DEMENTIAS Alzheimer’s Disease (Cortical) Vascular Dementia Frontotemporal Dementias: FTDP-17, Pick Disease
Dementia of the Alzheimer Type (DAT) : Dementia of the Alzheimer Type (DAT) 4 million suffering Americans 14 million estimated for 2050 65,000 current cases estimated in Puerto Rico 50,000 over 65 15,000 between 50 & 65 4th cause of death Complications of immobility in late stages > 100,000 / yr High cost to society $90 billion annually (1992) Severe caregiver impact #1 cause of institutionalization in U.S.A. #1 cause of Most frequent form of Dementia Prototypical cortical type of dementia (diffuse cortical atrophy) Involving de-afferation of cholinergic neurons from the Nucleus Basalis of Meynert to the cortex
DAT : DAT Currently, final diagnosis is not clinical Neuropathological confirmation is required Although the diagnosis if given clinically and antemortem Patients are still diagnosed primarily based on exclusion of other possible etiologies for dementia, although PET holds promise No available technological diagnostic method has proved more sensitive or specific than astute comprehensive clinical evaluation No features of the physical examination or laboratory evaluation are pathognomonic for DAT Early-onset DAT may have a more rapidly progressive course But no other consistent phenomenological separation between early-onset and late-onset has been found
AD Primary Symptoms : AD Primary Symptoms Frontal Lobe Syndrome Poor judgment Frontal release signs Palmomental Snout Disinhibition Affective changes Pathological crying or laughter Abulia Temporal Lobe Anterograde amnesia (since the early stages) Retrograde amnesia (later stages) Neuropsychiatric symptoms Hallucinations 20-30% Delusions 30-40%
AD Risk Factors: Definitive & Possible : AD Risk Factors: Definitive & Possible Age 50-64: 2% 65-74: 10% 75-84: 15-20% > 85: 33-50% Family history Early-onset pattern Sporadic Genetics APP mutations Presenilin 1 or 2 mutations Apo E4 allelle Homozygous x8-10 Mitochodrial mutations Cardiovascular Risk Factors Hypertension Diabetes Mellitus Hyperlipidemia HDL < 100 LDL > 60 CRP + Homocysteine + Obesity? Poor idea density (nun study) Vascular disease Severe head trauma history? (x2-4) Insulin-resistance reduction? Insulin promotes release of β - amyloid by competing for insulin degrading enzyme Late-onset Major Depression Chronic untreated Depression Female gender? (x3-4) INDIVIDUAL RISK ASSESSMENT (+) Family History ………... 30% (+) FHx + APO E 4 ………... 50% Age at onset is earlier in people with a family history of the disease
Genetic Factors in DAT : Genetic Factors in DAT Familiar, Early-Onset Familiar, Late-Onset Sporadic Late-Onset % of cases 2-10% > 90% of cases late-onset Genetics type Autosomal dominant with age-dependent penetrance Susceptibility genes influenced by environmental factors Susceptibility genes influenced by environmental factors Genetic links APP Ch.21 (7 mutations) Apo E 4 Ch. 19 Apo E 4 Ch. 19 “lowers age of onset” Presenilin 1 Ch.14 (80 mutations) E3 allele = 75% E2 = 10% E4 = 15% Presenilin 2 Ch.1 (6 mutations) Heterozygous E4 = x3 AD Homozygous E4-E4 = x8 AD Apo E 4 Ch. 19 Activation of endocytic pathways and accentuated Other candidates APP metabolism/A β generation & uptake: LDL-related receptor protein (LRP-1 receptor) Α 2-macroglobulin FE65 Lysosomal protease cathepsin D trafficking of proteases to endosomes seen in experimental models 60-75% sporadic < 33% of cases with > 1 first-degree relative (FAD) Account for 30-50% of all AD early-onset AD cases protective? are
