di
Anna Giulia Cattaneo, M.D.

A previous Editorial was aimed to describe most relevant features of Alzheimer disease (AD), recognized as the most frequent cause of cognitive impairment in aged people: however, cognitive impairment accompanying aging processes in humans is frequently associated to risk factors and eventually morphological alterations different from AD.    The aim of this Editorial is to focus attention on this condition, and especially on reversible dementias and cerebral vascular disease (VaD).  Differential diagnosis, risk factors and possible prevention of other types of mental decline are discussed.    It should be reminded that VaD is frequently associated with AD: the two conditions can have closer relation than a simple co-existence, the last one being a possible long-term sequel of poor cerebral irroration.

Classification of causes for mental impairment in aging: a diagnostic algorithm.

Difficulties in exhaustive diagnosis of mental decline rise from the frequency of criteria redefinition, and the complexity of pathological changes, frequently coexisting with those of other pathologies.   Memory, orientation (time and space relationships), social judgment and ability to manage complex problems, home affairs and hobbies, relationships with other people, and taking care of himself are affected in different measure in dependence from the degree and the type of cognitive defect.

The American Academy of Neurology proposed in recent years a diagnostic algorithm in the case of cognitive impairment.   The multi-step evaluation of the patient starts with history, physical, mental and cognitive testing, aimed to detect the presence of cognitive defect involving multiple domains.   If this condition is stated or suspected, it is mandatory to exclude reversible cases of cognitive impairment (depression, delirium, metabolic conditions like hypothyroidism or hypovitaminosis, intracranial space-occupying lesions, medication encephalopathy), and eventually treat it.   Once reversible causes are carefully, it is appropriate to proceed with neuropsychological testing with the addition of imaging, laboratory and molecular testing (Corey-Bloom J, Thal LJ, Galasko D, et al. Diagnosis and evaluation of dementia. Neurology 1995 (45) p 211 ~ 218).

1.      Secondary dementias

In aged individuals, mental impairment can be secondary to metabolic disorders (hypothyroidism, hypovitaminosis as an example), hypertensive encephalopathy, drugs and heavy metals intoxications, intracranial space-occupying lesions (tumours, haematomas, hydrocephalus) or chronic infections (intracranial TBC and chronic meningitis due to different agents, syphilis between others).

A wide number of medications, often used to treat symptoms associated to aging, can cause encephalopathy, and it will be always remembered that old people is much more prone to develop side effects than younger individuals.   The need to treat depression, insomnia, tremors, agitation and other neurological symptoms is often impeded by the toxicity of drugs.   These precipitate dementia or delirium, both by direct interfering with neurotransmission, and as an idiosyncratic complication.   The most common cause of delirium is the inappropriate use of long-acting benzodiazepines, but even sedative-hypnotics, histamine antagonists, and neuroleptics between others.  .   The central cholinergic deficiency documented in a number of degenerative dementias frequent in elderly patients (Alzheimer's and Parkinson's disease, or dementia with Lewy’s bodies) has been proposed as the reason for serious symptoms of mental decline induced in aged people by some anticholinergic drugs prescribed as antidepressive, sleep inducers, or to treat motion symptoms of Parkinson disease.  Digoxin is another drug frequently used in the elderly to treat cardiac pathologies.   While formulation is generally well tolerated, a particular care should be used because of renal excretion can be compromised in aged patients: the toxic effects can even be lethal for at the cardiac level, but a delirium, proposed on a n idiosyncratic base, can develop.   A special case is that of antipsychotic drugs, frequently used to cure agitation in aged subjects.   Clinical suspicion that the use of these agents (at least several of them) could precipitate acute ischemia and strokes has been discussed: while results are controversial, a cautious use of these agents seems to be appropriate.

Cognitive impairment associated with a treatable condition represent 10% to 20% of all cases of dementia: it has been evaluated that only 10% to 15%% of these are completely reversible, and an additional 10% has a partial response to treatment of underlying condition.   Depression, medication encephalopathy, and metabolic disorders dominated the reversible cases.   Secondary dementia is often superimposed to another condition, such as Alzheimer or Parkinson disease: these cases are partially or non-responders.    Infectious diseases are frequently poorly responsive to treatment in aged people, for immunity depression and for pharmacological hypersensitivity.

