ISSN: 0975-766X CODEN: IJPTFI Available through Online ... · PSP is pathologically defined by the accumulation of tau protein and neuropil threads in the subthalamic nucleus, pallidum,

Suman Yadav*et al. /International Journal Of Pharmacy&Technology

IJPT | July-2013 | Vol. 5 | Issue No.2 | 2607-2621 Page 2607

ISSN: 0975-766X

CODEN: IJPTFI

Available through Online Review Article

www.ijptonline.com CURRENT PATHOLOGIC DETERMINANTS OF COMPLEX NEURODEGENERATIVE

DISEASES: A REVIEW 1Suman Yadav*

1,

2Ahamed Noor mansoori,

3Jatan Singh Sisodiya

Department of Pharmacology, M. Pharm, 3rd Semester, Jaipur College of Pharmacy, Sitapura -302022.

Affliated to Rajasthan University of Health Science, Jaipur.

Email: [email protected] Received on 10-06-2013 Accepted on 28-06-2013

Abstract

Neurodegenerative diseases are characterized by selective and progressive loss of specific populations of neurons,

which determines the clinical presentation. The same neuronal populations can be affected in a number of different

disorders. Given that the clinical presentation reflects the particular population of neurons that are targets of the disease

process, it is clear that for any given clinical syndrome, more than one neurodegenerative disease can account for the

clinical syndrome. Because of this clinical ambiguity, neurodegeneration is the umbrella term for the progressive loss

of structure or function of neurons, including death of neurons. There are many parallels between different

neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Our main aim is to

solve these problems and carried out the proper treatment for Neurodegenerative Disease.

Key Words: Alzheimer’s disease, Neurons, Dementia, Creutzfeldt - Jakob disease, Argyrophilic grains

Introduction

By definition a neurodegenerative disease is one in which there is selective and progressive loss of specific populations

of neurons for reasons that in most cases remain unknown. The goals of research on neurodegenerative disorders are to

determine the molecular basis of selective vulnerability and common final pathways of progressive neuronal loss. In

the most common neurodegenerative disorders there are biochemical changes in a specific protein that often produces

characteristic inclusion bodies within neurons or glia, or both. [1-3]

. The same neuronal populations can be affected in a

number of different disorders. For example, neurons in the hippocampus and brainstem monoaminergic nuclei are

vulnerable in a wide range of distinct clinic-pathologic entities. [4]



Given that the clinical presentation reflects the particular population of neurons that are targets of the disease process, it

is clear that for any given clinical syndrome, there will usually be more than one neurodegenerative disease that can

account for the clinical syndrome. Because of this ambiguity, for the purpose of this brief review neurodegenerative

disorders are classified according to the underlying molecular pathology rather than their clinical presentation. [5-6]

Alzheimer’s Disease (AD)

Normal Alzheimer’s Disease

Fig. 1: Pathology characteristics of Alzheimer’s disease

Alzheimer’s (AHLZ-high-merz) is a disease of the brain that causes problems with memory, thinking and behavior. It

is not a normal part of aging. Alzheimer’s gets worse over time. Although symptoms can vary widely, the first problem

many people notice is forgetfulness severe enough to affect their ability to function at home or at work, or to enjoy

lifelong hobbies. [7]

Alzheimer's disease develops differently for every individual, there are many common symptoms. Early symptoms are

often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common

symptom is difficulty in remembering recent events. [8-10]

Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's

disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue

damage in AD or a marker of an immunological response. Alterations in the distribution of different neurotrophic

factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been

described in AD. [11]

Medication

Five medications are used for treat of the AD, mostly including acetyl cholinesterase inhibitors like tacrine,

rivastigmine, galantamine, donepezil and memantine.



1. Acetyl cholinesterase inhibitors are employed to reduce the rate at which acetylcholine is broken down, thereby

increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic

neurons. [12]

2. Cholinesterase inhibitors approved for the management of AD symptoms are donepezil and galantamine

and rivastigmine . There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease,

and some evidence for their use in the advanced stage. [13]

3. Only donepezil is approved for treatment of advanced AD dementia. Glutamate is a useful

excitatory neurotransmitter of the nervous system.[14]

4. Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on

the glutaminergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. [15]

Familial British Dementia (Fbd) [16-19]

Fig. 2: Coronal brain slices showing extensive hemorrhage in the region of the right anterior basal ganglia. The

hemispheric white matter has a granular appearance in several areas.