Mild Cognitive Impairment : Mild Cognitive Impairment Features 17-34% annual prevalence among elderly populations Subjective vague complaints of declining cognitive performance ↓ Memory - most common No loss of function Mild deficits measurable on Neuropsychological Testing A “pre-Dementia” state 50% are diagnosed with DAT by 4 years 80% are diagnosed with DAT by 6 years 1-2% /yr for healthy elderly Subtypes Amnestic MCI Most common type 10-15% per year conversion to AD Early AD neuropathology Multiple Cognitive Domains (attentional, language, visuospatial) Cerebrovascular disease AD variant Single Non-memory Domain FTD DLB PPA PDD AD variant
Global Deterioration Scale : Global Deterioration Scale Phase MMSE 1 Normal 29-30 2 Normal Aged Forgetfulness 29 3 Mild Cognitive Impairment 25 4 Mild Alzheimer’s Disease 20 5 Moderate Alzheimer’s 14 6 Moderate - Severe Alzheimer’s 5 7 Severe Alzheimer’s Disease 0
Early Indicators : Early Indicators Neuropsychological Testing Future AD conversion General Recall (verbal) Verbal fluency ApoE 4 carriers Visual memory Learning retention Early AD detection Trail-B An important differential diagnosis = dementia of depression Neuroimaging Studies Neuronal function (FDG-PET) (sensitivity = 73%) (specificity = 73%) Early: parietal > temporal hypometabolism Later: added frontal hypometabolism Plaque-Tangle Load (FDDNP-PET) (in development) Temporal staining Even in ApoE4 patients with normal memory
Trail-Making Test, Part B : Trail-Making Test, Part B
PowerPoint Presentation : Normal Mild Alzheimer’s Moderate Alzheimer’s Severe Alzheimer’s
PowerPoint Presentation : Normal Brain MRI – T2 Alzheimer’s Disease Hippocampal + medial temporal atrophy MRI – T2
Alzheimer’s Hippocampal Atrophy : Alzheimer’s Hippocampal Atrophy
PowerPoint Presentation : Parietal hypometabolism Hippoccampal - medial temporal - atrophy Hippocampal hypometabolism MRI - T2 SPECT-TC MRI - SPECT overlay Parietal Atrophy Alzheimer’s Disease Mild parietal Mild parietal atrophy hypometabolism MRI – T2 SPECT - Tc
DAT: Pharmacologic Treatment : DAT: Pharmacologic Treatment Cholinesterase inhibitors Tacrine (Cognex) - hepatotoxic Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Remynil) NMDA receptor antagonist Memantine (Namenda) NSAIDS: (not cox-2) ASA Ibuprofen Indomethacin Antioxidants Vitamin E < 400 I.U. qd MAO A(B) Inhibitor Selegiline (Eldepryl) Estrogen Replacement Therapy
Available Cholinesterase Inhibitors : Available Cholinesterase Inhibitors Donepezil Achase inhibitor Rivastigmine Ach-ase & BuCh-ase inhibitor Galantamine + Ach-ase inhibitor & allosteric nicotinic receptor agonist Tacrine Hepatotoxic M 1 receptor Presynaptic cholinergic neuron Postsynaptic neuron AChase AChase Ach Nicotinic receptor ligand-gated excitatory ion channel BuChase Glial cell BuChase Glc AcCoA + Choline CAT
Normal NMDA Receptor Transmission : Normal NMDA Receptor Transmission Presynaptic glutaminergic neuron Postsynaptic neuron Mg 2+ Mg 2+ Ca 2+ Normal Noise level Signal Detected Resting State Glycine : obligatory co-agonist Glutamate Ca 2+ Mg 2+ NMDA receptor AMPA receptor Na + depolarizes
PowerPoint Presentation : Presynaptic glutaminergic neuron Postsynaptic neuron Mg 2+ Ca 2+ Signal Detected Mg 2+ Signal Not Detected Ca 2+ X 1. Pathologic Activation of NMDA Receptors 2. Impairment of Plastic Processes 3. Chronic Neurodegeneraton (excitotoxicity) Memantine: Noncompetitive Voltage-Dependent NMDA Receptor Antagonist Excessive noise level Memantine
DAT: Behavioral Complications : DAT: Behavioral Complications Depression, apathy Delusions (30-40%) Hallucinations (20-30%) Aggression Agitation / Activity Anxiety Sleep disturbances
DAT: Neuropsychiatric Symptoms : DAT: Neuropsychiatric Symptoms Neuropsychiatric symptom DAT w/o Frontal involvement, % DAT w Frontal involvement, % Irritability 0 84 Agitation 33 84 Apathy 50 66 Anxiety 16 66 Aberrant motor 0 50 Disinhibition 0 50 Depression 50 33 Appetite changes 0 16 Euphoria 0 16 Nighttime beh dist 0 16 Delusions 0 16 Hallucinations 0 0