2.      Cerebrovascular disease

a)      Small vessels disease

Lipohyalinosis and cerebral amyloid angiopathy are the most common causes for cerebral small vessels disease, responsible for a syndrome characterized by lacunar ischaemic small cortical infarct and petechial haemorrhages localized in the white matter.   White matter lesions (WML), cerebral infarcts and generalized brain atrophy were assessed on the baseline MRI. The clinical aspect is the subcortical ischaemic vascular syndrome, with seizures and cognitive impairment (SIVD).   The syndrome, more frequent in aged people, is associated with diabetes and arterial hypertension: the prevention of this risk factors seems to be the only effective therapeutic means, physiopathology of this disease being poorly understood at the present.    Vasculitis due to bacterial infections or to autoimmune diseases is distinct clinical entities, not confined to the late phases of human life.   Subcortical lesions can start with unapparent symptoms, like depression, slowed thought, poor problem solving and memory recalling abilities.   However, recognition, language and personality are generally unaffected, differently from what is commonly experienced in cortical degeneration, like in Alzheimer disease.   In addition to small vessels disease, subcortical syndromes in aged people are frequently due to degenerative encephalopathies, such as IPD and small vessels vascular disease.

b)      Large Vessel Atherothrombotic Disease

Neurological focal symptoms dominate this condition that is the local expression of a generalized arteriosclerosis.   It can be a consequence of local plaques formation, or of obstruction of cerebral vessels by thrombi formed in distant district of the body, as observed in poorly treated atrial fibrillation.   Mental decline and true dementia are referred as vascular dementia (VaD).   Clinical suspicion of cerebrovascular damage is supported by findings like gait disturbances, frequent falls or unsteadiness, urinary incontinence, pseudobulbar palsy, but histopathological findings and imaging positive for arteriosclerosis states the diagnosis.   The absence of neurofibrillary tangles, Lewy’s bodies and neuritic plaques exceeding those expected for age is typical for “pure” cerebrovascular disease, while this entity is quite uncommon.   Emergencies like stroke and palsies are events, complicating usually long-standing, misunderstood or poorly cured conditions.   An epidemiological study carried out in USA demonstrated a lowering of post-ischaemic dementias prevalence in aged people, during the period 1982-1999.  The phenomenon has been ascribed to a decline of vascular cognitive impairments, not to the Alzheimer disease: the supposed reason of that is better use of medication and prevention of stroke-associated risk factors, in addition to a better education among the old.   This late finding has been supported by a number of studies, showing lower incidence of cognitive impairment and better improve from stroke in people with better cognitive performance and education in the pre-stroke period.

Diagnostics procedures

In recent years physicians can dispose of powerful means for diagnostics, unpredictable until several decades ago.   Neurological diagnosis is now a multidisciplinary field, starting from the traditional clinical examination but requiring other technologies, sometimes sophisticated, to lead to a diagnostic level acceptable at the present level of knowledge.   This fact does not limit the traditional clinical diagnostic procedures into an obsolete field of action: a profound knowledge of all mechanisms that support the cognitive function in man and of the causes of disturbance are the sole means to lead to an accurate and precise diagnosis, prompt enough for obtaining the best results from the preventive or curative measures.   However, the possibility to associate to a well-conducted clinical care a number of fine and appropriate diagnostic procedures enhances the potential of the caregivers and the wellness of the patient.

In addition to neuropsychological testing for cognitive impairments, the Hachinski Ischemic Score is a useful test aimed to distinguish between VaD and other types of degenerative dementia.   It is based on the recognition of asymmetric neurological dysfunctions: while unable to distinguish between pure and mixed VaD, the sensitivity and specificity of this simple history-based test are estimated at 70% to 80%.

The chemical laboratory combined with molecular biology methods (both on blood or cerebral fluid samples) can be of great help in diagnosis of associated causes for mental decline.   Good examples are tests to detect impaired endocrine function, hypovitaminosis, drug or heavy metal encephalopathies, intracranial infections (do not forget tertiary syphilis, TBC and the most recent HIV, all conditions that can cause mental impairment).   The routine EEG can support in several cases a more refined diagnostic procedure, or be the first sign of the abnormality: however its role is very limited and additional.   The functional study of coagulation is of great importance: primary or secondary defects must be diagnosed and treated defect to prevent cerebral bleeding, and hyperviscosity should be treated to minimize ischaemic accidents.  It should be interesting to recall that VaD and secondary dementias are not included in so called “tauopathies”, in which aggregates of the tau protein are evident around cerebral lesions.   When present, this protein is a signal for associated AD.

