OlfactoryOlfactory Dysfunction & Dysfunction & Neurological Disorders Neurological Disorders

Son Espases Hospital Experience Son Espases Hospital Experience

Fernanda A MuFernanda A Muññoz Protooz Proto

ENT Resident ENT Resident

20152015

Introduction

““Olfactory dysfunction is a common and early symptom of many Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson's disease neurodegenerative diseases, particularly of Parkinson's disease

Alzheimer's disease (AD), and mild cognitive impairment Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementiaheralding its progression to dementia””

The aim of the study The aim of the study

To describe:

Prevalence

Spectrum of neurological diseases

Patients that consulted for loss of smell

Clinical findings

Risk factors

Materials and Methods

Retrospective study

All olfatometry between 2008 and 2015

Barcelona Smell Test-24 BAST-24

Barcelona Smell Test - 24 (BAST-24)

Materials and Methods

Materials and Methods

ResultsResults

From 2008 to 2015: 497 olfatometry

Mean age: 53 years

Mean age: 60 years

ResultsResults

ResultsResults

Summary of CasesSummary of Cases

Table 1. Summary of Results. Epidemiological results (Sex: 1:Male, 2: Female) , age, Olfactometry results, Smoke, Department of first visit, Neurological diagnosis, comorbilities. HT: Hypertension, HLP: Hyperlipidemia, DM: Diabetes Mellitus, BPH: Benign Prostatic Hyperplasia, MI: Myocardial infarction, OSA: Obstructive Sleep Apnea, OP: Osteoporosis, AR: Alergic Rhinitis.

Neurological Diagnosis

Cognitive Impairment and Cognitive Impairment and DementiaDementia

Cognitive Impairment and Cognitive Impairment and DementiaDementia

65% (15) 65% (15)

Diagnosis:Diagnosis:Cognitive Impairment 13

Mild amnesic cognitive impairment / incipient AD: 2: 2

Mild amnesic cognitive impairment 11

Mild cognitive impairment: 5: 5

Mild no-amnesic cognitive impairment 55

Vascular Mild cognitive impairment 11

Prodromic Alzheimer Disease: 1

Olfactory DysfunctionOlfactory DysfunctionCognitive Impairment/ DementiaCognitive Impairment/ Dementia

OlfactometryOlfactometry ResultsResults

Olfactory Olfactory DysfuctionDysfuction & Stroke& Stroke

Sex Age Det I Iden I Det V Iden V Smoke 1st visit  Diagnosis Comorbidities

2 67 40 5 100 0 ? NRL

Stroke, Mild no-amnesic cognitive

impairment

HLP, HT, DM, 3 Strokes

1 44 85 20 100 0 NO NRL Stroke HT, MI

1 70 0 0 50 0 ? NRL StrokeHT, HLP,

Cerebrovascular disease

1 61 100 25 100 0 NO NRL Stroke

HLP, DM, Cerebrovascular

disease, Auricular Flutter

Olfactometry Results: StrokeOlfactometry Results: Stroke

ComorbiditiesComorbidities

Dyslipidemia 43%

Hypertension 29%

Cerebrovascular disease: 29%

Acute myocardial infarction: 2 patients

Depression: 38%

Olfactory Dysfunction & Depression

Case Gender Age Diagnosis Comorbidities

1 2 86 Mild amnesic cognitive impairment / incipient AD HT, Depression, Glaucoma

3 2 58 Mild no-amnesic cognitive impairment HLP, Depression, Hyperthyrodism, GERD

4 2 62 Mild amnesic cognitive impairment / incipient AD Depression, Hypothyroid, Fibromyalgia, Parotid carcinoma

5 2 65 Mild cognitive impairment HLP, Depression, MI

7 1 64 Tremor (Incipient Parkinson) HLP, Depression,

8 2 61 Vascular Mild cognitive impairment Cerebrovascular disease, Depression

12 2 68 Mild no-amnesic cognitive impairment HLP, HT, OP, OSA, Fibromyalgia, Depression

16 1 55 Compressive cervical myelopathy, Hydrocephalus Depression

21 2 49 Mild cognitive impairment Cerebrovascular disease, Depression, Migraine, Alergic Rhinitis

Table 2. Summary of Results of patients diagnosed of depression and neurological disorder. Epidemiological results (Sex: 1:Male, 2: Female), age, neurological diagnosis, comorbidities HT: Hypertension, HLP: Hyperlipidemia, DM: Diabetes Mellitus, BPH: Benign Prostatic Hyperplasia, MI: Myocardial infarction, OSA: Obstructive Sleep Apnea, OP: Osteoporosis

Magnetic Resonance Magnetic Resonance

MRI study in 19/21 patients

Pathologic result: 16

Normal: 3

Finding:

4 cases of stoke: encefalomalacia in the 4 cases

Cortical atrophy in 9/16 cases

Microangiopathy lesions in 7/16

Hypoplastic olfactory tracts in in 3/16

Mini-Mental State Examination (MMTE)

MMSE in 11/21 patients

Average of 24 points:

Mild to moderate impairment

First Visit First Visit

DiscussionDiscussion

Mild cognitive impairment (MCI)Mild cognitive impairment (MCI)

Intermediate stage between the expected cognitive decline of Intermediate stage between the expected cognitive decline of normal aging and dementianormal aging and dementia

1010--15 % of MCI went on to develop dementia in each year that the 15 % of MCI went on to develop dementia in each year that the research results were followed up. research results were followed up.

Actually research has focused on identifying people with MCI whoActually research has focused on identifying people with MCI whowill go on to develop dementiawill go on to develop dementia

Patients could be offered a range of support at an early stage iPatients could be offered a range of support at an early stage in the n the illnessillness

Alzheimer Society. Mild cognitive impairment (MCI). Dr Alexander Kurz, Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, and Dr Basil Ridha, Institute of Neurology, University College London

Systematic review.