Familial British Dementia is not a specific disorder or disease. It is a syndrome associated with a progressive loss of

memory and other intellectual functions that is serious enough to interfere with performing the tasks of daily life. The

prevalence of dementia increases rapidly with age; it doubles every five years after age 60. Familial British Dementia

affects only 1% of people aged 60 64 but 30%–50% of those older than 85.

Familial Danish dementia (FDD), are caused by dominantly inherited autosomal mutations and are characterized by the

production of amyloidogenic peptides, neurofibrillary tangles and neurodegeneration. Different mutations in the BRI

(2) gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish



dementia (FDD). The mutant genes encode BRI-L and BRI-D, the precursors of fibrillogenic ABri and ADan peptides,

respectively.

BRI2 was originally described in relation to Familial British Dementia (FBD) an autosomal dominant

neurodegenerative disease characterized by the early onset of personality changes, memory and cognitive deficits,

spastic rigidity, and ataxia. Medication includes:

a. Aromatherapy

Few patients exploring the use of aromatherapy in people with dementia were identified. Melissa officinalis (lemon

balm) was shown to have a positive effect on agitation although patients in this study continued to receive neuroleptic

medication with dose adjustments possible during the study period; confounding the results.Use of Lavendula

officinalis (lavender oil) has not been proven to reduce associated symptoms in people with dementia.

b. Light therapy

Sleep disturbance in people with dementia can be particularly distressing for carers. Biological changes in the brain can

disrupt the normal circadian rhythm and sleep/wake cycle. Bright light affects the production of melatonin, which may

lessen these problems. Bright light therapy is a labour intensive intervention and there are problems in controlling the

studies for staff interaction and in maintaining blinding. Bright light therapy shows its effect on cognitive function in

patients with dementia is negligible (one of only six people).

c. Music therapy

It is suggests that exposure to music, tailored to the individual’s taste, can relieve agitation but not aggressive behaviour

in people with dementia. It is not possible to determine whether the beneficial effect seen is the result of music therapy

itself or other factors. Music therapy is easy to implement, but more research is needed to determine whether it is

beneficial to the person with dementia.

d. Multi-sensory stimulation

Multisensory stimulation (MSS) is not tolerated by everyone. The differences in severity of dementia between the

intervention and control groups in studies limit the conclusions that can

be drawn. Individuals exposed to multisensory environments showed less confusion and talked more spontaneously and

in normal length sentences.



Creutzfeldt-Jakob Disease (CJD) [20]

Fig. 3 : MR imaging findings in v Creutzfeldt-Jakob disease.

Standard antibiotic and antiviral medications do not affect the prion. A spinal fluid test is available that identifies the

prion protein (PrPsc); however, this test is not 100% sensitive. Physical examinations, neurological assessments, or

brain imaging studies cannot confirm Creutzfeldt-Jakob’s disease. Brain biopsy or autopsy is required to confirm the

diagnosis. Creutzfeldt-Jakob (CJD) is a rare cause of dementia that attracts considerable media attention. This prion-

mediated dementia may be related to mad cow disease. The typical CJD patient has a short survival and the mode of

transmission is unknown. The risk to the general population is quite low.

Progressive Supranuclear Palsy (PSP) [21-22]

PSP is pathologically defined by the accumulation of tau protein and neuropil threads in the subthalamic nucleus,

pallidum, red nucleus, substantia nigra, striatum, pontine tegmentum, oculomotor nucleus, medulla and dentate nucleus.

Similar histopathological findings can be seen in other forms of tauopathies complicating the pathological diagnosis of

PSP. The most specific features are star-shaped astrocytic tufts and neurofibrillary tangles that can be seen with light

microscopy and that immunostain strongly with antibodies to tau.

The cross-over of symptoms and similarities in pathology is sometimes reflected in a generic term 'tauopathy'. The

pathology of PSP can be particularly difficult to distinguish from CBD, leading some to group these disorders within a

single clinicopathological spectrum. Conversely, it has been proposed PSP-PNFA represents a separate subdivision of

PSP alongside Richardson’s syndrome, PSP-parkinsonism, PSP Primary Akinesia with Gait Freezing (PAGF), and a

PSP-Cortcobasal Syndrome (CBS).



Fig. 4: Imaging findings in PSP: Characteristic findings of PSP on structural imaging are the 'Mickey mouse' sign

(axial slices) and the 'humming bird' sign (on sagittal slices). Imaging may also exclude hydrocephalus,

extensive vascular disease, signs of normal pressure hydrocephalus and mass lesions.

Medication

1. Botulinum toxin

Botulinum toxin may be helpful in PSP for treating dystonia, such as retrocollis , and apraxia of eyelid opening,

reducing disability provoked by these symptoms. This must be used with cautions to avoid worsening of dysphagia.

