Hippocampus
Hippocampal formation - subiculum - hippocampus - dentate gyrus
1.Primary area
Frontal lobes Parietal lobes Temporal lobes Occipital lobes
Association areas
1.Parieto-occipito-temporal association areas 2.Prefrontal association area 3.Limbic association area
Functions of the parieto-occipitotemporal cortex in the nondominant hemisphere Interpreting music Nonverbal visual experiences Visuospatial
Thal (VA,MD)
Thal (VA,MD)
Thal (MD)
Dorsolateral: Executive dysfunction Orbitofrontal: Disinhition, Anosmia Medial frontal / anterior cingulate: apathy
Orbitofrontal syndrome
Disinhibition Impulsive Mood changes: Lability, irritability, hypomania, mania
3.Long-term memory
- yrs ,lifetime
Procedural
Approach To Dementia
Language
Visuospatial skills
Approach Dementia
Subcortical dement Cortical dementia severity Speed impair
Neuropsychology deficit
Gegenhalten ,less
Cortical vs Subcortical
Cortical
AD FTD
Subcortical
VaD PD, PSP, Huntingtons disease, Wilsons disease, SCA Hydrocephalus WM diseases Etc.
Approach Dementia
Anterior: FTD Posterior: AD Clinical course: -Progessive -Treatable
Reversible dementia
D E M E N T I A Drugs Emotional disorders Metabolic and endocrine disorders Eye and ear dysfunction Nutritional deficiencies Tumors, trauma Infections Atherosclerosis, Alcohol
Neurodegenerative disease
Alzheimers disease Frontotemporal dementia, CBD Parkinsonian dementia ;Parkinsons disease dementia ,DLB ,MSA
History Definite onset (can be dated) Duration before consulted Rapid progression Pts complaint of cognitive loss Pts description of cogitive loss Family awaren of dysfunction&severity Loss of social skills Hx psychopathology
Dementia
Unusual Long Unusual Variable (minimal) Vague Variable (usual in later stage) Late uncommon
Depression
Usual Short Usual Emphasized Detailed Usual Early common
Examination
Recent:remote memory loss Specific memory loss (patchy) Attention&concentration Dont know answers Near miss answers Performance on tasks of similar difficulties Pts emotional reaction to symptoms
Dementia
Recent>remote Uncommon Often poor Uncommon Variable(common in later stages) Consistent
Depression
Equal Common Often good Common Uncommon Variable
Examination (2)
Pts affect
Dementia
Depression
Pts efforts in attempting to perform tasks Pts efforts to cope with dysfunction
Maximal
Minimal
Feature
Onset
Delirium
Acute, often at night
Dementia
Insidious Generally stable over course of day Months to years Clear Usually normal
Course over 24 Fluctuating with lucid hours intervals during day, worse at night Duration Consciousness Attention Hours to weeks Reduced Globally disordered Hypoalert or hyperalert, Distractible Fluctuates over course of day
Feature
Orientation
Delirium
Usually impaired for time, tendency to mistake unfamiliar for familiar place and persons Disorganized Illusions and hallucinations (usually visual) Incoherent, hesitant, slow or rapid Always disrupted Either or both are present
Dementia
Often impaired
Thinking Perception
Often normal Difficulty in finding word Often fragmented sleep Often absent, esp in AD
INVESTIGATE Routine CBC ,ERS ,Urea or creatinine electrolyte ,Liver function test calcium ,glucose ,Vitamin B12 and folate ,Thyroid funtion test ,syphilis Common CT or MRI brain Occasional HIV ,CSF ,EEG ,SPECT
Biomarker in AD
Tau level AB 1-42 Neuropile Biomarker -elevated -decease -thread protein -nonspecific for AD and other -accurate differential AD from normal elderly subjects
Neuropsychiatry Test
DDX Stuporous
Akinetic mutism : a state of silent , alert appearing immobility. The patients eyes are open and may follow environmental events. There are regular sleep-wake cycles. He may be inert or may have occasional brief movements - Large frontal lobe injuries - Bilateral cingulate gyrus damage - Midbrain
Locked-in syndrome : The patient mute and paralyzed. The patient can communicate by eye movement. Intellectual function is not impaired Bilateral pontine lesions
Attention
Forward digit span : the numbers are given at a rate of one per second in a monotonous voice. 7 is normal. < 5 is abnormal
Individuals with normal attention perform the test perfectly Toxic or metabolic disorder Increased ICP Frontal lobe disorder Focal lesion of the posterior R hemisphere
Memory
1.Learning - examiners name,3 words ,3 objects 2.Backward memory - backward spelling ,serial subtraction
4.Retrograde memory
- retrieve knowledge from the past
Non-verbal memory
Patients are asked to copy several figures ; a few minutes later the patients must reproduce the drawings from memory Design fluency test
Language
Spontaneous speech : aphasia Language comprehension Repetition : pt with shortened digit span will be able
to repeat only brief phrases. Conversely, the digit span is a repetition test, pt with repetition disturbances will have abnormal digit spans.