Increased risk of later onset of AD in subjects with baseline hyposmia

Possible relationship between decreased olfaction in participants with MCI and conversion to AD but was inconclusive due to low follow-up rates.

AD is Incresing in prevalence AD is Incresing in prevalence

• The number of people with Alzheimer’s disease (AD) doubles for every 5-year interval past age 65

• Only 1-in-4 people with Alzheimer’s disease have been diagnosed.

• Alzheimer’s and dementia is most common in Western Europe.

The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve:•The olfactory epithelium•Olfactory bulb/tract•Primary olfactory cortices and their secondary targets.

Olfactory dysfunction is related to deposition of pathological proteins:α-synuclein, hyperphosphorylated tau protein neurofilament protein featured by neurofibrillary tangles, Lewy bodies and neurites

Inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes

Leading to cell death

Recent studies of olfactory dysfunction have focused its potentiRecent studies of olfactory dysfunction have focused its potential as al as an an early biomarker for the diagnosis early biomarker for the diagnosis of neurodegenerative disorders of neurodegenerative disorders and their disease progression. and their disease progression.

We also present neuropathological findings in the olfactory bulbWe also present neuropathological findings in the olfactory bulband tract in a large autopsy cohort (n = 536, 57.8 % female, meaand tract in a large autopsy cohort (n = 536, 57.8 % female, mean n age 81.3 years). age 81.3 years). The severity of olfactory bulb HPThe severity of olfactory bulb HPττ, A, Aββ, and , and ααSynuclein pathology correlated and increased significantly Synuclein pathology correlated and increased significantly (P < (P < 0.001) with increasing neuritic Braak stages, Thal A0.001) with increasing neuritic Braak stages, Thal Aββ phases, and phases, and cerebral Lewy body pathology, respectively. cerebral Lewy body pathology, respectively.

• Longitudinal study: MCI outpatients, CA-SIT Smell Identification • 88 MCI v/s 46 healthy control patients

MCI subjects have been divided into two groups,• 40% MCI olfactory-normal• 60% MCI olfactory-impaired

At 2-year follow-up, the 47% of MCI olfactory-impaired subjects and the 11% of MCI olfactory-normal subjects progressed to dementia.

In a logistic regression model,• Lower score in MMSE (95%; p = .004) • Pathological smell identification at baseline (95%, p = .03) were independently associated with the progression to dementia within 2 years.

Neurodegenerative conditions with dementia have particular difficulties with the recognition and identification of odours rather than the detection, suggesting a link to impairment of higher cognitive function.

Olfactory impairment has been shown to be predictive of conversion from mild cognitive impairment to Alzheimer's disease with 85.2% sensitivity.

Sensory considerations are likely to play a greater role in dementia care in the future, with the development of purpose-built dementia care facilities and the focus on non-pharmacological management strategies

• Olfactory deficits precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression.

RESULTS:• Prominent atrophy in the primary olfactory cortex (POC) and hippocampus was found in

both AD and MCI subjects.

CONCLUSIONS:• Decline in olfactory activity was correlated with the AD structural degeneration in the

POC.

• Olfactory fMRI may thus provide an earlier and more sensitive measure of functional neurodegeneration in AD and MCI patients.

ParkinsonParkinson

Parkinson Disease (PD) & Olfactory Parkinson Disease (PD) & Olfactory dysfuction (OD)dysfuction (OD)

1975 First report on olfactory dysfunction in Parkinson’s disease

The most common of neurodegenerative disorders manifesting hiposmia.

The prevalence of OD in PD ranges from 45% to 90%

Some authors argue that the diagnosis of PD should be reconsidered in patients with normal olfaction

Studies have revealed a reduced sense of smell in some individuals many years before they develop the classical motor signs of PD.

This implies that olfactory testing could be used as a preclinical marker

This finding is in line with an earlier TRODAT SPECT study which revealed that olfactory involvement occurs early in the disease process

Parkinson Disease (PD) & Olfactory Parkinson Disease (PD) & Olfactory dysfunction (OD)

• Hyposmia (typical non-motor features of PD)

• Volumetric magnetic resonance demonstrated close relationships between olfactory dysfunction and atrophy of amygdala and other limbic structures.

• Brain regions related to olfactory function are closely associated with cognitive decline

• Severe hyposmia is a prominent clinical feature that predicts the subsequent development of PDD. 18.7-fold increase in their risk of dementia

• Started a randomized, double-blind study using donepezil for the PD group with severe hyposmia.

How can we explain a relationship between depression and dementia?

Depression & Dementia

Depression may increase dementia risk, with a pooled estimate of1.97 (95% CI: 1.67-2.23).

It still does not distinguish between depression is a prodrome of dementia, or an independent causal risk factor.

There is a trend towards smaller effect sizes in studies with longer follow-up, which would be consistent with expectations if depression were part of the prodrome of dementia

Depression & Dementia

Conclusions Conclusions

OD is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson’s, Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementia.

OD is a predictive of conversion from MCI to AD with hifg sensitivity.

In AD, the deposition of pathological proteinsinvolve: olfactoryepithelium, olfactory bulb/tract, primary olfactory cortices andtheir secondary targets.

ConclusionsConclusions

OD in PD is a common finding and seems to be an early sign of PD and a predictive feature of Parkinson's disease with dementia (PDD)

Olfactory dysfunction and atrophy of amygdala and other limbic structures shows that severe hyposmia is a prominent clinical feature that predicts PDD.

It still does not distinguish clearly whether depression is a prodrome of dementia, or an independent causal risk factor.

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