2. Disease modifying therapies

The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study randomized PSP patients for

receiving riluzole, evaluating survival as primary outcome. This drug did not have a significant effect on survival

neither in the rate of functional deterioration.

3. Palliative methods

These recommendations are based on good practice and clinical experience. A multidisciplinary team is essential in

management of PSP. Physiotherapist, speech, language, and occupational therapists, and dietitians should be involved

in management of treatment. According to development of symptoms, different palliative methods should be

recommended.



a. b. c. d.

Fig. 5 :Brain MRI illustrative images of a patient with progressive supranuclear palsyError! Bookmark not defined.

a. Area of disease

b. Internal-1 and external-2 interpeduncular angles showing midbrain atrophy.

c. Quadrigeminal thickness showing atrophy .

d. Periaqueductal hypersignal .

Corticobasal Degeneration (CBD) [23-25]

CBD was considered a primary motor disorder characterised by asymmetrical rigidity with apraxia and variable other

features, including cortical sensory loss, alien limb behaviour, myoclonus and dystonia. Cognitive abilities were stated

to be relatively preserved. In fact, early diagnostic criteria stated that early dementia was an exclusion criterion. As a

result, CBD is now regarded as a complex disorder which affects motor and cognitive function, although the relative

importance of these two major features remains controversial.

Corticobasal degeneration (CBD) or Corticobasal Ganglionic Degeneration (CBGD) is a rare,

progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia. It is characterized by marked

disorders in movement and cognitive dysfunction. Clinical diagnosis is difficult, as symptoms of CBD are often similar

to those of other diseases, such as Parkinson's disease (PD) and progressive supranuclear palsy.

a. b.

Fig 6 : Corticobasal degeneration.

a. An axial fluid-attenuated inversion recovery image 3 years before autopsy shows no obvious asymmetric atrophy.

Subcortical hyperintensity is shown in the right frontal white matter (white arrow).



b. A macro specimen of this patient shows mild frontal atrophy with some asymmetry (arrow).

Medications

a. Tremor

Anticonvulsant medication and propranolol targeting tremor are beneficial only occasionally . Other considerations

include benzodiazepines, anticholinergic drugs, levodopa, primidone, and nadolol.

b. Physical therapy and speech therapy

It greatly limits the patient’s ability to learn new strategies when attempting to improve physical disabilities.

Constraint-induced movement therapy, now used with increasing frequency in stroke patients, was reported to provide

benefit for over two years in one CBS patient, with variable results in others . Long-term locomotor training has also

been reported to benefit a patient with mixed CBS and PSP features.

c. Surgery

Surgery is unlikely to help patients with CBD, as with most other atypical parkinsonism syndromes. One patient with

severe myoclonus and painful dystonia showed no improvement with stereotactic thalamotomy and right dorsal

rhizotomy of the fifth cervical to first thoracic spinal nerves.

d. Palliative therapy

Palliative therapy given the relentless progression of CBS, palliative interventions is an important aspect of continuing

care. Physical supports such as wheelchairs are oft en required, particularly when postural instability is prominent.

Argyrophilic Grain Disease (AGD) [26-29]

Argyrophilic grain disease (AGD) is a common sporadic neurodegenerative disease of old age characterized by the

presence of argyrophilic grains (AGs) dendritic-derived appendages as revealed with the Golgi methods together with

pre-tangle neurons in the limbic system, which accounts for about 5% of all demented cases.

Hyperphosphorylated tau also accumulates in oligodendroglialcoiled bodies and in limbic astrocytes. Ballooning

neurons in the amygdala are non-specific accompanying abnormalities. A new proposal for argyrophilic grains

distribution considers four stages. Clinical symptoms largely depend on the extension of argyrophilic grains together

with the very common associated tauopathies, mainly Alzheimer’s disease, progressive supranuclear palsy, corticobasal



degeneration and synucleinopathies. Pathogenesis of argyrophilic grains and related lesions herein proposed includes

oxidative stress that is followed by increased expression of oxidative response markers, and activation of stress kinases.

Argyrophilic grains (AGs)

The term is derived from their strong staining using the Gallyas silver iodide method. However, it is noteworthy that

AGs are not stained by all silver methods, 26 indicating that AGs have specific features. AGs are also labeled using

immune histochemistry against phosphor-tau protein, such as PHF-1 and AT8 antibodies.

Fig.7 : Neuropathological features of argyrophilic grain disease.

Picks Disease [30-31]

Pick's disease is a rare neurodegenerative disease that causes progressive destruction of nerve cells in the brain.