A number of Doppler techniques for arterial investigation have been developed to localize the lesion: between other, carotid ultrasonographic studies, duplex ultrasound, ophthalmic artery transcranial Doppler, transcranial Doppler (anterior or posterior) are useful, safe and quite simple.

Ophthalmic examinationand even retinal vascular imaging, cannot be neglected: this technique permits to find ocular lesions associated with neurological conditions and impaired cognitive function, like vascular or neural hypertension, systemic intoxications, infectious diseases.   It is accurate, non-invasive, quite simple and inexpensive, and can lead to often-unsuspected diagnosis.

However, the field in which major progress has been done is that of imaging.   MRI, magnetic resonance imaging, combined with functional imaging (PET, Positron Emission Tomography) leads to an integrated view of anatomical functional lesions of the intracranial content, unexpected until several decades ago, that can be very useful in clinical practice.   Thank to it, more invasive procedures like biopsies can be reserved to very selected cases.   This is very important in frail patients, often affected by multiple dysfunctions of coagulation or requiring drugs that can affect it.   The main problem is that imaging is often expensive, and therefore considered inappropriate to apply to aged people, at least as frequently as required.

Angiography is invasive and potentially dangerous, and should be limited in the most frail subjects,

Preventive measures.

While secondary encephalopathies are intrinsically reversible (with doubt concerning the entity of recovery), there is no standard symptomatic treatment for VaD, and still little is known on the measures for primary prevention: these last can be summarized in a few points.   However, recent works depose for a possible beneficial effect of preventive measures in reducing gravity and prevalence of post-Ischemic dementias.   Reduced prevalence  (from 5.7 to 2.9% during the period 1982-1999) has been recently reported in a cohort of more than 40,000 aged individuals from USA (Adv Gerontol. 2005;16:30-7).   The phenomenon can only be ascribed to a decline of vascular cognitive impairments, not to Alzheimer disease: the supposed reason of that is better use of medication and prevention of stroke-associated risk factors, in addition to a better education among the old.   This late finding has been supported by a number of studies, showing lower incidence of cognitive impairment and better improve from stroke in people with better cognitive performance and education in the pre-stroke period.

Ø      Pre-morbidity factors: a number of studies, carried out in populations different for social and political conditions, seems to be concordant in demonstrating that the degree of education, cognitive and social abilities before aging and morbidity (especially stroke) are associated with lower progression into mental decline, at least in non-Alzheimer diseases.

Ø      Actions against risk factors: Risk factors for VaD include age, hypertension, diabetes, smoking, cardiovascular disease, atrial fibrillation and other cardiac arrhythmias, left ventricular hypertrophy, hyperhomocysteinemia, orthostatic hypotension, hyperfibrinogenemia, sleep apnoea, infection, and high C-reactive protein.   An adequate identification of exposure to risk factors followed by measures to discourage and avoid it can be in selected cases an excellent preventive measure to avoid mental decline in reversible dementias.   Other potentially beneficial measures concern reduction of all not necessary drugs, stop smoking habits, control of body weight and maintenance of an active, and socially normal life even late in life.   Alimentary habits should be maintained at an acceptable standard, to avoid hypovitaminosis or poor protein intake: supplementation with vitamins and folate has been proved non-effective, while safe, when a specific defect was absent.

Ø      Actions against causative and risk agents: treatment of dismetabolic or nutritional conditions is proved to be an efficacious measure in reversible cases of cognitive impairment.   Early treatment of hypertension, diabetes and hyperlipemias, prevention of bleeding in coagulation defects or a cautious use of antiplatelets or antithrombotic therapies when necessary are useful preventive measures, possibly associated with the reduced prevalence of cognitive vascular impairment in the elderly found by recent statistics.

Ø      Supportive measures in patients suffering from serious functional impairment: even in this case, every possible effort should be necessary to ameliorate the clinical condition, minimize complications like those caused by immobilization and lack of regular social relationships.   The supportive presence of the family members, the presence of motivated, educated and not stressed or depressed caregiver are additional factors that can ameliorate the wellness and the function of the patient.

Present address:
DBSM, Università dell'Insubria
via J.H. Dunant,3 - 21100 Varese