Reading Writing
Word list generation is sensitive to anomia and word finding disturbances, lexical search abnormalities associated with frontal subcortical systems dysfunction and psychomotor retardation
Visuospatial skill
Visuospatial abilities Spatial attention Perception Construction Visuospatial problem solving Visuospatial memory
Construction tasks are the most widely used screening tests of visuospatial ability. Clock drawing Copying figures of increasing complexity
Tests of copying
Injury of the posterior aspect of the R hemisphere produces the most severe visuospatial deficits Dysfunction of frontal, occipital or L parietal lobe can affect drawing abilities The R hemisphere mediates the external configuration The L hemisphere mediates the internal details
Calculation
In MSE : addition, multiplication, subtraction and division One or 2 digit tasks : 16 + 32, 15 x 3 100-7: at least 5 serial It is determined by pts education and occupational history. Damage to the posterior aspect of the L hemisphere
Abstraction
This skill refer to the patients ability to derive a general principle from a specific example. Similarity Difference Similariy : identify the class or category of which 2 items are members Difference : identify the salient distinguishing feature between 2 similar items
Depends on the patients education These tests are culturally biased Abstraction is sensitive to many types of brain dysfunction Task failure is a nonspecific indicator of cerebral dysfunction Common in frontal systems disorders
MCI
Increase risk AD 12-15% per years Normal risk 1-2 % per year Non amnestic MCI or MCI with multiple domain impairment risk dementia not complete Neuropathological change ; choline acetyltranferase deficit and loss of cholinergic basal forebrain
Dementia
Early amnesia Yes Fluent aphasia Apraxia Agnosia Parkinsonian features Visual hallucination Fluctuation
No
Atherosclerotic Hx Behavioral Focal neurologic changes signs, motor signs Nonfluent aphasia
AD
DLB
VaD
FTD
ALZHEIMERS DISEASE
Most cases are sporadic Familial autosomal dominant form
MEMORY LOSS, APHASIA, APRAXIA AND VISUOSPATIAL ABNORMALITIES = HALLMARKS PRIMARY MOTOR AND SENSORY FUNCTIONS USUALLY NORMAL
Alzheimers disease : more than memory loss -Decline in cognitive -Loss of ADL -Non-cognitive symptoms -Psychiatric symptoms
Cognitive Deficits
Dysphasia : anomia ,aphasia Dyspraxia Disorientation Impaired calculation Impair judgement and problem-solving
- FRONTAL RELEASE SIGN - IMPAIRED STEREOGNOSIS AND GRAPHESTHESIA - SPEED OF GAIT LENGTH OF STEPS
PSYCHIATRIC SYMPTOMS
Anxiety ,depression ,blunted affect Hallucination ,delusion Physical and verbal aggressive ,repetitive mannerism ,uncooperativeness
Vascular Dementia
Relation between dementia and CVD: onset within 3 mo. of stroke, abrupt onset ,stepwise decline Complex interaction Vascular etiologies: cerebrovascular disease, and other vascular risk factors Changes in the brain: infarcts, white matter lesion (WMLs), atrophy Cognitive, behavior and other neurological deficit Criteria for VaD : Cerebrovascular disease and its effect on cognitve expands Mixed AD and CVD common VAD not diagnosis until at least 3 months after stroke
Categories of VAD