Symptoms include loss of speech (aphasia) and dementia. While some of the symptoms can initially be alleviated, the

disease progresses and patients often die within two to ten years.

A defining characteristic of the disease is build-up of tau proteins in neurons, accumulating into silver-staining,

spherical aggregations known as "Pick bodies". Pick bodies are almost always found in several different places in the

brain, including the dentate gyrus, the pyramidial cells of the CA1 sector and subiculum of the hippocampus, and the

neocortex as well as a plurality of other nuclei.

The person may appear totally unaware of the feelings of others, lacking any insight or empathy. Person suffering from

very cold, selfish and inconsiderate. They may experience severe mood swings. They may find concentration

impossible and become apathetic. In beginning there may be problems with speech or with memory, although people

may appear forgetful because of faulty attention and concentration. Problems with memory tend to develop because of



damage to the part of the brain which enables us to recall what words mean, who faces are, or what objects are for. This

is known as semantic memory.

Fig.7: MRI in a patient who has Pick's disease.

a. T1-weighted

b. T2-weighted fast spin-echo images show selective frontal atrophy, more apparent on the right side.

Medication

The drugs that are designed for the treatment of Alzheimer’s disease are contraindicated in Pick’s Disease as they may

increase aggression. Management lies in coping strategies such as side stepping issues rather than being confrontational

and working round obsessions rather than trying to change them. Speech Therapists and Occupational Therapists may

be helpful. A serious problem is boredom and carers have found such diverse new hobbies as art, music, rug making,

walking and jigsaw puzzles helpful.

Frontotemporal Dementia (FTD) [32-33]

Front temporal dementia (FTD) is a progressive neurodegenerative syndrome with diverse clinical presentations. Most

prominent features are progressive aphasia and bizarre affect with a personality change.

Fig.8 : MRI of Frontotemporal Dementia Disease



The microscopic abnormalities of this condition were first reported by Alois Alzheimer . He and Altman described

Argyrophilic inclusions (Pick bodies) and swollen cells (Pick cells) in the atrophic frontal and temporal brain regions

that have come to define the pathologic picture of Pick’s disease. To avoid confusion, Ii will refer to the clinical

syndrome as “front temporal dementia (FTD)” and to the microscopic picture of this specific histopathology condition

as “Pick’s disease.” It has become recognized over the years, moreover, that several different histopathology conditions

may underlie FTD.

All three conditions included neuronal drop-out and microvacuolation.

Type A: is the classic Pick’s disease with Pick bodies and swollen Pick cells.

Type B: includes only swollen cells, and today would probably be called Corticobasal degeneration .Adiscussion of the

clinical features of this condition is beyond the scope of this review, although we have seen patients with

pathologically-confirmed CBD whose major clinical presentation was a progressive aphasia.

Type C: Constantinidis describes a pattern similar to Pick’s disease but without the intracytoplasmic inclusions or the

swollen cells.

The class of drugs currently used to treat memory symptoms in Alzheimer's do not help FTD patients. These drugs

temporarily increase supplies of the messenger chemical acetylcholine to failing nerves, but FTD does not affect nerves

in the acetylcholine communication system.

Conclusion

This brief overview of neurodegenerative diseases highlights some common features of these clinically and

pathologically diverse disorders. Various treatments are available for neurodegenerative disorders. Research emphasis

needs to focus on understanding the pathogenesis of neurodegenerative disorders and developing neuroprotective or

disease-modifying strategies. Understanding the pathological causes of neurodegenerative disorders and developing

potential treatments are closely linked. Better methods of distinguishing the various pathological causes of

neurodegenerative disorders are clearly needed. Such efforts are academic, however, unless effective disease-

modifying therapies are found.



Disorder Anatomy Major Clinical Feature

Alzeimer Disease

Corticolimbic Dementia

Familial British Dementia

Corticolimbic &

cerebellar

Dementia & ataxia

Creutzfeldt-Jakob Disease

Cortical & basal

ganglia

Dementia & movement Disorder

Progressive Supranuclear

Palsy

Basal ganglia &

brainstem

Parkinsonism

Corticobasal Degeneration

Cortical & basal

ganglia

Focal cortical syndrome &

parkinsonism

Argyrophilic Grain Disease

Limbic Amnestic

cognitive

impairment

Pick’s Disease

Corticolimbic Dementia & focal cortical Syndrom

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Corresponding Author:

Suman Yadav*,

Email: [email protected]

Documents

ISSN: 0975-766X CODEN: IJPTFI Available through Online ... · PSP is pathologically defined by the accumulation of tau protein and neuropil threads in the subthalamic nucleus, pallidum,