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dementia
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NEUROPATHOBIOLOGICAL BASIS OF
DEMENTIA
NEUROPATHOBIOLOGICAL BASIS OF
DEMENTIA
M. Sajid DarmadipuraDEPT. OF NEUROSURGERY
NEUROSURGICAL FORUM, MARCH 2005
M. Sajid DarmadipuraDEPT. OF NEUROSURGERY
NEUROSURGICAL FORUM, MARCH 2005
DEMENTIADE = OUT OFMEN = MINDTIA = STATE OF
DEMENTIADE = OUT OFMEN = MINDTIA = STATE OF
A STATE OF BEING OUT OF ONE’S MINDAN ACQUIRED COGNITIVE IMPAIRMENT INVOLVING MULTIPLE DOMAINS OF FUNCTION IN THE ABSENCE OF A CLOUDING OF CONSCIUSNESS
A STATE OF BEING OUT OF ONE’S MINDAN ACQUIRED COGNITIVE IMPAIRMENT INVOLVING MULTIPLE DOMAINS OF FUNCTION IN THE ABSENCE OF A CLOUDING OF CONSCIUSNESS
DEMENTIADEMENTIAA syndrome consisting of progressive impairment
in two or more areas of cognition- memory- language- visuospital- thinking & problem solving- behaviour
Sufficient to interfere with work, social function, relationship
in the absence of delirium or major non organic psychiatric disorders
A syndrome consisting of progressive impairment in two or more areas of cognition- memory- language- visuospital- thinking & problem solving- behaviour
Sufficient to interfere with work, social function, relationship
in the absence of delirium or major non organic psychiatric disorders
( AM. PSYCHIATRIC ASSOCIATION IN DIAG. & STATISTICAL MANUAL OF
MENTAL DISORDERS, DSM – IV )
( AM. PSYCHIATRIC ASSOCIATION IN DIAG. & STATISTICAL MANUAL OF
MENTAL DISORDERS, DSM – IV )
Glossary, Functions Related To DementiaGlossary, Functions Related To Dementia
AMNESIA : disturbance of learning / memory due to
structural damage.LEARNING : the acquisition of new
knowledge of informationMEMORY : the process whereby newly acquired information is stored and retrieved for future use
recall is part of memory short term (seconds, minutes to 1 hour) long term memory : retention for extended period of time
Organic Brain Syndrome, Sindroma Otak Organik (SOO) :general term that means physical disturbance of the brain causing mental function deficit.
AMNESIA : disturbance of learning / memory due to
structural damage.LEARNING : the acquisition of new
knowledge of informationMEMORY : the process whereby newly acquired information is stored and retrieved for future use
recall is part of memory short term (seconds, minutes to 1 hour) long term memory : retention for extended period of time
Organic Brain Syndrome, Sindroma Otak Organik (SOO) :general term that means physical disturbance of the brain causing mental function deficit.
Causes of DementiaCauses of DementiaPrimary Degenerative Disease
Cortical : Alzheimer’s Dis. F–T Dementia (Pick’s Dis)
Subcortical : Progr. Supranucl. Palsy Huntington’s Dis. Parkinson’s Dis.
Cortical & SubCortical :Dementia with Lewy bodiesCorticobasal Deg.
Vascular DementiaMulti infarctBiswanger’s Dis.Primary Cerebral Amyloid AngiopthyCADASIL ( cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy )Anoxia ( secondary )Vasculitides
Others
Primary Degenerative DiseaseCortical : Alzheimer’s Dis.
F–T Dementia (Pick’s Dis)Subcortical : Progr. Supranucl. Palsy
Huntington’s Dis. Parkinson’s Dis.
Cortical & SubCortical :Dementia with Lewy bodiesCorticobasal Deg.
Vascular DementiaMulti infarctBiswanger’s Dis.Primary Cerebral Amyloid AngiopthyCADASIL ( cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy )Anoxia ( secondary )Vasculitides
Others
FTD12%
AD34%
VaD18%
DLB7%
Others29%
Younger than 65 years
Older than 65 %
DLB20%
AD55%
VaD20%
Others5%
BehaviourBehaviour
Sum of actions and psychomotor reactions that can be objectively observed and interpreted and that interfere with the subject’s environment.