Delusions : Delusions Most common Being stolen 40% Home misidentification 25% Wife or caregiver impostor 25% Abandonment / Conspiracy to institutionalize Jealousy / Infidelity Other Suspicious or Paranoid Misidentification Phantom boarder Peak in occurrence in the 5 th stage of deterioration Peak in magnitude in the 6 th stage of deterioration
Hallucinations & DAT : Hallucinations & DAT Visual: intruders, dead relatives, objects 21-49% Auditory: dead relatives, intruders With or without visual hallucinations Other: olfactory Vague or clearly defined Usually not disturbing Generally do not by themselves require treatment Except for a Therapeutic Lie Tend to occur later in the course (stages 5 & 6)
Sundowning Syndrome : Sundowning Syndrome Acute symptom and behavior exacerbation Disorientation & misidentification Hallucinations Delusions (paranoia) Agitation Aggression Time-associated to afternoon and evening hours
VASCULAR DEMENTIA : VASCULAR DEMENTIA
Vascular Dementia : Vascular Dementia “3 rd” most common dementia: 15-20% Caused by parenchymal infarction Cortical and/or Subcortical damage from Occlusive strokes: thrombotic (arteriosclerotic), thromboembolic or Hemorrhagic strokes Common features M > F Preexistent hypertension and CV risk factors Focal signs depending on location Hemiplegia, + Babinsky, aphasia, apraxia, aprosodia, (in advanced cases) pseudobulbar palsy Stepwise decline, heralded by delirium MRI: multiple cortical and/or subcortical ischemic or hemorrhagic strokes Other predisposing (etiological) conditions: Arteriosclerosis; cerebral amyloid angiopathy; polyarteritis nodosa; arteritis due to cocaine or amphetamines; SLE; meningovascular syphylis
FRONTOTEMPORAL DEMENTIAS (FTD) : FRONTOTEMPORAL DEMENTIAS (FTD) PICK COMPLEX DISORDERS Tauopathies Pick Complex Disorders FTD
FTD: Diagnostic Criteria Two Major Phenotypes + Parkinsonism : FTD: Diagnostic Criteria Two Major Phenotypes + Parkinsonism Behavioral : Frontal Predominant (most common) Hyperactive type Restless, distractible, disinhibited vs. Hypoactive type Apathetic, lacking initiative, reduced speech Diminished personal or social awareness and insight (“When did I quit doing that?”) Poor reasoning & judgment Frank Frontal Lobe Syndrome Utilization behaviors or repetitive-stereotyped or compulsive behaviors/speech Hyperorality Inappropriate sexuality Language : Temporal Predominant Naming: PPA variant (Primary Progressive Aphasia) Non-fluent aphasia Extends into repetition, reading, writing, and comprehension 50% eventually develop dementia Meaning (Semantic Dementia) Progressive loss of ability to understand the meaning of words Fluent aphasia , except for word-finding pauses ± Motor Neuron Disease: Fasciculations, muscle wasting, bulbar symptoms ± Frontal Release Signs: Glabellar, snout, grasp, palmomental
FTD: Primary Progressive Aphasia : MRI findings PET findings FTD: Primary Progressive Aphasia
Dementia Due to Pick’s Disease (a subtype of FTD) : Dementia Due to Pick’s Disease (a subtype of FTD) Frontal atrophy Temporal atrophy Pick’s Disease Lobar Atrophy Pick inclusion bodies
Diff Dx : Diff Dx FTD DAT Behavior Early Late Language Early Late Memory Late Early Executive Early Variable (e) Motor ALS vs. Parkinsonism Parkinsonism is present only late in the disease MRI atrophic changes Frontal &/or Temporal Hippocampal , then Parietal + Frontal PET-very early Frontal &/or Temporal hypometabolism Medial Temporal & Parietal hypometabolism
SUBCORTICAL DEMENTIAS 3 M’s: movement, mood, mentation : SUBCORTICAL DEMENTIAS 3 M’s: movement, mood, mentation Parkinson Disease Dementia (PDD) Dementia with Lewy Body (DLB) Parkinson-Plus Syndromes ----------- Progressive Supranuclear Palsy (PSP) ( ↓ L-dopa response & ↓ prognosis ) Corticobasal Ganglionic Degeneration (CBGD) Huntington Disease Dementia Lacunar Dementia Prion Diseases (CJD, GSSD) Binswanger’s Disease AIDS-Dementia Complex Subcortical Vascular Dementias