Multi-infarct dementia (MID) which develops gradually mini-strokes or transient ischaemic attacks (TIAs see below) ,MID affects the cerebral cortex, which is the outer Subcortical vascular dementia (Binswangers disease or lacunar) which involves vascular damage to the nerve cell fibres (deep white matter) by affecting the sheath nerve fibres in the brain (demyelination). Strategic VaD : thalamic dementia
NINDS-AIREN criteria
Supportive informations 1. Hx risk factors of CVD 2. Hx falling or gait disturbance 3. Early urinary incontinence wo urological conditions 4. Frontal lobe / extrapyramidal feature 5. Pseudobulbar feature
Diagnostic Labeling
Possible VAD; inclusion criteria by clinical evaluation, neurological ex, cognitive impairment, documented MMSE or Capacity Screen Examination, Hx stroke+ neuro def Propable VAD ; above + neuroimaging CT/MRI Definite VAD; above+ neuroimaging+ neuropathology
Clinical presentation
Small vessel disease Lacunes & white matter infarction = WHITE MATTER DISEASE Motor & Cognitive Executive Slowing Forgetfulnes Mood Changes Dysarthria Urinary Symptoms Short- Stepped Gait
Multi infarct , large sized artery Single/multi infarct, basal ganglia, thalamus, angular gyrus Multi subcortical lacunar, deep penetrating artery , most common Binswanger s subcortical leukoencephalopathy Combine small/ large infarct, subcortical and cortical ICH CADASIL Mixed with AD
Cerebral Autosomal Domonate Arteriopathy with Subcortical Infracts and Leukoencephalopathy (CADASIL)
Mid- adult life; mean 43.3 yrs Clinical manifestations; migrain with aura, seizure, organic psychiatric symp. Negative asso CVD risk factors, arteriosclerosis Subcortical dementia ,momory and frontal deficit
(Probable = 2/3
Possible = 1/3)
Clinical feature
Dementia in association with :
- fluctuations in cognition (especially attention and alertness) - visual hallucinations (typically well formed) - mild spontaneous Parkinsonism
Supportive features :
repeated or unexplained falls syncope or transient loss of consciousness neuroleptic sensitivity syndrome hallucinations in other modalities systematised delusions
Dementia :attention ,frontal-executive ,and visuospatial deficits ,short term memory better than AD ,100% Fluctuating cognition :variable altered level of attention or arousal ,60-80% Visual hallucination :recurrent ,variable degree ,50-75% Parkinsonism :spontaneous ,rigidity ,and bradykinesia ,intention tremor ,80-90%
Cognitive and neuropsychiatric feature appearing within 1 year of motor sign Dopaminergic provoke psychosis Antipsychotic agents induce motor disabilities Sensitivity reaction to neuroleptic drugs
Frontotemperal dementia
Clinical course during the first 2 years is as follows: Psychiatric abnormalities
Patients with orbitofrontal dysfunction become aggressive and socially inappropriate. They may steal or demonstrate obsessive or repetitive stereotyped behaviors.
Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or decreased spontaneity. Patients may be depressed early in the disease. These mood changes can predate amnesia.
Speech and language abnormalities often begin early and progress rapidly. Patients usually have relatively little limb apraxia and/or visuospatial dysfunction, thus distinguishing them from patients with diffuse bihemispheric impairment. Even memory impairment is relatively less severe than speech/language and behavioral changes. Incontinence can occur early. Parkinsonism, with its concomitant history of rigidity and gait impairment, can occur.
