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

Lymbic SystemLymbic System

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

GLUTAMATE

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

Neuro Fibrillatory Tangle (NFT)Neuro Fibrillatory Tangle (NFT)

( Aminoff and Daroff, 2003 )

Amyloid PlaquesAmyloid Plaques

( Aminoff and Daroff, 2003 )

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)