PDD: Parkinson’s Disease Dementia : PDD: Parkinson’s Disease Dementia Epidemiology 20 - 60 % of PD patients (most studies show 20-30%) 6-12x age-matched controls Relative risk = 1.7 Depression in 25% ↑ decline & disability Risk factors for dementia in PD Age > 70 Rare in early-age of onset pts Advanced PD PDRS > 25 (moderate level) ↑ cortical plaques & tangles Depression comorbidity Mania, agitation, disorientation or psychosis when treated with levodopa Facial masking at presentation Cardiovascular abnormalities Atypical PD features Bradykinesia & postural/gait disturbance > tremor Apo E2 Pathology Triad: tremor (resting), rigidity, bradykinesia Prototype of subcortical degenerative dementia Loss of neuromelanine -containing catecholaminergic neurons & others Substantia Nigra pars compacta Globus pallidus , putamen , caudate Locus Ceruleus Dorsal Motor Vagus Nucleus Cingulate gyrus & entorhinal cortex small neurons Lewy Body inclusions within surviving neurons ± diffusely in brain (+) α - synuclein : 1 º filamentous component of Lewy Body inclusions Normally assists in maintaining the integrity of transmitter-laden vesicles & facilitating vesicular transport from cell body to synapse Lewy Neurites Degenerating, ubiquitin (+) neuronal processes Dementia severity correlates with Degree of medial nigral cell loss Lewy neurites density in cornus ammonis 2 field of the hippocampus
Parkinson’s Disease : Parkinson’s Disease Normal SN-zona compacta Lewy body in a SN neuron, insoluble spherical alpha-synuclein polymers Parkinson’s Disease Normal Substantia Nigra (SN)
PPD: cognitive clinical features : PPD: cognitive clinical features Executive dysfunction Generating, maintaining, shifting & blending of sets Mental inflexibility Normal over-learned tasks Problems when shifting attention to novel stimuli Impaired problem solving Memory deficits Recent & retrograde Impaired recall (retrieval) > recognition (encoding) Temporally order or sequence new information Visuospatial deficits Language “Tip of the tongue” ↓ Naming & fluency Cognitive slowing (bradyphrenia) and motor slowing Core early deficit of basal ganglia disorders = Executive dysfunction The presence of dementia at the onset of illness does not support diagnosis of PD Mild cognitive changes are almost ubiquitous in PD The appearance of isolated cognitive deficits in PD is not a preamble to dementing illness Cognitive deficits are due to interruption of frontal-subcortical loops Frontal-subcortical deficits Related or similar syndromes: Progressive Supranuclear Palsy - vertical gaze palsy, axial extension Olivopontocerebellar Degeneration Vascular Dementia
DLB: Dementia With Lewy Body : DLB: Dementia With Lewy Body 2 nd most common dementia by autopsy (15-20%) 1 º dementia in 5-10% of all dementias Still under-diagnosed, most often diagnosed as AD Onset gradual in 60’s - 70’s Rapid progression? Mean duration 5-6 years Range 2-10 years MMSE drops 4-5 pts/yr Variable composition of sxs & illness course Most cases are sporadic. Few reports of autosomal dominant LB families. PDD variant? vs. LB variant of AD? vs. Distinct Disease (Diffuse LBD, Cortical LBD, Senile Dementia of LB type)? Pathology Lewy Bodies, Lewy Neurites & neuronal degeneration Lewy Bodies composed of α -synuclein Ubiquitin Amyloid Parkin Affected regions Substantia Nigra Paralimbic & Neocortical areas (+) β - amyloid senile plaques No NFTs Little medial temporal atrophy Occipital hypometabolism (PET) & occipital (delta) slowing on EEG Frequently mixed pathology (AD, DLB, FTD)
Dementia of Lewy Body : Dementia of Lewy Body Cerebral metabolism measured with FDG PET Alzheimer's Disease Diffuse Lewy-body Disease Note normal metabolism of occipital cortex Occipital cortex has decreased metabolism