Sum of actions and psychomotor reactions that can be objectively observed and interpreted and that interfere with the subject’s environment.
Includes : Motor activity
Language
Socially oriented actions
Affectively expression
Includes : Motor activity
Language
Socially oriented actions
Affectively expression
Harmoniously
Goal oriented /
Individual Specific plan
Harmoniously
Goal oriented /
Individual Specific plan
LIMBIC CIRCUITThe inner loop = PAPEZ’S CIRCUIT involved in memory processesThe outer loop = centered by AMIGDALA, and process emotional patterns, links with experience coming from the association cortex
LIMBIC CIRCUITThe inner loop = PAPEZ’S CIRCUIT involved in memory processesThe outer loop = centered by AMIGDALA, and process emotional patterns, links with experience coming from the association cortex
ENTORHINALCORTEX
HIPPOCAMPUS
THALAMUS
MAMILLARBODY
AMYGDALA
HIPPOTHALAMUS
PREFONTALCORTEX
ASSOCIATIONCORTEX
ANTERIOR CINGULATEGYRUS
AcetylcholineAcetylcholineBM = Basal nucleus of MeynertDB = Diagonal band of BrocaH = HipothalamusHIPP = Hippocampal formationPA & SO = Paraventricular and supraoptic nuclei of the hypo-thalamusPPT & LTD = Pedunculopontine tegmental nucleus and laterodorsal tegmental nucleusRF = Reticular FormationS = SeptumSNc = Subtantia nigra pars compactaTHAL= Thalamus
BM = Basal nucleus of MeynertDB = Diagonal band of BrocaH = HipothalamusHIPP = Hippocampal formationPA & SO = Paraventricular and supraoptic nuclei of the hypo-thalamusPPT & LTD = Pedunculopontine tegmental nucleus and laterodorsal tegmental nucleusRF = Reticular FormationS = SeptumSNc = Subtantia nigra pars compactaTHAL= Thalamus
NUC. ACC = nucleus accumbensSN = subtantia nigraVTA = ventral tegmental area
NUC. ACC = nucleus accumbensSN = subtantia nigraVTA = ventral tegmental area
DOPAMINE
AMYG = amygdala HYPO = hypothalamusPAG = periaqueductal gray area THAL = thalamusAMYG = amygdala HYPO = hypothalamusPAG = periaqueductal gray area THAL = thalamus
DementiasDementias
Normal Aging
Vascular DementiaBiswanger’s disease
Multiple Lacunar infarcts
CADASIL
DLB, Dementia with Lewy Bodies
DLBD, Diffuse Lewy Body Disease
PD with Dementia
ALZHEIMER’S DISEASE
Normal Aging
Vascular DementiaBiswanger’s disease
Multiple Lacunar infarcts
CADASIL
DLB, Dementia with Lewy Bodies
DLBD, Diffuse Lewy Body Disease
PD with Dementia
ALZHEIMER’S DISEASE
Alzheimer’s Disease(Alois Alzhemier 1864 – 1915)German Neuropathologist – Neurologist
Alzheimer’s Disease(Alois Alzhemier 1864 – 1915)German Neuropathologist – Neurologist
An extraordinary high prevalence “malignancy”, dramatically reduces QOL & Survival
One of the most important disease in medicine today
In USA 1.5 – 4 millions pop, increasing with age
Tremendous burden on families and health care system
An extraordinary high prevalence “malignancy”, dramatically reduces QOL & Survival
One of the most important disease in medicine today
In USA 1.5 – 4 millions pop, increasing with age
Tremendous burden on families and health care system
( Murray, 1996; Greicius et al., 2003)( Murray, 1996; Greicius et al., 2003)
Ach exerts its activationAch exerts its activationFrom 1 – the basal forebrain system
(nucl :Meynert’s n.med. setpti)→ widespread projections to c. cortex etc.
2 – the pedunculo ponto tegmental complex → projections ach neurons etc.
1. Form an Important Part of Cortical Arousal during :
• Attention• Learning• Memory
2. Constitute important links in RAS, participate in arousal & wakefullness
From 1 – the basal forebrain system (nucl :Meynert’s n.med. setpti)
→ widespread projections to c. cortex etc.