General neurologic examination may include some of the following abnormalities: Primitive reflexes such as grasp, suck, and snout (not palmomental reflex, which is often present in healthy individuals; Sjogren, 1997) Akinesia, plastic rigidity, or paratonia on motor examination (Beversdorf, 1998) Resting tremor (uncommon; its presence suggests Parkinson disease or a Parkinson-plus syndrome)
Mental status/neuropsychological examination may reveal the following: Verbal output that is often nonfluent Most patients have difficulty in naming common objects or pictures (anomia). Spontaneous speech can be sparse yet "fluent" in character, with preserved grammar. Perseveration Relatively preserved visuospatial and visual orientation skills
Clinical
Risk factors
VaD
Transient ischemic attack, strokes, Atherosclerotic risk factors: DM, HT Sudden or insidious Slow or stepwise Neurologic deficits Early abnormalities Slightly impaired early Markedly impaired early Subcortical >7 Less
AD
Onset Progression Neuro signs Gait Memory Executive function Type of dementia Hachinski Ischemic Score Neuroimaging
Insidious Gradually progressive Normal Normal Prominent Impaired in later stage Cortical <4
Clinical difference
Tremor Motor symptoms Axial involvement : postural instability, masked face Parkinsonism signs at dementia diagnosis Response to levodopa Less
DLB
PDD
More often Unilateral at onset Less
25-50%
All cases
Poor
Good
Parkinsonism Fluctuation Verbal memory
DLB
93.8 50-75 semantic memory 31.3
AD
Executive function
Attention, visuospatial function, constructional abilities Visual hallucination
Neuroleptics
Extrapyramidal
Clinical differences
Onset Early behavioral symptoms Early socially inappropriate behaviors Memory problems Language problems Visuospatial problems Motor signs Mood Most < 75 yrs Common Common
FTD
AD
markedly with age Unusual Later stage Presenting symptom Always associated with memory problems More Less Sadness, anhedonia, apathy, insomnia, guilty Inappetite Typically delusion of misidentification and persecutory (in moderate to severe cases)
Initially intact can occur as an isolated cognitive entity in PPA Less More often Irritability, anhedonia, withdrawal, alexithymia, euphoria,, no suicidal idea and guilt appetite, weight gain, CHO craving Rarely persecutory delusion, maybe jealous, somatic, religious and often bizarre
NPH
6th-7th decade 50%: known causes, 50% idiopathic Improvement after shunting 30-50% of idiopathic and 50-70% of secondary NPH Triad: gait difficulty, subcortical cognitive problems, urinary incontinence
NPH
Examination: Mild spasticity of lower extremities BBK present Strength leg preserved Cognitive impairment: Prominent attention, memory impairment, executive, frontal lobe dysfunction Subcortical dementia
Diagnostic tests
Neuropsychological assessment Neuroimaging techniques: CT, MRI CSF removal Cisternography Measurement of cerebral blood flow and metabolism Pressure monitoring and hydrodynamic tests
Increase adequctal flow on MRI CSF dynamic study isotope cistenography Biomarker E-4 alles of ApoE gene
Management
Nonpharmacologic treatment Patient, caregiver & healthcare workers education Caregiver support Patient psychological treatment Financial &legal issues Pharmacologic treatment Cognitive symptoms Non-cognitive symptoms: neuropsychiatric problems
Antiamyloid Therapies
No antiamyloid therapies are currently available. Immunization reduces pathological signs of AD in transgenic mice that have APP mutation. This clinical trial was interrupted when encephalitis developed in 6 % of the patients. Inhibitors to and secretase are under active study.
Cholinesterase inhibitors
AChEI in AD
Efficacy in mild to moderate AD AChEI in moderate to severe AD AChEI in VaD AChEI in DLB AChEI in dementia associated PD
Pharmacologic Rx in VaD
Aspirin Pentoxifylline Posatirelin Propentofylline Nicergoline Nimodipine Memantine AChIs
Memantine
N-methyl-D-aspartate antagonist Interfere glutamatergic excitotoxicity improvement on the function on hippocampal neurons Moderate-to-severe AD (alone and combine with AChE inhibitors).
Management of DLB
Target symptom include : - EPS - Cognitive impairment - Neuropsychiatric features (hallucination depression , sleep disorder, behavioral disturbance ) - ANS
Antiparkinsonian drug : lowest dose of levodopa monotherapy Neuroleptic agent : provoke severe EPS 50% in DLB, increase MR 2-3 times low dose atypical antipsychotic drugs Cholinesterase inhibitor : significant improved in fluctuating cognitive impairment, visual hallucination, apathy, anxiety, sleep disturbance
Imaging Brain
AD
AD
CADASIL IMAGING
Diagnosis ;MRI; numerous small deep infarction with diffuse myelin loss and pallor hemispheric WM ,internal capsule and basal ganglia ,and lacunar infract
Multiple infraction
Strategic infraction
FTD
Hydrocephalus
Hydrocephalus
hydrocephalus
Creutzfeldt-Jakob disease
Basal ganglia and cortical-subcortical involvement
MSA
(A) Hyperintense rim in the outer margin of putamen (black arrow), putaminal hypointensity and atrophy (white arrow) in a patient with MSA-p.
(B) Hyperintensity of the middle cerebellar peduncles (black arrow) and hot-cross bun sign (white arrow) in a patient with MSA-c on a T2-weighted image of 1.5-T MRI.
Wilsons disease
Hallervordan-Spatz disease
Hallervordan-Spatz disease
END