DLB: Clinical Consensus Criteria and their Differential Diagnosis : DLB: Clinical Consensus Criteria and their Differential Diagnosis Extrapyramidal motor symptoms (70%) Parkinsons’s Disease Parkinson’s Disease Dementia Progressive Supranuclear Palsy Multi System Atrophy Corticobasal Ganglionic Degeneration Creutzfeldt-Jacob Disease Visual Hallucinations (>70%) Fluctuating cognition (80-90%) delirium-like brief episodes of confusion Delirium (of different etiologies) Vascular Dementia (35-50% of cases) Delirium (of different etiologies) Vascular Dementia Alzheimer’s Disease Parkinson’s Disease Parkinson’s Disease Dementia Psychotic Depression Charles Bonnet-Syndrome ( ↓ v ision) Creutzfeldt-Jacob Disease Repeated falls…………… 1/3 Systematized delusions: theft, paranoia, phantom boarder Syncope………………….. 1/3 Hallucination of other modalities Transient loss of consciousness Depression Neuroleptic sensitivity REM sleep behavior disorder DLB central feature: progressive cognitive decline (severe loss of afferent neocortical cholinergic activity) 2/3 Core Features = Probable DLB 1/3 Core Features = Possible DLB Dementia onset < 12 months after start of PD DLB Supportive Features Due to severe reduction in striatal postsynaptic D 2 receptors Due to temporal LB density and DA / ACh imbalance Different from AD sundowning (Para-) sympathetic ganglia pathology Nigrostriatal degeneration DLB Core Features
PDD vs. DLB vs. AD: Neuropsychiatric & EPS Symptoms : PDD vs. DLB vs. AD: Neuropsychiatric & EPS Symptoms PDD DLB AD Visual Hallucinations ++ In association with anticholinergic dopaminergic drugs +++ Early Persistent hallucinations early in the course of disease + Late Hallucinations in late stages Delusions + +++ ++ Depression ++ ++ ++ Apathy + ++ ++ Tremor +++ ++ Unusual Rigidity +++ +++ + Bradykinesia EPS +++ First manifestations of disease, initially often asymmetrical +++ Similar severity as in PD, pronounced rigidity and bradykinesia + Rare, usually mild in late stages Fluctuations in cognition - +++ + Neuropsychology Impaired executive functions Early disturbances in attention , visuo-perceptive functions (clock, pentagons) Early impairment of declarative memory and attention +++ typical; ++ usually present; + present; - unusual manifestation
Dementia Due to Huntington Disease movement disorder, cognitive decline, psychiatric disturbance : Dementia Due to Huntington Disease movement disorder, cognitive decline, psychiatric disturbance Autosomal dominant Chromosome 4p short arm Excessive ( > 38) CAG repeats in the IT15 gene (interesting transcript number 15) Codes for protein huntingtin 5 - 10 / 100,000 M = F; white race Usually very early onset Late 30’s - early 40’s Paternal inheritance: earlier Death in 10-30 years Pathology Selective neuronal loss Caudate Putamen Marked ↓ in local GABA Differential Dx Chorea or chorea-like illnesses Prodrome ( ⅓ - ½) Depression, psychomotor slowing, anxiety, fidgeting, rigidity, irritability, change in personality (inappropriate, disinhibited) Mania 2-12% Suicide 6% Early course Generalized choreoathetosis, beginning in the face or arms Memory retrieval Executive dysfunction Cognitive flexibility Attention Judgment, sequencing, planning Frequent psychosis (paranoia, VH), and disorganized speech PET: Striatal hypometabolism Late course “Boxcar ventricles” (batwings) Atrophy of the heads of caudate nuclei Rx: Antipsychotic + SSRI Bupropion worsens chorea Striatum
Dementia Due to Huntington Disease : Dementia Due to Huntington Disease HD: Atrophy of the caudate and Left: HD Right: normal nucleus caudate hydrocephalus ex vacuo GFAP immunostain, showing gliosis
Dementia Due to Huntington Disease : Dementia Due to Huntington Disease Caudate head atrophy Caudate head hypometabolism MRI – T2 SPECT - Tc “Boxcar” or “Bat Wings” ventricles Control HD