2 – the pedunculo ponto tegmental complex → projections ach neurons etc.
1. Form an Important Part of Cortical Arousal during :
• Attention• Learning• Memory
2. Constitute important links in RAS, participate in arousal & wakefullness
Deficit of this system Deficit of this system
ADAD
Diagnosis of ADDiagnosis of ADHistoryComplete GENERAL NEUROLOGICAL
EXAMINATIONThere is overlap
- time of appearance- severity, degree and extend of specific region(s) affected
allow, not always, one dementia to beDISTINGUISHED from anotherMRI, SPECT, PET ScanBiopsy / Autopsy
HistoryComplete GENERAL NEUROLOGICAL
EXAMINATIONThere is overlap
- time of appearance- severity, degree and extend of specific region(s) affected
allow, not always, one dementia to beDISTINGUISHED from anotherMRI, SPECT, PET ScanBiopsy / Autopsy
AD is characterized byAD is characterized by
Amyloid plaques, clumps of amyloid, between neurons
NFT, bundles of twisted filaments within neurons, made up of tau
Amyloid plaques, clumps of amyloid, between neurons
NFT, bundles of twisted filaments within neurons, made up of tau
TAU = A hyper phosphorylated form of tubule associated protein
ß Amyloid Protein (ßAP) =
major constituent plaques in AD
TAU = A hyper phosphorylated form of tubule associated protein
ß Amyloid Protein (ßAP) =
major constituent plaques in AD
TreatmentAD & other dementiasTreatmentAD & other dementias
NS cases, Neurosurgically consideredEXCLUDE METAB diseasesAD ( in AD, a marked reduction in choline acetyltransferase and Ach)Ach E catalyzes degradation of Ach. Drugs that inhibit Ach E, effectively increase concentration of neurotransmitters at post synaps / motor end plate
NS cases, Neurosurgically consideredEXCLUDE METAB diseasesAD ( in AD, a marked reduction in choline acetyltransferase and Ach)Ach E catalyzes degradation of Ach. Drugs that inhibit Ach E, effectively increase concentration of neurotransmitters at post synaps / motor end plate
Treatment of ADTreatment of AD
Drugs that slow progression of disease
Drugs that treat particular neuropsychiatric symptoms
Drugs that prevent the disease
NOTE : cholinergic projections from the basal forebrain
Drugs that slow progression of disease
Drugs that treat particular neuropsychiatric symptoms
Drugs that prevent the disease
NOTE : cholinergic projections from the basal forebrain
• Ach E inhibitors• Ach E inhibitorsTARCINE : non selective Ach E inhibitor
approved 1993, short half life → 4 dd, prominent cholinergic effect, LFT disturbed
DONEPEZIL : approved 1996, selective, longer half live, milder cholinergic effect
RIVASTIGMINE :– recently approved in US– less drop outs– better as evaluated by ADAS sub scale
GALANTAMINE : approved in US
TARCINE : non selective Ach E inhibitor approved 1993, short half life → 4 dd,
prominent cholinergic effect, LFT disturbed
DONEPEZIL : approved 1996, selective, longer half live, milder cholinergic effect
RIVASTIGMINE :– recently approved in US– less drop outs– better as evaluated by ADAS sub scale
GALANTAMINE : approved in US
• Memantine : glutamate activity is often disrupted in AD; combine with Ach E inhibitors
• Memantine : glutamate activity is often disrupted in AD; combine with Ach E inhibitors
Ach E inhibitor for dementias other than AD ?Note : overlaps among dementiasPD dementia like disorders include :
- AD- AD with LB- FT D / Pick’s D- VD
(NINDS, 2005)
Why not ?
Ach E inhibitor for dementias other than AD ?Note : overlaps among dementiasPD dementia like disorders include :
- AD- AD with LB- FT D / Pick’s D- VD
(NINDS, 2005)
Why not ?
Ach E inhibitor for traumatic mental dysfunction ?
SURE !In animal (Chen at al, 1998)In patients (Tenovuo, 2004)
Ach E inhibitor for traumatic mental dysfunction ?
SURE !In animal (Chen at al, 1998)In patients (Tenovuo, 2004)