Dementia Due to HIV Disease (AIDS Dementia Complex) : Dementia Due to HIV Disease (AIDS Dementia Complex) >50% of AIDS patients; 14 % of HIV total Reduced incidence with HAART Often insidious, several years after diagnosis Rapidly progressive: months to a year Direct pathophysiological effect of the virus Mechanisms Macrophage activation Cellular proteins (chemokines recruit monocytes, proinflammatory cytokines, NO) HIV protein (virotoxins: gp 120, gp41, Tat) Autoimmune disease (anti0CNS antiodies ADC occurs when CD4 + count < 200 cell/mm 3 Possible associated damage from CNS tumors or opportunistic infections Prominent slowness (psychomotor retardation) & apathy CSF: (+) lymphocytes & nl- ↑ protein Diffuse, multifocal destruction of the white matter and subcortical structures MRI: cortical atrophy and widespread patchy leukoencephalopathy
Dementia Due to HIV Disease AIDS Dementia Complex : Dementia Due to HIV Disease AIDS Dementia Complex HIV encephalitis = AIDS Dementia Complex HIV encephalitis is characterized by diffuse myelin damage (spongy myelinopathy, gliosis), neuronal loss, vascular damage, microglial nodules, and lymphocytic infiltrates. HIV envelope glycoproteins cause the membranes of HIV-infected macrophages to fuse, forming multinucleated giant cells( MGC) , which are the hallmark of HIV encephalitis. MRI-T2 weighted image at the level of the lateral ventricles displays a diffuse white matter abnormality consisting of increased signal. The cortical sulci are prominent given the age of the subject, indicating atrophy . HIV leukoencephalopathy tends to involve the periventricular white matter and the centrum semiovale. f MRI (a) Dynamic cerebral blood volume (CBV) image from a healthy control subject (left) and an HIV+ patient (right) with moderate dementia (ADC Stage 2). Increase in the cortical and deep gray dynamic CBV in the patient with dementia is apparent. (b) Functional MRI images from the same patient obtained before (left) and after (right) 6 months of treatment with zidovudine. Improvement in dementia (ADC Stage 2 to 0) with treatment was accompanied by a reduction in the cortical and deep gray matter dynamic CBV. Representative dynamic contrast functional MRI images of normalized cerebral blood volumes at the level of the basal ganglia. The scale goes from white to yellow to red, which represents low to moderate to high relative blood volume. Smirniotopoulos JG, et al.Neuroimaging Clin N Am 1997, 7(3):615-37. Tracey I, et al.. Neurology 1998, 50(6):1821-6
Dementia Due to Creutzfeldt-Jacob Disease : Dementia Due to Creutzfeldt-Jacob Disease “Hockey stick” sign (striatal hyperintensity) MRI – T2 Spongiform encephalopathy CJD: severe brain atrophy Cerebellar degeneration
Dementia Due to Creutzfeldt-Jacob Disease : Dementia Due to Creutzfeldt-Jacob Disease One of the subacute spongiform encephalopathies Produced by direct neurotoxic effects of slow viruses (prions) on cortex and basal ganglia Most are spontaneous mutations of prion protein gene (PrP Super C ) Short arm of chromosome 20 (178N/129V) (+ prenatal testing) But 5-15% have familial component Iatrogenic transmission by surgical instruments, EMG electrodes, human-derived Growth Hormone & gonadotropics, corneal transplantation, dura matter grafts; also health care workers Cross-species transmission of nvCJD: > 100 UK cases of new variant CJD = mad-cow BSE 4 US cases = elk & deer CWD Triad Involuntary movements (myoclonus), tremor, ataxia Dementia. Also lability, delusions, hallucinations, personality change Periodic EEG activity (high voltage, often biphasic-triphasic, synchronous slow sharp wave complexes at 0.5-2 Hz) Early onset: 40-60 Very rapid progression (sporadic 8 months; familial 26 months; nvCJD 60 months) Prodrome: anxiety and depression, then lack of coordination Neuroimaging: non-specific atrophy Possible basal ganglia and thalamus hyperintensities on MR-T2 “Hockey stick” sign: putamen + head of the caudate (striatal) hyperintensity Bilateral “Pulvinar” sign, specially in nvCJD cases CSF: normal CSF protein 14-3-3; also found in viral encephalitis & stroke